The development of an EU-wide nutrition and physical activity expert knowledge base to support a personalised mobile application across various EU population groups.

A healthy lifestyle comprising regular physical activity and an adequate diet is imperative for the prevention of non-communicable diseases such as hypertension and some cancers. Advances in information computer technology offer the opportunity to provide personalised lifestyle advice directly to the individual through devices such as smartphones or tablets. The overall aim of the PROTEIN project (Wilson-Barnes et al., 2021) was to develop a smartphone application that could provide tailored and dynamic nutrition and physical activity advice directly to the individual in real time. However, to create this mobile health (m-health) smartphone application, a knowledge base of reference ranges for macro-/micronutrient intake, anthropometry, biochemical, physiological and sleep parameters was required to underpin the parameters of the recommender systems. Therefore, the principal aim of this emerging research paper is to describe the process by which experts in nutrition and physiology from the PROTEIN consortium collaborated to develop the nutritional and physical activity requirements, based upon existing recommendations, for 10 separate population groups living within the EU including, but not limited to healthy adults, adults with type 2 diabetes mellitus, cardiovascular disease, excess weight, obesity and iron deficiency anaemia. A secondary aim is to describe the development of a library of 24-h meal plans appropriate for the same groups and also encompassing various dietary preferences and allergies. Overall, the consortium devised an extensive nutrition and physical activity knowledge base that is pertinent to 10 separate EU user groups, is available in 7 different languages and is practically implemented via a library of culturally appropriate, 24-h meal plans.

The impact of age on vitamin D receptor expression, vitamin D metabolism and cytokine production in ex vivo Rhodococcus equi infection of equine alveolar macrophages.

Rhodococcus equi (R. equi), a pneumonia-causing intracellular bacterium, results in significant morbidity and mortality in young foals, while healthy adult horses rarely develop disease. Survival and replication within alveolar macrophages (AMφ) are the hallmarks of R. equi's pathogenicity. The vitamin D receptor (VDR) and its ligand, the active vitamin D metabolite 1,25(OH)2D, are important in immune responses to intracellular bacteria. The vitamin D/VDR pathway regulates the downstream production of cytokines in infected human AMφ. The immunomodulatory role of the vitamin D/VDR pathway in equine leukocytes is unknown. The objective of the current study was to determine the impact of R. equi infection and age on synthesis of 1,25(OH)2D, VDR expression, and cytokine production in an ex vivo model of R. equi infection in equine AMφ. AMφ were collected from ten healthy foals at 2-, 4- and 8-weeks old and from nine healthy adult horses once via bronchoalveolar lavage. AMφ were mock infected (CONTROL) or infected with a virulent laboratory strain of R. equi for 7 days (INFECTED). VDR expression was determined via RT-qPCR from cell lysates. 1,25(OH)2D and cytokines were measured in cell supernatant by immunoassays. VDR expression was impacted by age (P = 0.001) with higher expression in AMφ from 8-week-old foals than from 2-week-old foals and adults. There was no significant effect of infection in foal AMφ, but in adults, relative VDR expression was significantly lower in INFECTED AMφ compared to CONTROL AMφ (P = 0.002). There was no effect of age or infection on 1,25(OH)2D concentration (P > 0.37). Mean TNFα production was significantly higher from INFECTED compared to CONTROL AMφ from 4- and 8-week-old foals and adults (P < 0.005). Mean IFNγ production was significantly higher from AMφ from foals at 8-weeks-old compared to 2-weeks-old (P = 0.013) and higher from INFECTED AMφ than from CONTROL AMφ in foals at 4-weeks-old and in adults (P < 0.027). The proportion of samples producing IL-1ß and IL-10 was also significantly higher from INFECTED compared to CONTROL AMφ isolated from 4-week-old foals (P < 0.008). Similarly, in adult samples, IL-17 was produced from a greater proportion of INFECTED compared to CONTROL samples (P = 0.031). These data document age-associated changes in VDR expression and cytokine production in equine AMφ in response to R. equi infection. This preliminary investigation supports the need for further research to fully elucidate if the vitamin D pathway has an immunomodulatory role in the horse.

Age-related changes in vitamin D metabolism and vitamin D receptor expression in equine alveolar macrophages: A preliminary study.

The vitamin D receptor (VDR)-vitamin D axis modulates pulmonary immunity in people but its role in equine immunity is unknown. Bacterial pneumonia causes high morbidity/mortality in foals and alveolar macrophages (AMφ) are important for pulmonary defenses. Age-related variations in vitamin D-mediated function of AMφ might contribute to the foal's susceptibility to pneumonia. Our aim was to assess the impact of age on equine vitamin D metabolism and VDR expression in AMφ. AMφ and plasma was collected from healthy foals (2, 4 and 8 weeks old) and adult horses (once). AMφ VDR expression was determined via RT-qPCR and plasma vitamin D metabolites quantified via immunoassays. Data were analyzed with linear mixed models. Inactive-vitamin D metabolite concentrations were lowest in foals at 2 weeks and lower at 2 and 4 weeks compared to adults (P < 0.001). Active-vitamin D metabolite concentrations were higher in foals than adults (P < 0.05). VDR expression was detected in AMφ in all animals and was highest in 2-week-old foals. Vitamin D metabolism and AMφ VDR expression are impacted by age in horses. This may have immunological consequences in foals given the key role that the VDR-vitamin D axis has in pulmonary immunity in other species.

Long-term effects of clinical interventions on nutritional status in patients with chronic pancreatitis - A systematic review.

BACKGROUND AND AIMS: Malnutrition in chronic pancreatitis is complex and multifactorial, with malabsorption, pain, toxic dependencies and co-morbidities, such as diabetes, each playing a role. The aims of this systematic review were to assess the impact of nutritional intervention on markers of nutritional status in this complex patient group. MATERIALS AND METHODS: A systematic review of EMBASE and PubMed was carried out in February 2020, identifying 2620 articles. After screening to exclude those reporting short term changes (less than 3 months), with only one data point, or in the wrong population, eight papers were selected for analysis. RESULTS: Seven studies documented the impact of a nutritional intervention, one was an observational study only. Overall, studies were limited by predominantly retrospective designs, heterogenous populations and poor control of potentially confounding variables. Data could not be combined due to variability in reporting methods. All studies exploring nutritional intervention, whether that consisted of advice by a specialist dietitian, dose escalation of pancreatic enzymes, oral nutritional supplements or enteral feeding, demonstrated improved body weight and pain control, whereas patients who did not receive an intervention deteriorated nutritionally. CONCLUSION: Patients with chronic pancreatitis benefit from nutritional intervention. Further work is required to explore the impact of nutritional intervention on body composition and functional outcomes.

Long-term changes in nutritional status and body composition in patients with malignant pancreatic disease - A systematic review.

BACKGROUND AND AIMS: Patients with pancreatic cancer often experience significant deterioration in nutritional status over time. Malnutrition is complex and multifactorial, with malabsorption, pain, toxic dependencies, co-morbidities and malignant processes all playing a role. The aims of this systematic review were to assess nutritional changes over time and identify tolerance of nutritional intervention, thus identifying potential areas for further research to improve patient outcomes. MATERIALS AND METHODS: A systematic review of MEDLINE, EMBASE and PubMed was carried out in February 2020, identifying 2620 articles. After screening to exclude those reporting short-term measures, with only one data point, or in the wrong population, thirteen papers were selected for analysis (four trials in neo-adjuvant treatment, five in populations undergoing palliative treatment for pancreatic cancer, and four in mixed populations undergoing pancreatic resection). RESULTS: Overall, studies were limited by predominantly retrospective designs, and poor control of potentially confounding variables. Meta-analysis could not be performed due to heterogenicity in study design and reporting methods. Surgery in mixed cohorts did not appear to result in weight loss. Only one small intervention study was identified. Patients with pancreatic cancer experienced a decline in nutritional status, with 44-63% of patients undergoing neoadjuvant chemotherapy having low muscle mass prior to starting treatment. CONCLUSION: There is a paucity of data regarding nutritional intervention in pancreatic cancer. Future work should include the use of validated functional and clinical assessment tools to further explore the impact of nutritional intervention, and the relationship between nutritional status and outcome.

Effects of pituitary pars intermedia dysfunction and Prascend (pergolide tablets) treatment on endocrine and immune function in horses.

It remains unclear how pituitary pars intermedia dysfunction (PPID) and pergolide treatment (Prascend [pergolide tablets]) affect endocrine and immune function in horses. To evaluate these effects, blood was collected regularly from 28 university-owned horses (10 Non-PPID, 9 PPID control [PC], and 9 PPID treatment [PT]) over approximately 15 mo. Pergolide treatment was initiated after Day 0 collections. Analyses included ACTH, insulin, total cortisol, free cortisol, complete blood counts, plasma myeloperoxidase, and cytokine/receptor gene expression in basal whole blood and in vitro stimulations (PMA/ionomycin, heat-inactivated Rhodococcus equi, and heat-inactivated Escherichia coli) of whole blood and peripheral blood mononuclear cells (PBMCs). The results were analyzed using a linear mixed model (SAS 9.4) with significance set at P < 0.05. Significant group (P = 0.0014) and group-by-time (P = 0.0004) effects were observed in resting ACTH such that PT horses differed from Non-PPID horses only at Day 0. PT horses had significantly lower changes in ACTH responses to thyrotropin-releasing hormone stimulation tests than PC horses at non-fall time points only, mid-late February 2018 (P = 0.016) and early April 2018 (P = 0.0172). When PT and PC horses did not differ, they were combined before comparison to Non-PPID horses. No significant group or group-by-time effects were seen in resting insulin, total cortisol, or free cortisol; however, significant time effects were observed in these measures. PPID horses had lower absolute lymphocyte (P = 0.028) and red blood cell (P = 0.0203) counts than Non-PPID horses. In unstimulated whole blood, PPID horses had increased IL-8 expression compared with Non-PPID horses (P = 0.0102). In addition, PPID horses had decreased interferon γ production from PBMCs after stimulation with R. equi (P = 0.0063) and E. coli (P = 0.0057) and showed increased transforming growth factor ß expression after E. coli stimulation (P = 0.0399). The main limitations of this study were a limited sample size and an inability to truly randomize the PPID horses into treatment groups. Resting ACTH is likely the best choice for determining successful responses to pergolide. Neither PPID nor pergolide appears to influence insulin, total cortisol, and free cortisol. As measured, systemic immune function was altered in PPID horses, and it is likely that these horses are indeed at increased risk of opportunistic infection. Despite reducing ACTH, pergolide treatment did not appear to influence immune function.

Down syndrome caregivers' support needs: a mixed-method participatory approach.

BACKGROUND: The purpose of the study was to explore the support needs of caregivers of children with Down syndrome from their perspective using a mixed-method participatory research approach. METHODS: Concept mapping methodology was used to obtain caregiver perspectives. Twenty-one caregivers answered the question 'Are parents of individuals with Down syndrome supported, why or why not?' Caregivers were involved in the analysis of the data through concept mapping procedures. RESULTS: Sorted data were analysed with multidimensional scaling and cluster analysis. Participants generated eight thematic clusters representing the support needs of caregivers of children with Down syndrome. The themes included online and social support, support system gaps, areas where support is lacking, Down syndrome community support, financial support, advocacy needs, educational support and concerns for community programming. CONCLUSIONS: Themes align with previous research on support needs of parents of children with developmental disabilities. The study highlights the need for more local organisations to offer support that is affordable and accessible for families. Results will support future programme planning for services for individuals caring for those with Down syndrome.

Impact of myoglobin oxygenation state prior to frozen storage on color stability of thawed beef steaks through retail display.

Consumers consider beef color to be an indicator of freshness and therefore it is a major factor when purchasing beef. The ideal conditions for maintaining color throughout retail display following frozen storage have yet to be well established. Therefore, the objective of this study was to determine the effects of myoglobin oxygenation levels (especially high oxygenation) during freezing on color stability of thawed steaks during retail display (RD) and to determine the impact that frozen storage duration, aging, and packaging films have on meat color after thawing under RD conditions. USDA Choice strip loins (n = 36) were aged for 4 or 20 d. Steaks were randomly assigned to a myoglobin oxygenation level [deoxymyoglobin (DeOxy; packaged within 3 min), oxygenation (Oxy; oxygenated in air for 30 min), or high oxygenation (HiOxy; packaged for 24 h in 80% O2)]. Steaks were then vacuum packaged in oxygen permeable or impermeable film and immediately frozen (-10 °C). Following either 0, 2, 4, or 6 months of frozen storage at -5 °C, steaks were removed from the packaging and immediately placed under simulated RD conditions for 7 d. During RD, instrumental color and subjective color were measured every day after the initial 24 h thaw period. Steaks were analyzed for instrumental color (L*, a*, b*), a*:b* ratio, percentage oxymyoglobin, metmyoglobin, and deoxymyoglobin, delta E, redness ratio, subjective discoloration, and lipid oxidation. For all days of RD, steaks that were frozen for 0 months had higher a* values (greater redness) than steaks frozen for 6 months which typically had the lowest a* values (P < .0001). HiOxy steaks frozen for 6 months had the lowest amounts of percentage oxymyoglobin than all other frozen storage periods and myoglobin oxygenation levels on days 4-7 of RD (P < .05). The HiOxy steaks frozen for 4 and 6 months had higher percentage metmyoglobin than DeOxy and Oxy, regardless of packaging (P < .05). Delta E, discoloration, and lipid oxidation were greatest for HiOxy steaks compared to Oxy and DeOxy (P < .05). Extended storage brought about detrimental color effects for all differing levels of myoglobin oxygenation. The HiOxy steaks through the first few days of RD and frozen for under 6 months provided had bright cherry red color, similar to that of DeOxy and Oxy. However, with extended frozen storage and RD, HiOxy steaks had worse color characteristics (more discoloration) than the other myoglobin oxygenation levels.

Identification of macrolide- and rifampicin-resistant Rhodococcus equi in environmental samples from equine breeding farms in central Kentucky during 2018.

Rhodococcus equi causes severe pneumonia in foals and is most often recognized in people as an opportunistic pathogen. Longitudinal studies examining antimicrobial-resistant R. equi from environmental samples are lacking. We hypothesized that antimicrobial-resistant R. equi would be detectable in the ground (pasture soil or stall bedding) and air at breeding farms with previous documentation of foals infected with resistant isolates, and that concentrations of resistant isolates would increase over time during the foaling season. In this prospective cohort study, ground and air samples were collected from stalls and paddocks in January, March, May and July of 2018 at 10 horse-breeding farms with history of foal pneumonia attributed to macrolide- or Rifampicin-resistant R. equi. Environmental samples were cultured in the presence and absence of macrolides and Rifampicin to select for resistant organisms. Data were analyzed with linear mixed-effects and Hurdle models. Concentrations of total R. equi in bedding or air of stalls were significantly (P < 0.05) higher in January than other months. The proportion of resistant R. equi in soil samples from paddocks was significantly (P < 0.05) higher than stall bedding during all months. For each month, air samples from paddocks had a significantly (P < 0.05) higher proportion of resistant isolates than those from stalls. Fifty-five percent of resistant soil isolates and 34% of resistant air isolates were considered virulent by identification of the vapA gene. Concentrations of resistant R. equi isolates did not increase over time during the foaling season. Antimicrobial-resistant R. equi can persist in the environment at farms with a history of pneumonia caused by resistant R. equi infections, and exposure to resistant isolates in paddocks and stalls appears stable during the foaling season. Resistant isolates in the environment not only pose a risk for disease but also can serve as a repository for dissemination of resistance genes.

25-Hydroxyvitamin D status, light exposure and sleep quality in UK dwelling South Asian and Caucasian postmenopausal women.

There is a lack of research into 25-hydroxyvitamin D (25(OH)D) status, light exposure and sleep patterns in South Asian populations. In addition, results of research studies are conflicting as to whether there is an association between 25(OH)D status and sleep quality. We investigated 25(OH)D status, self-reported and actigraphic sleep quality in n = 35 UK dwelling postmenopausal women (n = 13 South Asians, n = 22 Caucasians), who kept daily sleep diaries and wore wrist-worn actiwatch (AWL-L) devices for 14 days. A subset of n = 27 women (n = 11 South Asian and n = 16 Caucasian) also wore a neck-worn AWL-L device to measure their light exposure. For 25(OH)D concentration, South Asians had a median ± IQR of 43.8 ± 28.2 nmol/L, which was significantly lower than Caucasians (68.7 ± 37.4 nmol/L)(P = 0.001). Similarly, there was a higher sleep fragmentation in the South Asians (mean ± SD 36.9 ± 8.9) compared with the Caucasians (24.7 ± 7.1)(P = 0.002). Non-parametric circadian rhythm analysis of rest/activity patterns showed a higher night-time activity (L5) (22.6 ± 14.0 vs. 10.5 ± 4.4; P = 0.0008) and lower relative amplitude (0.85 ± 0.07 vs. 0.94 ± 0.02; P < 0.0001) in the South Asian compared with the Caucasian women. More South Asians (50%) met the criteria for sleep disorders (PSQI score >5) than did Caucasians (27%) (P = 0.001, Fishers Exact Test). However, there was no association between 25(OH)D concentration and any sleep parameter measured (P > 0.05) in either ethnic group. South Asians spent significantly less time in illuminance levels over 200 lx (P = 0.009) than did Caucasians. Overall, our results show that postmenopausal South Asian women have lower 25(OH)D concentration than Caucasian women. They also have higher sleep fragmentation, as well as a lower light exposure across the day. This may have detrimental implications for their general health and further research into sleep quality and light exposure in the South Asian ethnic group is warranted.

Vitamin D status and associated genetic polymorphisms in a cohort of UK children with non-alcoholic fatty liver disease.

BACKGROUND: Vitamin D deficiency has been associated with non-alcoholic fatty liver disease (NAFLD). However, the role of polymorphisms determining vitamin D status remains unknown. OBJECTIVES: The objectives of this study were to determine in UK children with biopsy-proven NAFLD (i) their vitamin D status throughout a 12-month period and (ii) interactions between key vitamin D-related genetic variants (nicotinamide adenine dinucleotide synthase-1/dehydrocholesterol reductase-7, vitamin D receptor, group-specific component, CYP2R1) and disease severity. METHODS: In 103 paediatric patients with NAFLD, serum 25-hydroxyvitamin D (25OHD) levels and genotypes were determined contemporaneously to liver biopsy and examined in relation to NAFLD activity score and fibrosis stage. RESULTS: Only 19.2% of children had adequate vitamin D status; most had mean 25OHD levels considered deficient (<25 nmol·L-1 , 25.5%) or insufficient (<50 nmol·L-1 , 55.3%). Patients had significantly lower 25OHD levels in winter months (95% CI: 22.7-31.2 nmol·L-1 ) when compared with spring (30.5-42.1 nmol·L-1 ; P = 0.0089), summer (36.3-47.2 nmol·L-1 ; P < 0.0001) and autumn (34.2-47.5 nmol·L-1 ; P = 0.0003). Polymorphisms in the nicotinamide adenine dinucleotide synthase-1/dehydrocholesterol reductase-7 (rs3829251, rs12785878) and vitamin D receptor (rs2228570) genes were independently associated with increased steatosis; while a group-specific component variant (rs4588) was associated with increased inflammation in liver biopsies. CONCLUSIONS: Children with NAFLD in the UK have particularly low winter vitamin D status, with vitamin D insufficiency prevalent throughout the year. Polymorphisms in the vitamin D metabolic pathway are associated with histological severity of paediatric NAFLD.

Targeting MDMX and PKCδ to improve current uveal melanoma therapeutic strategies.

Uveal melanoma (UM) is the most frequent ocular cancer in adults, accounting for ~5% of the total melanoma incidence. Although the primary tumor is well treatable, patients frequently develop metastases for which no curative therapy exists. Highly activated protein kinase C (PKC) is a common feature of UM and has shown potential as therapeutic intervention for UM patients. Unfortunately, PKC inhibition as single treatment appears to have only limited clinical benefit. Combining PKC inhibition with activation of p53, which is rarely mutated in UM, by MDM2 inhibitors has shown promising results in vitro and in vivo. However, clinical studies have shown strong adverse effects of MDM2 inhibition. Therefore, we investigated alternative approaches to achieve similar anticancer effects, but with potentially less adverse effects. We studied the potential of targeting MDMX, an essential p53 inhibitor during embryonal development but less universally expressed in adult tissues compared with MDM2. Therefore, targeting MDMX is predicted to have less adverse effects in patients. Depletion of MDMX, like the pharmacological activation of p53, inhibits the survival of UM cells, which is enhanced in combination with PKC inhibition. Also pan-PKC inhibitors elicit adverse effects in patients. As the PKC family consists of 10 different isoforms, it could be hypothesized that targeting a single PKC isoform would have less adverse effects compared with a pan-PKC inhibitor. Here we show that specifically depleting PKCδ inhibits UM cell growth, which can be further enhanced by p53 reactivation. In conclusion, our data show that the synergistic effects of p53 activation by MDM2 inhibition and broad spectrum PKC inhibition on survival of UM cells can also largely be achieved by the presumably less toxic combination of depletion of MDMX and targeting a specific PKC isoform, PKCδ.

Pharmacokinetics of the anticonvulsant levetiracetam in neonatal foals.

BACKGROUND: Seizures are a common manifestation of neurological disease in the neonatal foal and are an important cause of morbidity and mortality in this population. Current antiepileptic options are effective, but often have undesirable adverse effects, short duration of action and high cost. Levetiracetam has an ideal safety and pharmacokinetic profile in multiple species, including the adult horse, and may be a safe and cost-effective alternative anticonvulsant in neonatal foals. Due to differences in drug disposition and clearance dosages in neonates, dosing recommendations in other species or adult horses cannot be extrapolated to foals. OBJECTIVE: To establish the pharmacokinetic profile of single-dose i.v. and intragastric administration of levetiracetam in healthy neonatal foals. STUDY DESIGN: Randomised crossover experimental study. METHODS: Levetiracetam was administered as a single dose to six healthy foals (ages 1-10 days) at a dose of 32 mg/kg bwt i.v. or intragastrically. Plasma levetiracetam concentrations were measured using a validated HPLC protocol. RESULTS: After i.v. administration to healthy foals, levetiracetam had a mean (±s.d.) elimination half-life of 7.76 ± 0.51 h, a mean systemic clearance of 61.67 ± 10.96 (mL/h/kg) and a mean apparent volume of distribution at steady state of 0.670 ± 0.124 (L/kg). Following intragastric administration, levetiracetam had a peak concentration of 38.34 ± 7.42 mg/L and time to achieve peak concentration was 0.875 (0.5-1.5) h. Mean bioavailability for IG administration was excellent (103.04 ± 14.51%). No significant differences in pharmacokinetic variables between routes and order of administration were observed. MAIN LIMITATIONS: Small sample size and single-dose administration. CONCLUSIONS: Levetiracetam has excellent intragastric bioavailability in foals and is predicted to maintain plasma concentrations at or above the proposed target concentration with twice daily i.v. or oral administration. Once-daily administration may be possible in some foals based on the therapeutic range recommended in other species.

Bioavailability and tolerability of nebulised dexamethasone sodium phosphate in adult horses.

BACKGROUND: Nebulisation of the injectable dexamethasone sodium phosphate (DSP) would offer an inexpensive way of delivering a potent corticosteroid directly to the lungs of horses with asthma. However, this approach would be advantageous only if systemic absorption is minimal and if the preservatives present in the formulation do not induce airway inflammation. OBJECTIVE: To investigate the bioavailability of nebulised DSP and determine whether it induces airway inflammation or hypothalamic-pituitary-adrenal (HPA) axis suppression in healthy adult horses. STUDY DESIGN: Randomised crossover experiment. METHODS: Dexamethasone sodium phosphate was administered to six healthy adult horses at a dose of 5 mg q. 24 h for 5 days via nebulised, or intravenous (i.v.) routes. Plasma dexamethasone concentrations were measured by UPLC/MS-MS to calculate bioavailability. Cytological examination of bronchoalveolar fluid was performed at baseline and after the last dose of DSP. A validated chemiluminescent immunoassay was used to measure basal serum cortisol concentrations. RESULTS: After nebulisation to adult horses, dexamethasone had a mean (±s.d.) maximum plasma concentration of 0.774 ± 0.215 ng/mL and systemic bioavailability of 4.3 ± 1.2%. Regardless of route of administration, there was a significant decrease in the percentage of neutrophils in bronchoalveolar lavage fluid over time. During i.v. administration, basal serum cortisol concentration decreased significantly from baseline to Day 3 and remained low on Day 5. In contrast, basal serum cortisol concentration did not change significantly during administration via nebulisation. MAIN LIMITATIONS: Small sample size and short period of drug administration. CONCLUSIONS: Dexamethasone sodium phosphate administered via nebulisation had minimal systemic bioavailability and did not induce lower airway inflammation or HPA axis suppression in healthy horses.

Polygenic loading for major depression is associated with specific medical comorbidity.

Major depressive disorder frequently co-occurs with medical disorders, raising the possibility of shared genetic liability. Recent identification of 15 novel genetic loci associated with depression allows direct investigation of this question. In cohorts of individuals participating in biobanks at two academic medical centers, we calculated polygenic loading for risk loci reported to be associated with depression. We then examined the association between such loading and 50 groups of clinical diagnoses, or topics, drawn from these patients' electronic health records, determined using a novel application of latent Dirichilet allocation. Three topics showed experiment-wide association with the depression liability score; these included diagnostic groups representing greater prevalence of mood and anxiety disorders, greater prevalence of cardiac ischemia, and a decreased prevalence of heart failure. The latter two associations persisted even among individuals with no mood disorder diagnosis. This application of a novel method for grouping related diagnoses in biobanks indicate shared genetic risk for depression and cardiac disease, with a pattern suggesting greater ischemic risk and diminished heart failure risk.

Steroids, steroid precursors, and neuroactive steroids in critically ill equine neonates.

Hypothalamic-pituitary-adrenal axis (HPAA) dysfunction has been associated with sepsis and mortality in foals. Most studies have focused on cortisol, while other steroids have not been investigated. The objectives of this study were to characterise the adrenal steroid and steroid precursor response to disease and to determine their association with the HPAA response to illness, disease severity, and mortality in hospitalised foals. All foals (n=326) were classified by two scoring systems into three categories: based on the sepsis score (septic, sick non-septic [SNS] and healthy) and the foal survival score (Group 1: 3-18%; Group 2: 38-62%; Group 3: 82-97% likelihood of survival). Blood concentrations of adrenocorticotropic hormone (ACTH) and steroids were determined by immunoassays. ACTH-cortisol imbalance (ACI) was defined as a high ACTH/cortisol ratio. Septic foals had higher ACTH, cortisol, progesterone, 17α-OH-progesterone, pregnenolone, and androstenedione concentrations as well as higher ACTH/cortisol, ACTH/progesterone, ACTH/aldosterone, and ACTH/DHEAS ratios than SNS and healthy foals (P<0.01). Foals with DHEAS of 0.4-5.4ng/mL were more likely to have ACI (OR=2.5). Foals in Group 1 had higher ACTH, aldosterone, progesterone, and cortisol concentrations as well as ACTH/cortisol, ACTH/progesterone, and ACTH/DHEAS ratios than foals in Groups 2 and 3 (P<0.01). High progesterone concentrations were associated with non-survival and the cutoff value below which survival could be predicted was 23.5ng/mL, with 75% sensitivity and 72% specificity. In addition to cortisol, the response to the stress of illness in foals is characterised by the release of multiple adrenal steroids. DHEAS and progesterone were good predictors of HPAA dysfunction and outcome in hospitalised foals.

Neoadjuvant chemoradiotherapy with concurrent cisplatin/5-fluorouracil is associated with increased pathologic complete response and improved survival compared to carboplatin/paclitaxel in patients with locally advanced esophageal cancer.

Trimodal therapy consisting of neoadjuvant chemoradiation followed by esophagectomy has become the standard of care in North America for locally advanced esophageal cancer. While cisplatin/5-fluorouracil has been a common concurrent chemotherapy regimen since the 1980s, its utilization has declined in recent years as the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) trial regimen of carboplatin/paclitaxel has become widely adopted. The efficacy of the CROSS regimen compared to alternate chemotherapy choices, however, has rarely been evaluated when each is used as a component of a trimodal treatment approach. The aim of this study is to report our institutional experience with these two concurrent chemotherapy regimens at a specialized esophageal cancer center.We performed an Institutional Review Board-approved retrospective review of a prospectively maintained institutional foregut registry from a single National Cancer Institute-designated cancer center. Esophageal cancer patients who completed trimodal therapy with a chemotherapy regimen of either carboplatin/paclitaxel or cisplatin/5-fluorouracil were identified and divided into groups based on their chemotherapy regimens. Multivariable logistic regression was used to analyze pathologic complete response rates, while the Kaplan-Meier and Cox proportional hazards models were utilized to evaluate recurrence-free and overall survival. Analytical models were adjusted for age, clinical stage, radiation dose, histologic subtype (adenocarcinoma vs. squamous cell carcinoma), and time interval from completion of neoadjuvant therapy to surgery.One hundred and forty-two patients treated between January of 2000 and July of 2015 were identified as meeting inclusion criteria. Of this group, 87 had received the CROSS regimen of carboplatin/paclitaxel, while 55 had completed cisplatin/5-fluorouracil. Multivariable analysis demonstrated that the cisplatin/5-fluorouracil.group had an increased odds of pathologic complete response (odds ratio = 2.68, 95% confidence interval, P = 0.032), as well as significantly improved recurrence-free survival (hazard ratio = 0.39, 95% confidence interval 0.21-0.73, P = 0.003) and overall survival (hazard ratio = 0.46, 95% confidence interval 0.24-0.87, P = 0.016), compared to the carboplatin/paclitaxel group.Concurrent chemotherapy with cisplatin/5-fluorouracil in locally advanced esophageal cancer is associated with higher rates of pathologic complete response and improved recurrence-free and overall survival compared to the CROSS regimen of carboplatin/paclitaxel. This suggests that, for select patients, alternate neoadjuvant chemotherapy approaches, such as cisplatin/5-fluorouracil, merit reconsideration as potential primary treatment choices in the management of this highly morbid disease.

Higher bone resorption excretion in South Asian women vs. White Caucasians and increased bone loss with higher seasonal cycling of vitamin D: Results from the D-FINES cohort study.

Few data exist on bone turnover in South Asian women and it is not well elucidated as to whether Western dwelling South Asian women have different bone resorption levels to that of women from European ethnic backgrounds. This study assessed bone resorption levels in UK dwelling South Asian and Caucasian women as well as evaluating whether seasonal variation in 25-hydroxyvitamin D [25(OH)D] is associated with bone resorption in either ethnic group. Data for seasonal measures of urinary N-telopeptide of collagen (uNTX) and serum 25(OH)D were analysed from n=373 women (four groups; South Asian postmenopausal n=44, South Asian premenopausal n=50, Caucasian postmenopausal n=144, Caucasian premenopausal n=135) (mean (±SD) age 48 (14) years; age range 18-79years) who participated in the longitudinal D-FINES (Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England) cohort study (2006-2007). A mixed between-within subjects ANOVA (n=192) showed a between subjects effect of the four groups (P<0.001) on uNTX concentration, but no significant main effect of season (P=0.163). Bonferroni adjusted Post hoc tests (P≤0.008) suggested that there was no significant difference between the postmenopausal Asian and premenopausal Asian groups. Season specific age-matched-pairs analyses showed that in winter (P=0.04) and spring (P=0.007), premenopausal Asian women had a 16 to 20nmolBCE/mmol Cr higher uNTX than premenopausal Caucasian women. The (amplitude/mesor) ratio (i.e. seasonal change) for 25(OH)D was predictive of uNTX, with estimate (SD)=0.213 (0.015) and 95% CI (0.182, 0.245; P<0.001) in a non-linear mixed model (n=154). This showed that individuals with a higher seasonal change in 25(OH)D, adjusted for overall 25(OH)D concentration, showed increased levels of uNTX. Although the effect size was smaller than for the amplitude/mesor ratio, the mesor for 25(OH)D concentration was also predictive of uNTX, with estimate (SD)=-0.035 (0.004), and 95% CI (-0.043, -0.028; P<0.001). This study demonstrates higher levels of uNTX in premenopausal South Asian women than would be expected for their age, being greater than same-age Caucasian women, and similar to postmenopausal Asian women. This highlights potentially higher than expected bone resorption levels in premenopausal South Asian women which, if not offset by concurrent increased bone formation, may have future clinical and public health implications which warrant further investigation. Individuals with a larger seasonal change in 25(OH)D concentration showed an increased bone resorption, an association which was larger than that of the 25(OH)D yearly average, suggesting it may be as important clinically to ensure a stable and steady 25(OH)D concentration, as well as one that is high enough to be optimal for bone health.

Calm Merino ewes have a higher ovulation rate and more multiple pregnancies than nervous ewes.

In 1990, two selection lines of Merino sheep were established for low and high behavioural reactivity (calm and nervous temperament) at the University of Western Australia. Breeding records consistently showed that calm ewes weaned 10% to 19% more lambs than the nervous ewes. We hypothesise that calm ewes could have a higher ovulation rate than nervous ewes and/or calm ewes could have a lower rate of embryo mortality than nervous ewes. We tested these hypotheses by comparing the ovulation rate and the rate of embryo mortality between the calm and nervous lines before and after synchronisation and artificial insemination. Merino ewes from the temperament selection lines (calm, n=100; nervous, n=100) were synchronised (early breeding season) for artificial insemination (day 0) (intravaginal sponges containing fluogestone acetate and eCG immediately after sponge withdrawal). On day-17 and 11 ovarian cyclicity and corpora lutea, and on days 30 and 74 pregnancies and embryos/foetuses were determined by ultrasound. Progesterone, insulin and leptin concentrations were determined in blood plasma samples from days 5, 12 and 17. Ovarian cyclicity before and after oestrus synchronisation did not differ between the lines, but ovulation rate did (day-17: calm 1.63; nervous 1.26; P<0.01; day 11: calm 1.83; nervous 1.57; P<0.05). Ovulation rate on day 11 in nervous ewes was higher than on day-17. Loss of embryos by day 30 was high (calm: 71/150; nervous: 68/130); but nervous ewes had a lower proportion (15/47) of multiple pregnancies compared with calm ewes (30/46; P<0.01). Reproductive loss between days 30 and 74 represented 7.3% of the overall loss. Temperament did not affect concentrations of progesterone, but nervous ewes had higher insulin (32.0 pmol/l±1.17 SEM; P=0.013) and lower leptin (1.18 µg/l±0.04 SEM; P=0.002) concentrations than calm ewes (insulin: 27.8 pmol/l±1.17 SEM; leptin: 1.35 µg/l±0.04 SEM). The differences in reproductive outcomes between the calm and nervous ewes were mainly due to a higher ovulation rate in calm ewes. We suggest that reproduction in nervous ewes is compromised by factors leading up to ovulation and conception, or the uterine environment during early pregnancy, that reflect differences in energy utilisation.