Idelalisib-Induced Pneumonitis in Chronic Lymphocytic Leukemia.

Idelalisib, a phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, effectively treats relapsed chronic lymphocytic leukemia (CLL). While this targeted approach offers a therapeutic edge, particularly in B-cell malignancies, it is associated with complications such as pneumonitis. This report details idelalisib-induced pneumonitis, highlighting the importance of early diagnosis and tailored treatment in achieving a favorable patient outcome.

Single nuclei RNA-seq reveals a medium spiny neuron glutamate excitotoxicity signature prior to the onset of neuronal death in an ovine Huntington's disease model.

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. The 73 polyglutamine repeat is somatically stable and therefore likely captures a prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. To better understand the disease-initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild-type controls. We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in medium spiny neurons, the cell type preferentially lost early in HD. Further, we observed an upregulation of astrocytic glutamate uptake transporters and medium spiny neuron GABAA receptors, which may maintain glutamate homeostasis. Taken together, these observations support the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade-initiating process but the threshold of toxicity may be regulated by several protective mechanisms. Addressing this biochemical defect early may prevent neuronal loss and avoid the more complex secondary consequences precipitated by cell death.

Effects of Transport Duration and Pre-Transport Fasting on Blood Biochemistry in Dorper × Mongolian Sheep.

Transport is a high-risk time for sheep, especially if the distances are long and sheep are fasted for a long time beforehand. Two experiments were conducted to compare transport durations of 1 hour (1 h) and 3 hours (3 h) and the effects of feeding before transport using Dorper × Mongolian sheep, which are typical of the region and may be tolerant of the high temperatures in the Inner Mongolian summer. Thirty 4-month-old male sheep were randomly divided into two treatment groups, with 15 sheep/treatment in each experiment, to evaluate the effects on blood biochemical indicators, stress hormone levels, rectal temperatures, and antioxidant status of lambs in summer. In Experiment 1, the levels of triglycerides and free fatty acids after 3 h transport were significantly lower than after 1 h transport (p < 0.05). The levels of thyroxine and malondialdehyde in blood were greater after 3 h transport than 1 h transport (p < 0.05). Creatine kinase levels after 3 h transport tended to be lower than after 1 h transport (p = 0.051). In Experiment 2, the levels of urea and superoxide dismutase in the group fasted pre-transport was significantly lower than those of the group fed pre-transport (p < 0.05). The serum cortisol level in the pre-transport fed group was higher compared to the group fed pre-transport (p = 0.04). Total antioxidant capacity in the pre-transport fasted group tended to be lower compared to that in the pre-transport fed group (p < 0.0001). We conclude that the reduction in nutritional status of sheep transported for longer and without feed pre-transport suggests that transporting sheep in hot conditions in northern China after fasting for a long period should be restricted. However, a decrease in the stress induced by transport following fasting is worthy of further study.

Delayed Presentation of Malignancy-Associated Pseudoachalasia of the Gastric Cardia.

Pseudoachalasia is a condition in which symptoms, manometry, and imaging findings highly resemble primary achalasia but has a secondary etiology. The majority of patients with pseudoachalasia have the condition as the result of a malignancy, most often at the gastroesophageal junction. There may be issues with timely identification of this malignancy as symptoms are often obscure with diagnostic testing yielding nonspecific results. We describe a case of a 65-year-old diabetic female smoker with a four-month history of intractable vomiting, abdominal pain, and weight loss who was belatedly found to have an adenocarcinoma at the gastric cardia necessitating a total gastrectomy and chemotherapy administration. The case educates clinicians on the clinical alarm symptoms related to malignant pseudoachalasia and stresses the paramount importance of performing a timely esophagogastroduodenoscopy in all cases of achalasia, even with seemingly normal imaging, to rule out pseudoachalasia related to malignancy.

Farm Animal Welfare-From the Farmers' Perspective.

Improvements in the welfare of animals in the intensive production industries are increasingly being demanded by the public. Scientific methods of welfare improvement have been developed and are beginning to be used on farms, including those provided by precision livestock farming. The number of welfare challenges that animals are facing in the livestock production industries is growing rapidly, and farmers are a key component in attempts to improve welfare because their livelihood is at stake. The challenges include climate change, which not only exposes animals to heat stress but also potentially reduces forage and water availability for livestock production systems. Heat-stressed animals have reduced welfare, and it is important to farmers that they convert feed to products for human consumption less efficiently, their immune system is compromised, and both the quality of the products and the animals' reproduction are adversely affected. Livestock farmers are also facing escalating feed and fertiliser costs, both of which may jeopardise feed availability for the animals. The availability of skilled labour to work in livestock industries is increasingly limited, with rural migration to cities and the succession of older farmers uncertain. In future, high-energy and protein feeds are unlikely to be available in large quantities when required for the expanding human population. It is expected that livestock farming will increasingly be confined to marginal land offering low-quality pasture, which will favour ruminant livestock, at the expense of pigs and poultry unable to readily digest coarse fibre in plants. Farmers also face disease challenges to their animals' welfare, as the development of antibiotic resistance in microbes has heralded an era when we can no longer rely on antibiotics to control disease or improve the feed conversion efficiency of livestock. Farmers can use medicinal plants, pro-, pre- and synbiotics and good husbandry to help maintain a high standard of health in their animals. Loss of biodiversity in livestock breeds reduces the availability of less productive genotypes that survive better on nutrient-poor diets than animals selected for high productivity. Farmers have a range of options to help address these challenges, including changing to less intensive diets, diversification from livestock farming to other enterprises, such as cereal and pseudocereal crops, silvopastoral systems and using less highly selected breeds. These options may not always produce good animal welfare, but they will help to give farm animals a better life.

The Effects of Occupation, Education and Dwelling Place on Attitudes towards Animal Welfare in China.

Attitudes to animal welfare are not understood well in China, the country with the highest output of farm animals in the world. We surveyed attitudes of the public around China using a team of researchers to conduct individual interviews, with 1301 respondents in total. Contrary to results obtained in several other countries, high school leavers were more concerned about animal welfare than those who had obtained a university degree. We speculate that this may reflect the labour market currently existing in China, with limited opportunities for graduates. Scientists were less supportive, and artists more supportive, of good animal welfare. Urban dwellers were more concerned about animal welfare than rural residents, with village residents in the middle, which confirmed our theory that such a difference prevails in developing countries, where a large proportion of the rural population are involved in agriculture. It is concluded that education level, occupation and living place all have pronounced influences on attitudes to animal welfare in China, some of which follow international trends.

Somatic CAG Repeat Stability in a Transgenic Sheep Model of Huntington's Disease.

Somatic instability of the huntingtin (HTT) CAG repeat mutation modifies age-at-onset of Huntington's disease (HD). Understanding the mechanism and pathogenic consequences of instability may reveal therapeutic targets. Using small-pool PCR we analyzed CAG instability in the OVT73 sheep model which expresses a full-length human cDNA HTT transgene. Analyses of five- and ten-year old sheep revealed the transgene (CAG)69 repeat was remarkably stable in liver, striatum, and other brain tissues. As OVT73 sheep at ten years old have minimal cell death and behavioral changes, our findings support instability of the HTT expanded-CAG repeat as being required for the progression of HD.

The Effects of Housing on Growth, Immune Function and Antioxidant Status of Young Female Lambs in Cold Conditions.

Cold conditions in northern China during winter may reduce sheep growth and affect their health, especially if they are young, unless housing is provided. We allocated 45 two-month-old female lambs to be housed in an enclosed building, a polytunnel, or kept outdoors, for 28 days. The daily weight gain and scalp and ear skin temperature of outdoor lambs were less than those of lambs that were housed in either a house or polytunnel; however, rectal temperature was unaffected by treatment. There was a progressive change in blood composition over time, and by the end of the experiment, outdoor lambs had reduced total antioxidant capacity (T-AOC), catalase (CAT), glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD) and increased malondialdehyde compared to those in the house or polytunnel. In relation to immune responses in the lambs' serum, in the polytunnel, immunoglobulin A (IgA), tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) were higher and immunoglobulin G (IgG) lower compared with the concentrations in lambs that were outdoors. Over the course of the experiment, genes expressing heat shock proteins and antioxidant enzymes increased in lambs in the outdoor treatment, whereas they decreased in lambs in the indoor treatments. It is concluded that although there were no treatment effects on core body temperature, the trends for progressive changes in blood composition and gene expression indicate that the outdoor lambs were not physiologically stable; hence, they should not be kept outdoors in these environmental conditions for long periods.

Humans can identify reward-related call types of chickens.

Humans can decode emotional information from vocalizations of animals. However, little is known if these interpretations relate to the ability of humans to identify if calls were made in a rewarded or non-rewarded context. We tested whether humans could identify calls made by chickens (Gallus gallus) in these contexts, and whether demographic factors or experience with chickens affected their correct identification context and the ratings of perceived positive and negative emotions (valence) and excitement (arousal) of chickens. Participants (n = 194) listened to eight calls when chickens were anticipating a reward, and eight calls in non-rewarded contexts, and indicated whether the vocalizing chicken was experiencing pleasure/displeasure, and high/low excitement, using visual analogue scales. Sixty-nine per cent of participants correctly assigned reward and non-reward calls to their respective categories. Participants performed better at categorizing reward-related calls, with 71% of reward calls classified correctly, compared with 67% of non-reward calls. Older people were less accurate in context identification. Older people's ratings of the excitement or arousal levels of reward-related calls were higher than younger people's ratings, while older people rated non-reward calls as representing higher positive emotions or pleasure (higher valence) compared to ratings made by younger people. Our study strengthens evidence that humans perceive emotions across different taxa, and that specific acoustic cues may embody a homologous signalling system among vertebrates. Importantly, humans could identify reward-related calls, and this ability could enhance the management of farmed chickens to improve their welfare.

BridgePRS leverages shared genetic effects across ancestries to increase polygenic risk score portability.

Here we present BridgePRS, a novel Bayesian polygenic risk score (PRS) method that leverages shared genetic effects across ancestries to increase PRS portability. We evaluate BridgePRS via simulations and real UK Biobank data across 19 traits in individuals of African, South Asian and East Asian ancestry, using both UK Biobank and Biobank Japan genome-wide association study summary statistics; out-of-cohort validation is performed in the Mount Sinai (New York) BioMe biobank. BridgePRS is compared with the leading alternative, PRS-CSx, and two other PRS methods. Simulations suggest that the performance of BridgePRS relative to PRS-CSx increases as uncertainty increases: with lower trait heritability, higher polygenicity and greater between-population genetic diversity; and when causal variants are not present in the data. In real data, BridgePRS has a 61% larger average R2 than PRS-CSx in out-of-cohort prediction of African ancestry samples in BioMe (P = 6 × 10-5). BridgePRS is a computationally efficient, user-friendly and powerful approach for PRS analyses in non-European ancestries.

Nutrients as Risk Factors and Treatments for Gestational Diabetes.

Gestational diabetes (GDM), traditionally defined as any form of glucose intolerance first detected in pregnancy [...].

The effects of replacing wheat and soyabean meal with duckweed (Lemna minor) and including enzymes in the diet of laying hens on the yield and quality of eggs, biochemical parameters, and their antioxidant status.

Duckweed is a rapidly growing aquatic plant, which could be used in the diet of laying hens to enhance carbon capture and improve land use efficiency. Digestion may be improved by supplementation with exogenous enzymes. We replaced soyabean meal and wheat with duckweed in a 10-week study with 432, 60-week-old Hy-Line W-36 layers, divided into six isocaloric and isonitrogenous dietary treatments, each with eight replicates. Two factors were investigated: first, duckweed substituted for wheat gluten meal and soyabean meal at 0, 7.5 and 15% of the diet, and second, with and without a multi-enzyme supplement (500 mg/kg). Duckweed did not affect egg output or weight, but it improved yolk color (P = 0.01) and reduced the liver enzymes aspartate aminotransferase (P = 0.04) and alanine aminotransferase (P = 0.02) in serum, suggesting hepatoprotective effects. Enzyme addition did not alter the effects of including duckweed in the diet, but it increased feed intake (P = 0.03). It is concluded that, as well as offering the potential to increase land productivity, inclusion of duckweed in the diet of laying hens enhances egg yolk color and hepatoprotection, without detrimental effects on performance.

Farmers' Perspectives of the Benefits and Risks in Precision Livestock Farming in the EU Pig and Poultry Sectors.

More efficient livestock production systems are necessary, considering that only 41% of global meat demand will be met by 2050. Moreover, the COVID-19 pandemic crisis has clearly illustrated the necessity of building sustainable and stable agri-food systems. Precision Livestock Farming (PLF) offers the continuous capacity of agriculture to contribute to overall human and animal welfare by providing sufficient goods and services through the application of technical innovations like digitalization. However, adopting new technologies is a challenging issue for farmers, extension services, agri-business and policymakers. We present a review of operational concepts and technological solutions in the pig and poultry sectors, as reflected in 41 and 16 European projects from the last decade, respectively. The European trend of increasing broiler-meat production, which is soon to outpace pork, stresses the need for more outstanding research efforts in the poultry industry. We further present a review of farmers' attitudes and obstacles to the acceptance of technological solutions in the pig and poultry sectors using examples and lessons learned from recent European projects. Despite the low resonance at the research level, the investigation of farmers' attitudes and concerns regarding the acceptance of technological solutions in the livestock sector should be incorporated into any technological development.

Associations of appetitive traits with growth velocities from infancy to childhood.

Several studies have reported associations between appetitive traits and weight gain during infancy or childhood, but none have directly compared these associations across both age periods. Here, we tested the associations between appetitive traits and growth velocities from birth to childhood. Appetitive trait data were collected using the Children's Eating Behaviour Questionnaire (CEBQ) in 149 children from the Cambridge Baby Growth Study at age 9-17 years. These participants also provided anthropometric measurements during infancy (birth, 3, 12, 18, and 24 months) and childhood (5 to 11 years). Standardized growth velocities (in weight, length/height, BMI, and body fat percentage) for 0-3 months, 3-24 months, and 24 months to childhood were estimated using individual linear-spline models. Associations between each of the eight CEBQ traits and each growth velocity were tested in separate multilevel linear regression models, adjusted for sex, age at CEBQ completion, and the corresponding birth measurement (weight, length, BMI, or body fat percentage). The three food-approach traits (food responsiveness, enjoyment of food and emotional overeating) were positively associated with infancy and childhood growth velocities in weight, BMI, and body fat percentage. By contrast, only one of the food-avoidant traits, satiety responsiveness, was negatively associated with all growth velocities. Significant associations were mostly of similar magnitude across all age periods. These findings reveal a broadly consistent relationship between appetitive traits with gains in weight and adiposity throughout infancy and childhood. Future interventions and strategies to prevent obesity may benefit from measuring appetitive traits in infants and children and targeting these as part of their programs.

Pregnancy glucagon-like peptide 1 predicts insulin but not glucose concentrations.

AIMS: Incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) cause increased insulin secretion in non-pregnant adults, but their role in pregnancy, where there are additional metabolically-active hormones from the placenta, is less clear. The aim of the present study was to assess if fasting and post-load incretin concentrations were predictive of pregnancy insulin and glucose concentrations. METHODS: Pregnant women (n = 394) with one or more risk factors for gestational diabetes were recruited at 28 weeks for a 75 g oral glucose tolerance test (OGTT). Glucose, insulin, GLP-1 and GIP were measured in the fasting state and 120 min after glucose ingestion. RESULTS: Fasting plasma GLP-1 concentrations were associated with plasma insulin (standardised ß' 0.393 (0.289-0.498), p = 1.3 × 10-12; n = 306), but not with glucose concentrations (p = 0.3). The association with insulin was still evident when adjusting for BMI (ß' 0.271 (0.180-0.362), p = 1.1 × 10-8; n = 297). Likewise, at 120 min the OGTT GLP-1 concentrations were associated with plasma insulin concentrations (ß' 0.216 (0.100-0.331), p = 2.7 × 10-4; n = 306) even after adjusting for BMI (ß' 0.178 (0.061-0.294), p = 2.9 × 10-3; n = 296), but not with glucose (p = 0.9). GIP concentrations were not associated with insulin or glucose concentrations at either time point (all p > 0.2). In pregnancy plasma GLP-1, but not GIP, concentrations appear to be predictive of circulating insulin concentrations, independently of associations with BMIs. CONCLUSIONS: These results suggest that the relationship between insulin and incretins is preserved in pregnancy, but that other factors, such as placental hormones or counter-regulatory hormones, may be more important determinants of glycaemia and gestational diabetes aetiology.

Controlled release of MT-1207 using a novel gastroretentive bilayer system comprised of hydrophilic and hydrophobic polymers.

In the present study, novel gastroretentive bilayer tablets were developed that are promising for the once-a-day oral delivery of the drug candidate MT-1207. The gastroretentive layer consisted of a combination of hydrophilic and hydrophobic polymers, namely polyethylene oxide and Kollidon® SR. A factorial experiment was conducted, and the results revealed a non-effervescent gastroretentive layer that, unlike most gastroretentive layers reported in the literature, was easy to prepare, and provided immediate tablet buoyancy (mean floating lag time of 1.5 s) that lasted over 24 h in fasted state simulated gastric fluid (FaSSGF) pH 1.6, irrespective of the drug layer, thereby allowing a 24-hour sustained release of MT-1207 from the drug layer of the tablets. Furthermore, during in vitro buoyancy testing of the optimised bilayer tablets in media of different pH values (1.0, 3.0, 6.0), the significant difference (one-way ANOVA, p < 0.001) between the respective total floating times indicated that stomach pH effects on tablet buoyancy are important to be considered during the development of non-effervescent gastroretentive formulations and the choice of dosing regimen. To the best of our knowledge, this has not been reported before, and it should probably be factored in when designing dosing regimens. Finally, a pharmacokinetic study in Beagle dogs indicated a successful in vivo 24-hour sustained release of MT-1207 from the optimised gastroretentive bilayer tablet formulations with the drug plasma concentration remaining above the estimated minimum effective concentration of 1 ng/mL at the 24-hour timepoint and also demonstrated the gastroretentive capabilities of the hydrophilic and hydrophobic polymer combination. The optimised formulations will be forwarded to clinical development.

Mycophenolate Mofetil-Induced Colonic Injury Manifesting Endoscopically As Ischemic Colitis.

Mycophenolate mofetil (MMOF) is a commonly used immunosuppressive prodrug in kidney transplant patients. However, it is not without side effects. The most common of these is diarrhea which inadvertently leads to colonoscopic and endoscopic evaluation when all other workup returns negative. Colonoscopies often show diffuse ulcers and colitis changes depending on the degree of diarrhea. In rare situations, MMOF-induced ischemic colitis may occur on gross endoscopy. We describe an unusual phenomenon of an adult male status post renal transplant with histopathologically diagnosed MMOF-induced colitis who developed gross endoscopic findings concerning ischemic colitis. Our case highlights the importance of recognizing that MMOF-induced colonic changes can rarely mimic ischemic colitis. With this in mind, we aim for gastroenterologists to better understand the varying endoscopic colonic findings of this immunosuppressive drug.

Immunomodulatory Effects of Natural Feed Additives for Meat Chickens.

Broiler chickens are increasingly kept in large numbers in intensive housing conditions that are stressful, potentially depleting the immune system. With the prohibition of the use of antibiotics in poultry feed spreading worldwide, it is necessary to consider the role of natural feed additives and antibiotic alternatives to stimulate the chickens' immune systems. We review the literature to describe phytogenic feed additives that have immunomodulatory benefits in broilers. We initially review the major active ingredients from plants, particularly flavonoids, resveratrol and humic acid, and then describe the major herbs, spices, and other plants and their byproducts that have immunomodulatory effects. The research reviewed demonstrates the effectiveness of many natural feed additives in improving the avian immune system and therefore broiler health. However, some, and perhaps all, additives have the potential to reduce immunocompetence if given in excessive amounts. Sometimes additives are more effective when given in combination. There is an urgent need to determine tolerance levels and optimum doses for additives deemed most suitable to replace antibiotics in the diet of broiler chickens. Effective replacement is most likely with readily available additives, such as olive oil byproducts, olive leaves and alfalfa. It is concluded that effective replacement of antibiotic function with plant-derived additives will be possible, but that further research is necessary to determine optimum doses.

Leptin and IGF-1 in Infancy Are Associated With Variants in DHCR7 and CYP2R1 That Relate With Type 1 Diabetes and 25OHD.

CONTEXT: Vitamin D has been variably implicated in risk of developing type 1 diabetes based on cohorts of at-risk individuals. Emergent type 1 diabetes in childhood is putatively preceded by altered growth. OBJECTIVE: We explored whether polymorphisms in vitamin D metabolism genes modify risk of type 1 diabetes via effects on growth in a prospective, population-based cohort of infants. METHODS: The Cambridge Baby Growth Study enrolled newborns from Cambridgeshire, UK, for follow-up in infancy. In 612 infants, we genotyped single nucleotide polymorphisms in vitamin D metabolism genes that relate with type 1 diabetes: rs10741657 and rs12794714 in CYP2R1, rs12785878 in DHCR7, and rs10877012 in CYP27B1. Multivariate linear regression analyses tested associations between genotypes and anthropometric indices (weight, length, and skinfold thickness) or growth-related hormones (C-peptide, IGF-1, and leptin) in infancy. RESULTS: Birth weight showed borderline associations with the diabetes risk-increasing alleles in CYP2R1, rs10741657 (ß = -.11, P = .02) and rs12794714 (ß = -.09, P = .04). The risk-increasing allele rs12794714 was also associated with higher IGF-1 levels at age 24 months (ß = .30, P = .01). At age 3 months, the risk-increasing allele rs12785878 in DHCR7, known to negatively associate with 25-hydroxyvitamin D levels, showed a positive association with leptin levels (ß = .23, P = .009), which was pronounced in girls (P = .004) vs boys (P = .7). CONCLUSION: The vitamin D metabolism genes DHCR7 and CYP2R1 might influence infancy leptin and IGF-1 levels respectively. These findings open the possibility for a developmental role of vitamin D that is mediated by growth-related hormones with implications for the onset of type 1 diabetes autoimmunity.