Disease States Research Articles

Atypical sphingosine-1-phosphate metabolites—biological implications of alkyl chain length

AbstractSphingosine-1-phosphate (S1P) is a bioactive lipid signaling molecule with pleiotropic implications by both auto- and paracrine signaling. Signaling occurs by engaging five G protein-coupled receptors (S1P1-5) or intracellular pathways. While the extensively studied S1P with a chain length of 18 carbon atoms (d18:1 S1P) affects lymphocyte trafficking, immune cell survival and inflammatory responses, the biological implication of atypical S1Ps such as d16:1 or d20:1 remains elusive. As S1P lipids have far-reaching implications in health and disease states in mammalian organisms, the previous contrasting results may be attributed to differences in S1P’s alkyl chain length. Current research is beginning to appreciate these less abundant atypical S1P moieties. This review provides an up-to-date foundation of recent findings on the biological implications of atypical S1P chain lengths and offers a perspective on future research endeavors on S1P alkyl chain length–influenced signaling and its implications for drug discovery.

Cationic Lipid Modification of Nuclear Hormone Receptor-Ligands: A Strategy for Developing a New Class of Targeted Anticancer Therapeutics

Ubiquitous expression patterns of nuclear hormone and their receptors (NHRs) have their own roles in performing essential functions in controlling hormone responsive element-promoted gene transcription. In diseased states such as cancer, NHRs play crucial roles and hence targeting these receptors are essential as it gives us a window of opportunity for developing targeted anticancer therapeutics. In comparison to traditional chemotherapy drugs, targeted therapeutic drugs are hypothetically advantageous in terms of efficacy and safety and hence the idea of developing such targeted drugs are inclined to become a mainstream cancer treatment option. This review selectively compiles data regarding NHR-targeting, while majorly focusing on cancer treatment using anticancer small molecules and/or nanotherapeutics targeting estrogen receptor, progesterone receptor, glucocorticoid receptor, and vitamin D receptor. In this study, we selectively emphasized on estrogen receptor. Herein, we mainly highlight the strategy of lipid-modification to convert respective receptor ligands into NHR-targeted anticancer molecules as well as nanotherapeutics. We focused on the strategy of chemical conjugation of those ligands with twin-aliphatic carbon chain-based cationic lipids. The strategy successfully led to the development of a new class of anticancer therapeutics. These are either small-molecule anticancer agents or selfaggregating nanotherapeutics. In spite of great anticancer output, the concept of NHR-targeted anti-cancer therapy still needs to overcome further hurdles before those are projected for clinical settings.

Physical activity and the risk of developing 8 age-related diseases: epidemiological and Mendelian randomization studies

BackgroundWe aimed to characterize the associations between physical activity levels and the risk of developing age-related diseases in the Coronary Artery Risk Development in Young Adults (CARDIA) study and used Mendelian randomization (MR) to assess whether there are causal relationships between physical activity levels and the risk of developing 8 age-related diseases (coronary atherosclerosis, ischemic heart disease, angina, Alzheimer’s disease, hypertension, type 2 diabetes, hyperlipidemia, and venous thromboembolism).MethodsBased on the data available in the CARDIA, we obtained data related to five disease states: coronary heart disease, hypertension, diabetes, hyperlipidemia, and venous thromboembolism. Binary logistic regression analysis estimated the multivariable-adjusted associations between different physical activity statuses and diseases. For the MR study, we used summary-level data from a recently published genome-wide association study on physical activity (including vigorous physical activity and accelerometer-based physical activity) conducted with participants from the UK Biobank study. We selected the above 8 age-related diseases as our outcomes.ResultsIn the CARDIA-based analysis, the risk of developing coronary heart disease [OR (95% CI): 0.562 (0.397–0.795)], hypertension [OR (95% CI): 0.703 (0.601–0.821)], diabetes [OR (95% CI): 0.783 (0.620–0.988)], and hyperlipidemia [OR (95% CI): 0.792 (0.662–0.949)] was negatively related to physical activity status when participants achieved the physical activity target. Our MR results support a negative causal association between genetically determined vigorous physical activity levels and the risk of developing 3 age-related diseases, namely, angina, hypertension and type 2 diabetes. Moreover, our results also support a negative causal association between genetically determined accelerometer-based physical activity levels and the risk of developing angina.ConclusionsPromotion of physical activity is likely to prevent specific age-related diseases.

Transcriptional profiling in microglia across physiological and pathological states identifies a transcriptional module associated with neurodegeneration

Microglia are the resident immune cells of the central nervous system and are involved in brain development, homeostasis, and disease. New imaging and genomics technologies are revealing microglial complexity across developmental and functional states, brain regions, and diseases. We curated a set of publicly available gene expression datasets from human microglia spanning disease and health to identify sets of genes reflecting physiological and pathological microglial states. We also integrated multiple human microglial single-cell RNA-seq datasets in Alzheimer’s disease (AD), multiple sclerosis (MS), and Parkinson’s disease, and identified a distinct microglial transcriptional signature shared across diseases. Analysis of germ-line DNA identified genes with variants associated with AD and MS that are overrepresented in microglial gene sets, including the disease-associated transcriptional signature. This work points to genes that are dysregulated in disease states and provides a resource for the analysis of diseases in which microglia are implicated by genetic evidence.

Influencing factors of self-management ability among dry eye patients in west China.

To investigate the current situation and influencing factors of self-management ability in dry eye patients in west China. A total of 265 patients clinically diagnosed with dry eye received a convenience survey questionnaire at West China Hospital of Sichuan University. All participants completed the rating scale of health self-management skill for adults (AHSMSRS), Huaxi Emotional-Distress Index (HEI), e-health literacy scale (e-HEALS) and Brief Illness Perception Questionnaire (Brief-IPQ). A generalized linear model was employed to establish a multivariate linear model with demographic data, psychological state, e-HEALS, and illness perception as independent variables and health self-management skill score as the dependent variable. The mean score for health self-management skill was 165.58±15.79. Multivariate analysis revealed that advanced age, better illness perception and improved psychological state were associated with better health self-management ability among dry eye patients. Furthermore, the health self-management ability of patients with a disease duration less than 1y was found to be higher compared to those with a disease duration exceeding 1y. The health self-management ability of dry eye patients in west China is relatively high. Age, duration of disease, illness perception and psychological state are the influencing factors on the health self-management ability of dry eye patients.

Quantification of persulfidation on specific proteins: are we nearly there yet?

Hydrogen sulfide (H2S) played a pivotal role in the early evolution of life on Earth before the predominance of atmospheric oxygen. The legacy of a persistent role for H2S in life's processes recently emerged through its discovery in modern biochemistry as an endogenous cellular signalling modulator involved in numerous biological processes. One major mechanism through which H2S signals is protein cysteine persulfidation, an oxidative post-translational modification. In recent years, chemoproteomic technologies have been developed to allow the global scanning of protein persulfidation targets in mammalian cells and tissues, providing a powerful tool to elucidate the broader impact of altered H2S in organismal physiological health and human disease states. While hundreds of proteins were confirmed to be persulfidated by global persulfidome methodologies, the targeting of specific proteins of interest and the investigation of further mechanistic studies are still underdeveloped due to a lack of stringent specificity of the methods and the inherent instability of persulfides. This review provides an overview of the processes of endogenous H2S production, oxidation, and signalling and highlights the application and limitations of current persulfidation labelling approaches for investigation of this important evolutionarily conserved biological switch for protein function.

Outcomes of a patient support programme for subcutaneous immunoglobulin therapy in patients with primary or secondary immunodeficiencies or chronic inflammatory demyelinating polyneuropathy.

Subcutaneous immunoglobulin (SCIg) therapy is important in the treatment of primary (PID) and secondary immunodeficiencies (SID) and chronic inflammatory demyelinating polyneuropathy (CIDP). Patient support programmes (PSPs) help patients self-administer medication regimens and play a more active role in the self-management of their medical conditions. To describe the effectiveness of the CSL Behring CARES PSP in optimising the quality use of SCIg in a hospital-free environment. This retrospective, observational study analysed records of patients enroled in the CSL Behring CARES PSP. Key outcomes were accessibility and effectiveness. Data were extracted from the patient database and analysed using descriptive methods. Seven hundred eighty-nine patients with PID (30.8%), SID (53.4%) and CIDP (15.8%) were enroled in the CARES PSP, 92.8% of whom were referred from public hospitals and the remaining from private hospitals. Of the total patient population, 697 (88.3%) received the nurse-led SCIg self-administration training and education (COACH), out of which 656 (94.1%) completed training and achieved competency after an average of 2.3 training sessions. The proportions of patients who achieved competency were similar across age groups and prior SCIg hospital education status. This is the largest real-world evidence study that describes the effectiveness of SCIg PSPs across three therapeutic disease states. These PSPs can optimise hospital resources such as infusion nurse time and allocation of infusion chairs that were once used for intravenous immunoglobulin infusions, improve patient access to SCIg therapy and enable patients self-administer SCIg outside a hospital environment.

Potential role of bacterial pathogens in the immunopathogenesis of ovarian cancer

The development of next-generation sequencing (NGS) techniques allowed conducting research with greater efficiency and determining the microbial pattern of niches in the human body that were previously considered sterile. Observed changes in the microbiome composition of patients with cancer lesions increasingly indicate the role of microorganisms in the tumour induction and progression. Overgrowth of certain pathogenic strains within the tissue may cause inflammation, which in its chronic form may lead to destabilization of host genome. Such changes may result in altering the expression of genes encoding proteins involved in significant metabolic pathways and promote pathogenic cell functions such as proliferation stimulation, apoptosis inhibition and modulation of inflammatory response. Consequently, these events may lead to tissue destruction, disruption of physiological processes and development of disease states including cancer. In light of emerging reports on the role of changes in the composition of the microbiota in tumorigenesis induction and the presence of pathogenic strains in the ovarian cancer (OC) tumour microenvironment (TME), the hypothesis of a potential role for bacteria in the pathogenesis of this cancer is also gaining interest. The following review presents a summary of scientific research indicating potential role of TME bacteria in the immunopathogenesis of OC.

Novel Machine Learning of DNA Methylation Patterns to Diagnose Complex Disease: Identification of Cerebral Palsy with Concurrent Epilepsy.

Spastic cerebral palsy (CP) is a common pediatric-onset disability with an estimated prevalence of 0.2%. It is a complex condition characterized by muscle stiffness, contractures, and abnormal movement. Spastic CP is difficult to diagnose. Although nearly all affected children are born with it or acquire it immediately after birth, many are not identified until after 19 months of age with the diagnosis often not confirmed until 5 years of age. In addition, CP frequently co-occurs with other complex conditions that can complicate diagnosis and treatment. For example, an estimated 42% of spastic CP cases have co-occurring epilepsy. Recent studies indicate that altered DNA methylation patterns in peripheral blood cells are associated with CP and may have diagnostic value.Accordingly, the purpose of this study is to assess the diagnostic value of methylation in CP with more complex disease states. We evaluated machine learning classification for detecting CP based on DNA methylation pattern analysis in the context of co-occurrent epilepsy. Blood samples from 30 study participants diagnosed with epilepsy (n=4), spastic CP (n=10), both (n=8), or neither (n=8) were analyzed by Illumina MethylationEpic arrays. A novel machine learning algorithm using a Support Vector Machine (SVM) or Linear Discriminant Analysis (LDA) was developed to identify methylation loci that classified CP from controls and to measure the classification ability of identified methylation loci. The isolation of informative methylation loci was performed in a binary comparison between CP and controls, as well as in a 4-way comparison that included epilepsy. Median F1 scores for SVM-based analysis were 0.67 in 4-class comparison, and 1.0 in the binary classification. SVM outperformed LDA (median F1 0.57 and 0.86, respectively). Overall, the novel machine learning based algorithm was able to classify study participants with spastic CP and/or epilepsy from controls with significant performance.

EmbedGEM: A framework to evaluate the utility of embeddings for genetic discovery

Abstract Machine learning (ML)-derived embeddings are a compressed representation of high content data modalities. Embeddings can capture detailed information about disease states and have been qualitatively shown to be useful in genetic discovery. Despite their promise, embeddings have a major limitation: It is unclear if genetic variants associated with embeddings are relevant to the disease or trait of interest. In this work we describe EmbedGEM (Embedding Genetic Evaluation Methods), a framework to systematically evaluate the utility of embeddings in genetic discovery. EmbedGEM focuses on comparing embeddings along two axes: Heritability and disease relevance. As measures of heritability, we consider the number of genome-wide significant associations and the mean χ2 statistic at significant loci. For disease relevance, we compute polygenic risk scores for each embedding principal component, then evaluate their association with high-confidence disease or trait labels in a held-out evaluation patient set. While our development of EmbedGEM is motivated by embeddings, the approach is generally applicable to multivariate traits, and can readily be extended to accommodate additional metrics along the evaluation axes. We demonstrate EmbedGEM’s utility by evaluating embeddings and multivariate traits in two separate datasets: I) a synthetic dataset simulated to demonstrate the ability of the framework to correctly rank traits based on their heritability and disease relevance, and ii) a real data from the UK Biobank including metabolic and liver-related traits. Importantly, we show that greater disease relevance does not automatically follow from greater heritability.

Glucoraphanin and sulforaphane mitigate TNFα-induced Caco-2 monolayers permeabilization and inflammation

Intestinal permeabilization is central to the pathophysiology of chronic gut inflammation. This study investigated the efficacy of glucoraphanin (GR), prevalent in cruciferous vegetables, particularly broccoli, and its derivative sulforaphane (SF), in inhibiting tumor necrosis factor alpha (TNFα)-induced Caco-2 cell monolayers inflammation and permeabilization through the regulation of redox-sensitive events. TNFα binding to its receptor led to a rapid increase in oxidant production and subsequent elevation in the mRNA levels of NOX1, NOX4, and Duox2. GR and SF dose-dependently mitigated both these short- and long-term alterations in redox homeostasis. Downstream, GR and SF inhibited the activation of the redox-sensitive signaling cascades NF-κB (p65 and IKK) and MAPK ERK1/2, which contribute to inflammation and barrier permeabilization. GR (1 μM) and SF (0.5–1 μM) prevented TNFα-induced monolayer permeabilization and the associated reduction in the levels of the tight junction (TJ) proteins occludin and ZO-1. Both GR and SF also mitigated TNFα-induced increased mRNA levels of the myosin light chain kinase, which promotes TJ opening. Molecular docking suggests that although GR is mostly not absorbed, it could interact with extracellular and membrane sites in NOX1. Inhibition of NOX1 activity by GR would mitigate TNFα receptor downstream signaling and associated events. These findings support the concept that not only SF, but also GR, could exert systemic health benefits by protecting the intestinal barrier against inflammation-induced permeabilization, in part by regulating redox-sensitive pathways. GR has heretofore not been viewed as a biologically active molecule, but rather, the benign precursor of highly active SF. The consumption of GR and/or SF-rich vegetables or supplements in the diet may offer a means to mitigate the detrimental consequences of intestinal permeabilization, not only in disease states but also in conditions characterized by chronic inflammation of dietary and lifestyle origin.

A novel assay of excess plasma kallikrein-kinin system activation in hereditary angioedema

BackgroundCleaved high-molecular-weight kininogen (HKa) is a disease state biomarker of kallikrein-kinin system (KKS) activation in patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH), the endogenous inhibitor of plasma kallikrein (PKa).ObjectiveDevelop an HKa-specific enzyme-linked immunosorbent assay (ELISA) to monitor KKS activation in the plasma of HAE-C1INH patients.MethodsA novel HKa-specific antibody was discovered by antibody phage display and used as a capture reagent to develop an HKa-specific ELISA.ResultsSpecific HKa detection following KKS activation was observed in plasma from healthy controls but not in prekallikrein-, high-molecular-weight kininogen-, or coagulation factor XII (FXII)-deficient plasma. HKa levels in plasma collected from HAE-C1INH patients in a disease quiescent state were higher than in plasma from healthy controls and increased further in HAE-C1INH plasma collected during an angioedema attack. The specificity of the assay for PKa-mediated HKa generation in minimally diluted plasma activated with exogenous FXIIa was demonstrated using a specific monoclonal antibody inhibitor (lanadelumab, IC50 = 0.044 µM).ConclusionsAn ELISA was developed for the specific and quantitative detection of HKa in human plasma to support HAE-C1INH drug development. Improved quantification of the HKa biomarker may facilitate further pathophysiologic insight into HAE-C1INH and other diseases mediated by a dysregulated KKS and may enable the design of highly potent inhibitors targeting this pathway.

Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset.

Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. Studies of human T1D immunobiology have predominantly focused on circulating immune cells in the blood, while mouse models suggest diabetogenic lymphocytes primarily reside in pancreas-draining lymph nodes (pLN). A comprehensive study of immune cells in human T1D was conducted using pancreas draining lymphatic tissues, including pLN and mesenteric lymph nodes, and the spleen from non-diabetic control, β cell autoantibody positive non-diabetic (AAb+), and T1D organ donors using complementary approaches of high parameter flow cytometry and CITEseq. Immune perturbations suggestive of a proinflammatory environment were specific for T1D pLN and AAb+ pLN. In addition, certain immune populations correlated with high T1D genetic risk independent of disease state. These datasets form an extensive resource for profiling human lymphatic tissue immune cells in the context of autoimmunity and T1D.

Abstract B054: Protease activity as a biomarker and potential target among pancreatic cancer patients

Abstract Background: The pancreas produces digestive proteases, which are often elevated in diseased states and capable of indiscriminate cell surface receptor cleavage. High levels of digestive protease activity have been implicated in the pathophysiology of pancreatic ductal adenocarcinoma (PDAC). We hypothesize that elevated digestive protease activity might downregulate or cleave immune cell receptors from the surface of cancer cells and contribute to the resistance of PDAC to immunotherapy. We have focused initially on major histocompatibility complex (MHC)-1, a ubiquitous receptor essential for antigen presentation, and CD155, an adhesion molecule over-expressed on cancer cells that regulates immune surveillance through binding to the TIGIT and CD226 receptors on leukocytes. Methods: The Rapid Assay for Protease Detection (RAPD) assay is a novel assay developed at our institution that utilizes fluorescent charge-changing peptide substrates to produce a positively charged fluorescent product fragment upon cleavage by the target protease. The RAPD assay was used to analyze protease activity levels in PDAC patients (N=50) and healthy (N=25) plasma samples. We also analyzed plasma samples obtained from an orthotopic KPC-derived mouse model for PDAC. We investigated the effects of specific proteases as well as plasma samples from PDAC and healthy subjects on MHC-1 and CD-155 receptor cleavage in cultured cells in vitro. Utilizing flow cytometry and immunofluorescent imaging, receptor loss was quantified for different proteases and plasma samples. Results: We observed elevated activity levels of digestive protease chymotrypsin as well as cathepsin-S and MMP-2 in the plasma of PDAC patients compared to healthy subjects. Similar patterns of protease activity were seen in plasma from tumor-bearing mice compared to non-tumor-bearing mice. Additionally, our results suggest loss of CD155 and MHC-1 from pancreatic cancer cells when incubated with trypsin and cathepsin-S. Incubation of cells with PDAC plasma also decreases the number of cells expressing MHC-1 and CD155 compared to control plasma, with greater differences observed in plasma with higher protease levels. Higher levels of cleaved CD155 are also detectable by ELISA in human and mouse PDAC plasma than in control plasma. Also, the protease activity (MMP2 and trypsin) correlates with plasma levels of CD155 and PD-L1. Conclusions: These studies begin to elucidate a possible role of digestive proteases in the ability of PDAC to evade the immune system. Ongoing experiments are exploring other immune receptors (including checkpoints) and whether specific protease inhibitors can block immune receptor cleavage. These experiments will inform subsequent experiments combining protease inhibitors with immunotherapy in mouse models. Citation Format: Utsav Joshi, Heather Farris, Jorge De La Torre De La Torre, kim Nguyen-Ta1, Michael Heller, Geert Schmid-Schonbein, Rebekah White. Protease activity as a biomarker and potential target among pancreatic cancer patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B054.

Age-related changes in the hair follicle and hair shaft in women in the parietal region

Introduction. Medical trichology is a promising and modern direction of cosmetology, engaged in the study of the scalp and hair, both in the state of health and various diseases. However, with all the variety of various scientific publications, there are very few works devoted to the study of morphological changes in normal physiological aging of a person.Aim. To reveal the dynamics of morphological changes in the hair bulb and hair shaft in women in the parietal region to elderly age.Materials and methods. The work is based on the results of microscopic examination of 80 women, the study sample consisted of conditionally healthy individuals. The examined women were divided into three groups depending on their age. The first group included 27 women of the first period of mature age (26.9 ± 0.70 years). The second group consisted of 30 women of the second period of mature age (47.1 ± 1.20 years). The third group was formed by 23 women of old age (62.1 ± 1.09 years). Hair sampling was performed in the parietal region of the head by combing out the hair that had already fallen out (without pulling it out of the skin!). The width of the hair bulb and hair shaft were measured. The percentage of bulbs containing an internal root sheath to the total number of bulbs was calculated.Results and discussion. With age, a decrease in the number of hair follicles with internal root sheath (p < 0.01) along with a tendency to decrease the width of the hair follicle and hair shaft (p > 0.05) was noted in women in the parietal region.Conclusions. The results of this study add to the information available in the scientific literature about age-related changes occurring in the hair bulb and hair shaft in women by old age. The data obtained will be useful for trichologists in medical practice to create clinical recommendations for the early prevention of age-related alopecia areata.

Effects of Omega-3 Polyunsaturated Fatty Acids on the Formation of Adipokines, Cytokines, and Oxylipins in Retroperitoneal Adi-Pose Tissue of Mice.

Oxylipins and specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) are mediators that coordinate an active process of inflammation resolution. While these mediators have potential as circulating biomarkers for several disease states with inflammatory components, the source of plasma oxylipins/SPMs remains a matter of debate but may involve white adipose tissue (WAT). Here, we aimed to investigate to what extent high or low omega (n)-3 PUFA enrichment affects the production of cytokines and adipokines (RT-PCR), as well as oxylipins/SPMs (liquid chromatography-tandem mass spectrometry) in the WAT of mice during lipopolysaccharide (LPS)-induced systemic inflammation (intraperitoneal injection, 2.5 mg/kg, 24 h). For this purpose, n-3 PUFA genetically enriched mice (FAT-1), which endogenously synthesize n-3 PUFAs, were compared to wild-type mice (WT) and combined with n-3 PUFA-sufficient or deficient diets. LPS-induced systemic inflammation resulted in the decreased expression of most adipokines and interleukin-6 in WAT, whereas the n-3-sufficient diet increased them compared to the deficient diet. The n-6 PUFA arachidonic acid was decreased in WAT of FAT-1 mice, while n-3 derived PUFAs (eicosapentaenoic acid, docosahexaenoic acid) and their metabolites (oxylipins/SPMs) were increased in WAT by genetic and nutritional n-3 enrichment. Several oxylipins/SPMs were increased by LPS treatment in WAT compared to PBS-treated controls in genetically n-3 enriched FAT-1 mice. Overall, we show that WAT may significantly contribute to circulating oxylipin production. Moreover, n-3-sufficient or n-3-deficient diets alter adipokine production. The precise interplay between cytokines, adipokines, and oxylipins remains to be further investigated.

Potential of Exosomes as Multifunctional Nanocarriers for Targeted Drug Delivery.

Exosomes are small vesicles that form when multivesicular bodies fuse with the plasma membrane and are released into body fluids. They play a vital role in facilitating communication between cells by transferring different biomolecules, including DNA, RNA, proteins, and lipids, over both short and long distances. They also function as vital mediators in both states of health and disease, exerting an impact on several physiological processes. Exosomes have been modified to overcome the limitations of natural exosomes to enhance their potential as carriers for drug delivery systems, and these modifications aim to improve the drug delivery efficiency, enhance tissue and organ targeting, and prolong the circulating half-life of exosomes. This review discussed recent advancements in exosome nanotechnology, as well as the progression and use of exosomes for drug delivery. The potential commercialisation and challenges associated with the use of exosome-based drug delivery systems were also discussed, aiming to motivate the development of exosome-based theranostic nanoplatforms and nanotechnology for improved healthcare treatments.

262 Why are some cows skinny? An evaluation of stress and immune factors

Abstract For the mature cow with low body condition scores (BCS), being too thin can accompany health issues, reduced pregnancy rates, more days to rebreeding, and decreased milk production resulting in lighter calves at weaning. In addition, reduced fat insulation in low BCS cows during the winter equates to additional feed requirements for warmth. The hypothesis of this study was that stress and immune factors contribute to low BCS in mature cows. The objective of this study was to determine whether there were differences in hematology parameters, hair cortisol concentrations, and plasma cytokine concentrations among animals with low body condition (BCS ≤ 4). Over a 3 yr study, we collected 62 pairs of cows which included cows with a BCS ≤ 4, and a matched control animal born in the same year with the same or similar breed composition from the same population of animals with a BCS of 5 or higher. Hematology parameters, cytokine concentration, and cortisol concentrations were analyzed using a model with BCS classification and sample year as fixed effects and age in years as a covariate. Hemoglobin, hematocrit, red blood cell and mean platelet volume were all less among the low BCS cows, and neutrophil count was greater (P < 0.05). Platelet, monocyte counts, mean corpuscular volume, and mean corpuscular hemoglobin tended to be greater in low BCS cows (0.05 < P ≤ 0.1), and lymphocyte count tended to be less. Hair cortisol concentrations, a longer-term measure of cortisol, tended to be greater in low BCS cows (P = 0.09). None of the 15 cytokines tested differed with BCS. The combination of reduced RBC parameters with greater neutrophils suggests that low BCS cows were responding to or were the reflection of some type of chronic stressor, such as a subclinical disease state or a physiologic stressor. This was also supported by the tendency for greater cortisol concentrations in low BCS cows. USDA is an equal opportunity provider and employer.

Acute lung pathology in the immunocompromised child.

Children with compromised immune systems, whether due to primary or secondary immunodeficiencies, are susceptible to a broad spectrum of acute intrathoracic pathologies. These include infections, pulmonary edema, and malignancies. Pulmonary issues are common and perilous in this population, necessitating prompt and precise diagnosis for effective management. This review aims to provide an overview of such conditions, focusing on the imaging appearances of the most prevalent acute lung conditions affecting immunocompromised children. It emphasizes the critical importance of an integrated clinical and radiological approach when diagnosing these acute pulmonary disease states.

The conceptualisation of cardiometabolic disease policy model in the UK

BackgroundDecision models are increasingly used to inform policy-making processes, and there is a need to improve their credibility. The estimation of health and economic outcomes generated from decision models is influenced by the development process itself. This paper aims to present the conceptual model development process of cardiometabolic disease (CMD) policy models in the UK setting.MethodsThis conceptual model followed the International Society of Pharmacoeconomics and Outcomes Research-Society of Medical Decision Making (ISPOR-SMDM) Modelling Good Research Practices Task Force-2.ResultsFirst, for the conceptualisation of the problem, the CMD disease staging, progression and current clinical guidelines were summarised, followed by a systematic review of published policy models. We critically appraised policy models such as cardiovascular disease and type 2 diabetes. Key messages from the review emphasised the importance of understanding various determinants influencing model development, including risk factors, model structure, models’ parameters, data utilisation, economic perspective, equality/equity consideration, transparency and validation process. Second, as a sequential process, is model conceptualisation, to determine which modelling types and their attributes best represent the defined problem. Expert opinions, including a clinician and experienced modellers, provided input on the state transition model to ensure the structure is clinically relevant. From this stage, the consideration and agreement to establish a disease state in a state transition model was discussed.ConclusionThis conceptual model serves as a basis for representing the systematic process for structuring a CMD policy model to enhance its transparency and credibility.