Radiomics-based prediction of local control in patients with brain metastases following postoperative stereotactic radiotherapy.

BACKGROUND: Surgical resection is the standard of care for patients with large or symptomatic brain metastases (BMs). Despite improved local control after adjuvant stereotactic radiotherapy, the risk of local failure (LF) persists. Therefore, we aimed to develop and externally validate a pre-therapeutic radiomics-based prediction tool to identify patients at high LF risk. METHODS: Data were collected from A Multicenter Analysis of Stereotactic Radiotherapy to the Resection Cavity of Brain Metastases (AURORA) retrospective study (training cohort: 253 patients from two centers; external test cohort: 99 patients from five centers). Radiomic features were extracted from the contrast-enhancing BM (T1-CE MRI sequence) and the surrounding edema (FLAIR sequence). Different combinations of radiomic and clinical features were compared. The final models were trained on the entire training cohort with the best parameter set previously determined by internal 5-fold cross-validation and tested on the external test set. RESULTS: The best performance in the external test was achieved by an elastic net regression model trained with a combination of radiomic and clinical features with a concordance index (CI) of 0.77, outperforming any clinical model (best CI: 0.70). The model effectively stratified patients by LF risk in a Kaplan-Meier analysis (p < 0.001) and demonstrated an incremental net clinical benefit. At 24 months, we found LF in 9% and 74% of the low and high-risk groups, respectively. CONCLUSIONS: A combination of clinical and radiomic features predicted freedom from LF better than any clinical feature set alone. Patients at high risk for LF may benefit from stricter follow-up routines or intensified therapy.

Colonization, spread and persistence of Salmonella (Typhimurium, Infantis and Reading) in internal organs of broilers.

Transfer of Salmonella to internal organs of broilers over a 35 d grow-out period was evaluated. A total of 360 one-day old chicks were placed in 18 floor pens of 3 groups with 6 replicate pens each. On d 0, broilers were orally challenged with a cocktail of Salmonella (equal population of marked serovars; nalidixic acid-resistant S. Typhimurium, rifampicin-resistant S. Infantis, and kanamycin-resistant S. Reading) to have 3 groups: L (low; ∼2 log CFU/bird); M (medium; ∼5 log CFU/bird); and H (High; ∼8 log CFU/bird). On d 2, 7 and 35, 4 birds/pen were euthanized and ceca, liver, and spleen samples were collected aseptically. Gizzard samples (4/pen) were collected on d 35. The concentration of Salmonella in liver and spleen were transformed to binary outcomes (positive and negative) and fitted in glm function of R using cecal Salmonella concentrations (log CFU/g) and inoculation doses (L, M, and H) as inputs. On d 2, H group showed greater (P ≤ 0.05) cecal colonization of all 3 serovars compared to L and M groups. However, M group showed greater (P ≤ 0.05) colonization of all 3 serovars in the liver and spleen compared to L group. Salmonella colonization increased linearly in the ceca and quadratically in the liver and spleen with increasing challenge dose (P ≤ 0.05). On d 35, L group had greater (P ≤ 0.05) S. Infantis colonization in the ceca and liver compared to M and H groups (P ≤ 0.05). Moreover, within each group on d 35, the concentration of S. Reading was greater than those of S. Typhimurium and S. Infantis for all 3 doses in the ceca and high dose in the liver and gizzard (P ≤ 0.05). Salmonella colonization diminished in the ceca, liver, and spleen during grow-out from d 0 to d 35 (P ≤ 0.05). On d 35, birds challenged with different doses of Salmonella cocktail showed a similar total Salmonella spp. population in the ceca (ca. 3.14 log CFU/g), liver (ca. 0.54 log CFU/g), spleen (ca. 0.31 log CFU/g), and gizzard (ca. 0.42 log CFU/g). Estimates from the fitted logistic model showed that one log CFU/g increase in cecal Salmonella concentration will result in an increase in relative risk of liver and spleen being Salmonella-positive by 4.02 and 3.40 times (P ≤ 0.01), respectively. Broilers from H or M group had a lower risk (28 and 23%) of being Salmonella-positive in the liver compared to the L group when the cecal Salmonella concentration is the same (P ≤ 0.05). Oral challenge of broilers with Salmonella spp. with various doses resulted in linear or quadratic increases in Salmonella colonization in the internal organs during early age and these populations decreased during grow-out (d 35). This research can provide guidance on practices to effectively mitigate the risk of Salmonella from chicken parts and enhance public health.

Modified "SUPERhip2" to Reconstruct Postinfectious Femoral Neck Pseudoarthrosis (Hunka Type 3): A Case Report.

CASE: We report a case of a 3-year-old girl who developed a post-infectious femoral neck pseudoarthrosis after a proximal hematogenous femoral osteomyelitis (type 3 according to Hunka classification of the sequelae of the septic hip in children). The patient was treated by a modified "SUPERhip 2" procedure (a reconstructive procedure described to reconstruct congenital femoral neck pseudoarthrosis). This report describes the surgical technique in details and discusses the advantages, pitfalls, and complications and possible complications. CONCLUSION: Our modification simplifies the "SUPERhip 2" procedure. Postinfectious neck pseudoarthrosis was successfully treated, and we believe this modification is applicable for the treatment of congenital femoral neck pseudoarthrosis as well.

Exploring the causes and consequences of non-nursing tasks among nurses in Jordan: An in-depth qualitative investigation.

AIM: To investigate the perceptions of Jordanian nurses regarding Non-Nursing Tasks (NNTs) and their consequences, as well as the underlying factors that contribute to the occurrence of NNTs. BACKGROUND: Nurses play a crucial role in providing high-quality patient care, but they often engage in NNTs, which can hinder their ability to deliver care effectively. Western countries have primarily conducted research on NNTs, while Middle Eastern countries such as Jordan have received limited attention. Expanding our understanding of NNTs is essential for improving nursing care. METHODS: A qualitative-exploratory approach was adopted. The research was conducted at three hospitals in Amman, Jordan. A purposeful sampling approach was used to select the participant and a focus group-interview method was used to gather the data. The derived data were analyzed using a thematic analysis approach. RESULTS: The final sample of this study included 38 participants. The findings highlighted that nurses often perform NNTs due to staff shortages and limited resources, as well as weaknesses in nursing administration and education. The finding also highlights the consequences of NNTs on nurses' professional lives, including impaired nursing care, physical and mental health strain, and a lack of efficiency and productivity. CONCLUSIONS: The present study's results provide valuable insights into the impact of NNTs on nurses in Jordan. These findings underscore the need for healthcare stakeholders to actively address the issue of NNTs. It also emphasized the need for more explicit job descriptions and processes, along with support for nurses to fulfilling their responsibilities and prioritizing patient care.

Experiences on health-related quality of life of Jordanian patients living with heart failure: A qualitative study.

BACKGROUND: Quantitative studies have provided valuable statistical insights into Health-Related Quality of Life (HRQoL) among patients with Heart Failure (HF), yet they often lack the depth to fully capture the nuanced, subjective experiences of living with HF particularly in the specific context of Jordan. This study explores the personal narratives of HF patients to understand the full impact of HF on their daily lives, revealing HRQoL aspects that quantitative metrics often miss. This is crucial in developing regions, where the increasing prevalence of HF intersects with local healthcare practices, cultural views, and patient expectations, providing key insights for tailored interventions and better patient care. METHODS: Utilizing a phenomenological qualitative design, this study conducted face-to-face semi-structured interviews with 25 HF patients to deeply explore their lived experiences. Thematic analysis was employed to identify major themes related to their perceptions of HF as a disease, its impact on various HRQoL domains, and their recommended strategies to enhance HRQoL. RESULTS: The study involved 25 participants (13 males, 12 females), aged 26-88 years (mean 63), with diverse education and heart failure (HF) severities. It revealed three themes: HF perceptions, its impact on health-related quality of life (HRQoL) across physical, psychosocial, spiritual, cognitive, and economic domains, and HRQoL improvement strategies. Participants had varied HF knowledge; some lacked basic understanding. The physical impact was most significant, affecting daily life and causing symptoms like breathing difficulties, coughing, edema, and fatigue. This physical aspect influenced their psychosocial and spiritual lives, cognitive functions, and economic stability, leading to fear, frustration, worry, social isolation, spiritual and cognitive challenges, and employment problems. CONCLUSIONS: The results underscores the need for holistic healthcare approaches, integrating medical, psychological, and social support. Key recommendations include integrated care models, comprehensive patient education, support networks, and policy interventions to enhance HF patient care.

Substituted 4H-3,1-benzoxazine-4-one Derivatives as Inhibitors of Cathepsin G.

BACKGROUND: Cathepsin G (CatG) is a cationic serine protease with a wide substrate specificity. CatG has been reported to play a role in several pathologies, including rheumatoid arthritis, ischemic reperfusion injury, acute respiratory distress syndrome, and cystic fibrosis, among others. OBJECTIVE: We aim to develop a new class of CatG inhibitors and evaluate their potency and selectivity against a series of serine proteases. METHODS: We exploited chemical synthesis as well as chromogenic substrate hydrolysis assays to construct and evaluate the new inhibitors. RESULTS: In this communication, we report on a new class of CatG inhibitors of 4H-3,1-benzoxazin- 4-one derivatives. We constructed a small library of seven substituted 4H-3,1-benzoxazin-4-one derivatives and identified their inhibition potential against CatG. Five molecules were identified as CatG inhibitors with values of 0.84-5.5 µM. Inhibitor 2 was the most potent, with an IC50 of 0.84 ± 0.11 µM and significant selectivity over representative serine proteases of thrombin, factor XIa, factor XIIa, and kallikrein. CONCLUSION: Thus, we propose this inhibitor as a lead molecule to guide subsequent efforts to develop clinically relevant potent and selective CatG inhibitors for use as anti-inflammatory agents.

Pneumoperitoneum, pneumoretroperitoneum and pneumomediastinum: rare complications of perforation peritonitis: a case report.

BACKGROUND: Gas extravasation complications arising from perforated diverticulitis are common but manifestations such as pneumoperitoneum, pneumoretroperitoneum, and pneumomediastinum happening at the same time are exceedingly rare. This case report explores the unique presentation of these 3 complications occurring simultaneously, their diagnosis and their management, emphasizing the importance of interdisciplinary collaboration for accurate diagnosis and effective management. CASE PRESENTATION: A 74-year-old North African female, with a medical history including hypertension, dyslipidemia, type 2 diabetes, goiter, prior cholecystectomy, and bilateral total knee replacement, presented with sudden-onset pelvic pain, chronic constipation, and rectal bleeding. Clinical examination revealed hemodynamic instability, hypoxemia, and diffuse tenderness. After appropriate fluid resuscitation with norepinephrine and saline serum, the patient was stable enough to undergo computed tomography scan. Emergency computed tomography scan confirmed perforated diverticulitis at the rectosigmoid junction, accompanied by the unprecedented presence of pneumoperitoneum, pneumoretroperitoneum, and pneumomediastinum. The patient underwent prompt surgical intervention with colo-rectal resection and a Hartmann colostomy. The postoperative course was favorable, leading to discharge one week after admission. CONCLUSIONS: This case report highlights the clinical novelty of gas extravasation complications in perforated diverticulitis. The unique triad of pneumoperitoneum, pneumoretroperitoneum, and pneumomediastinum in a 74-year-old female underscores the diagnostic challenges and the importance of advanced imaging techniques. The successful collaboration between radiologists and surgeons facilitated a timely and accurate diagnosis, enabling a minimally invasive surgical approach. This case contributes to the understanding of atypical presentations of diverticulitis and emphasizes the significance of interdisciplinary teamwork in managing such rare manifestations.

Role of myeloid cells in ischemic retinopathies: recent advances and unanswered questions.

Myeloid cells including microglia and macrophages play crucial roles in retinal homeostasis by clearing cellular debris and regulating inflammation. These cells are activated in several blinding ischemic retinal diseases including diabetic retinopathy, where they may exert both beneficial and detrimental effects on neurovascular function and angiogenesis. Myeloid cells impact the progression of retinal pathologies and recent studies suggest that targeting myeloid cells is a promising therapeutic strategy to mitigate diabetic retinopathy and other ischemic retinal diseases. This review summarizes the recent advances in our understanding of the role of microglia and macrophages in retinal diseases and focuses on the effects of myeloid cells on neurovascular injury and angiogenesis in ischemic retinopathies. We highlight gaps in knowledge and advocate for a more detailed understanding of the role of myeloid cells in retinal ischemic injury to fully unlock the potential of targeting myeloid cells as a therapeutic strategy for retinal ischemia.

New Triazole-Based Potent Inhibitors of Human Factor XIIa as Anticoagulants.

Factor XIIa (FXIIa) functions as a plasma serine protease within the contact activation pathway. Various animal models have indicated a substantial role for FXIIa in thromboembolic diseases. Interestingly, individuals and animals with FXII deficiency seem to maintain normal hemostasis. Consequently, inhibiting FXIIa could potentially offer a viable therapeutic approach for achieving effective and safer anticoagulation without the bleeding risks associated with the existing anticoagulants. Despite the potential, only a limited number of small molecule inhibitors targeting human FXIIa have been documented. Thus, we combined a small library of 32 triazole and triazole-like molecules to be evaluated for FXIIa inhibition by using a chromogenic substrate hydrolysis assay under physiological conditions. Initial screening at 200 µM involved 18 small molecules, revealing that 4 molecules inhibited FXIIa more than 20%. In addition to being the most potent inhibitor identified in the first round, inhibitor 8 also exhibited a substantial margin of selectivity against related serine proteases, including factors XIa, Xa, and IXa. However, the molecule also inhibited thrombin with a similar potency. It also prolonged the clotting time of human plasma, as was determined in the activated partial thromboplastin time and prothrombin time assays. Subsequent structure-activity relationship studies led to the identification of several inhibitors with submicromolar activity, among which inhibitor 22 appears to demonstrate significant selectivity not only over factors IXa, Xa, and XIa, but also over thrombin. In summary, this study introduces novel triazole-based small molecules, specifically compounds 8 and 22, identified as potent and selective inhibitors of human FXIIa. The aim is to advance these inhibitors for further development as anticoagulants to provide a more effective and safer approach to preventing and/or treating thromboembolic diseases.

Hatchery and Dietary Application of Synbiotics in Broilers: Performance and mRNA Abundance of Ileum Tight Junction Proteins, Nutrient Transporters, and Immune Response Markers.

This study investigated the effects of a synbiotic consisting of inulin, Enterococcus faecium, Pediococcus acidilactici, Bifidobacterium animalis, and Lactobacillus reuteri given orally to day (d)-of-hatch (DOH) broiler chicks at the hatchery and in the feed for a 21 d period. A total of 480 Cobb male broilers were randomly divided into one of four treatments using a 2 × 2 factorial design as follows: (1) control (CTRL) group receiving a gel-only oral application on DOH at the hatchery prior to transport and a non-medicated basal corn/soybean meal starter diet; (2) hatchery synbiotic (HS) receiving an oral gel containing the synbiotic (0.5 mL/bird) at the hatchery and the basal diet; (3) CTRL + dietary synbiotic at 0.5 kg/MT (DS); and (4) HS + dietary synbiotic at 0.5 kg/MT (HSDS). On d 7 and d 21, one bird per pen (eight replicate pens/group) was euthanized, and the ileum was immediately removed for qPCR analysis. Data were subjected to a 2-way ANOVA using GLM procedure (JMP Pro17). A significant diet × hatchery interaction was observed in feed conversion ratio (FCR) from d 14 to d 21 (p = 0.013) where the HS, DS, and HSDS treatments had a significantly lower FCR compared to the CTRL. However, no significant interaction effect was observed for body weight gain (BWG) or FCR during the overall experimental period. No significant interaction was observed in mRNA abundance of the evaluated genes in the ileum on d 7 and d 21. Gel application with the synbiotic significantly reduced sodium-dependent glucose cotransporter 1 (SGLT1) mRNA abundance on d 7 (p = 0.035) in comparison to birds receiving gel alone. Regardless of hatchery application, dietary synbiotic supplementation significantly reduced Toll-like receptor (TLR)2, TLR4, and interleukin (IL)-10 mRNA abundance on d 7 (p = 0.013). In conclusion, these findings showed that hatchery and dietary synbiotic application could have a potential beneficial impact on broiler intestinal immunity by regulating the TLR response, a key element of innate immunity. FCR was improved from d 14 to d 21 after synbiotic application. Future research involving extended grow-out studies with a disease challenge would expand on the implications of an early application of synbiotics.

Revisiting the effect of cholesteryl sulfate on clotting and fibrinolysis: Inhibition of human thrombin and other human blood proteases.

Cholesteryl sulfate (CS) was quantitatively synthesized by microwave-assisted sulfonation of cholesterol followed by sodium exchange chromatography. In vitro effects of CS on human thrombin and other serine proteases of the coagulation and fibrinolysis processes were investigated using a series of biochemical and biophysical techniques. CS was found to inhibit thrombin with an IC50 value of 140.8 ± 21.8 µM at pH 7.4 and 25 ○C. Michaelis-Menten kinetics indicated that thrombin inhibition by CS is non-competitive (allosteric) in nature. Fluorescence-based binding studies indicated that CS binds to thrombin with a KD value of 180.9 ± 18.9 µM. Given the lack of competition with heparins and a hirudin peptide in competitive inhibition assays, it appears that CS does not bind to thrombin's exosites 1 or 2 and it rather recognizes a different allosteric exosite. CS was found to partially inhibit thrombin-mediated fibrinogen activation with an IC50 value of 175.5 ± 17.5 µM and efficacy of ∼26.0 ± 6.6%. Likewise, CS selectively doubled the activated partial thromboplastin time with EC2x of 521 µM. Interestingly, CS was found to also inhibit factors Xa and XIa as well as plasmin with IC50 values of ∼85-250 µM and efficacy of 94-100%. Nevertheless, CS most potently inhibited factor XIIa with an IC50 Value of ∼17 µM and efficacy of 60%. Surprisingly, CS did not inhibit factor IXa. These results encourage further in vitro and in vivo investigation of CS to better understand its (patho-) physiological roles in coagulation and hemostasis.

The multifaceted role of proteases and modern analytical methods for investigation of their catalytic activity.

We discuss the diverse functions of proteases in the context of their biotechnological and medical significance, as well as analytical approaches used to determine the functional activity of these enzymes. An insight into modern approaches to studying the kinetics and specificity of proteases, based on spectral (absorption, fluorescence), mass spectrometric, immunological, calorimetric, and electrochemical methods of analysis is given. We also examine in detail electrochemical systems for determining the activity and specificity of proteases. Particular attention is given to exploring innovative electrochemical systems based on the detection of the electrochemical oxidation signal of amino acid residues, thereby eliminating the need for extra redox labels in the process of peptide synthesis. In the review, we highlight the main prospects for the further development of electrochemical systems for the study of biotechnologically and medically significant proteases, which will enable the miniaturization of the analytical process for determining the catalytic activity of these enzymes.

The Economic Burden of Diabetic Retinopathy in Jordan: Cost Analysis and Associated Factors.

Objective: Diabetic retinopathy (DR) is the leading cause of visual loss worldwide in patients with diabetes mellitus (DM). The aims of our study are to describe the costs associated with (DR) and to evaluate its economic impact in Jordan. Methods: Retrospectively, we included all patients with DM and classified them according to the severity of DR. Data regarding medical history, ophthalmic history, stage of DR, presence of DME, and the ophthalmic procedures and operations were collected. The total DR-related cost was measured as a direct medical cost for the outpatient and inpatient services. Results: Two hundred and twenty-nine patients were included in the study. Only 49.7% of the patients presented without DR, and 21% presented with diabetic macular edema (DME) unilaterally or bilaterally. The DR-related cost was significantly associated with insulin-based regimens, longer duration of DM, higher HbA1c levels, worse stage of DR at presentation, the presence of DME at presentation, the presence of glaucoma, and increased mean number of intravitreal injections, laser sessions, and surgical operations. Multivariate analysis should the presenting stage of DR, presence of DME, and the presence of DME be the independent factors affecting the DR-related cost. Conclusion: This study is the first study to be conducted in Jordan and encourages us to establish a screening program for DR for earlier detection and treatment. DM control and treatment compliance will reduce the heavy costs of the already exhausted healthcare and financial system.

Performance, fatty acid composition, and liver fatty acid metabolism markers of broilers fed genetically modified soybean DP-3Ø5423-1.

Several genetically modified (GM) plants have been produced and approved by regulatory agencies worldwide for cultivation and commercialization. Soybean and its by-products are major components of poultry diets and approximately 74% of world production is obtained from GM soybean events. The aim of this study was to evaluate the nutrient composition of DP-3Ø5423-1 extruded full-fat soybean meal (FFSBM) and near isoline non-GM control FFSBM included in broiler diets. Also assessed were their effects on bird performance, body composition, intestinal morphology, tissue fatty acid profile, and mRNA abundance of fatty acid metabolism markers. A total of 480 Ross 308 d of hatch birds were randomly allocated to 24 floor pens in a 2 × 2 factorial arrangement with diet and gender as main factors. Birds were fed diets containing 20% of either DP-3Ø5423-1 or control FFSBM for 35 d. Data were subjected to a 2-way ANOVA using the GLM procedure of JMP (Pro13). No significant interaction (P > 0.05) was observed between treatment groups in terms of performance and carcass composition. Morphological measurements of the jejunum and ileum were not influenced by the SBM treatments. Dietary addition of the DP-3Ø5423-1 FFSBM resulted in higher monounsaturated fatty acid composition of the thigh muscle and abdominal fat. Moreover, dietary treatment had no significant impact on the mRNA abundance of metabolic markers ACCα, FAS, MTTP, SREBP1, PPARα, PPARγ, AMPK-α1, SOD, CAT, and GPx in the liver. In conclusion, our results showed that DP-3Ø5423-1 extruded FFSBM is nutritionally equivalent to non-GM near-isoline counterpart with a comparable genetic background as evidenced by feed analyses except for fatty acid composition. Furthermore, the findings of this study clearly indicate that the examined DP-3Ø5423-1 FFSBM yields similar bird performance as conventional FFSBM.

Fellowship Accreditation: Experiences From Health Care Simulation Experts.

Background The field of health care simulation continues to grow, accompanied by a proliferation of fellowship programs, leading to fellowship accreditation efforts. There is controversy around the best approach to accreditation. Objective The authors sought to understand perspectives of simulation leaders on fellowship accreditation to best inform the growth and maturation of fellowship accreditation. Methods In 2020, simulation leaders identified through snowball sampling were invited to participate in a qualitative study. During one-on-one semistructured interviews, participants were asked about experiences as simulation leaders and their perspective on the purpose and impact of accreditation. The interviews were audio recorded and transcribed. Thematic analysis informed by a phenomenology framework was performed using a masked open coding technique with iterative refinement. The resulting codes were organized into themes and subthemes. Results A total of 45 simulation experts participated in interviews ranging from 25 to 67 minutes. Participants described discord and lack of consensus regarding simulation fellowship accreditation, which included a spectrum of opinions ranging from readiness for accreditation pathways to concern and avoidance. Participants also highlighted how context drove the perception of accreditation value for programs and individuals, including access to resources and capital. Finally, potential impacts from accreditation included standardization of training programs, workforce concerns, and implications for professional societies. Conclusions Simulation leaders underscored how the value of accreditation is dependent on context. Additional subthemes included reputation and resource variability, balancing standardization with flexibility and innovation, and implications for professional societies.

Varying conjunctival immune response adaptations of house finch populations to a rapidly evolving bacterial pathogen.

Pathogen adaptations during host-pathogen co-evolution can cause the host balance between immunity and immunopathology to rapidly shift. However, little is known in natural disease systems about the immunological pathways optimised through the trade-off between immunity and self-damage. The evolutionary interaction between the conjunctival bacterial infection Mycoplasma gallisepticum (MG) and its avian host, the house finch (Haemorhous mexicanus), can provide insights into such adaptations in immune regulation. Here we use experimental infections to reveal immune variation in conjunctival tissue for house finches captured from four distinct populations differing in the length of their co-evolutionary histories with MG and their disease tolerance (defined as disease severity per pathogen load) in controlled infection studies. To differentiate contributions of host versus pathogen evolution, we compared house finch responses to one of two MG isolates: the original VA1994 isolate and a more evolutionarily derived one, VA2013. To identify differential gene expression involved in initiation of the immune response to MG, we performed 3'-end transcriptomic sequencing (QuantSeq) of samples from the infection site, conjunctiva, collected 3-days post-infection. In response to MG, we observed an increase in general pro-inflammatory signalling, as well as T-cell activation and IL17 pathway differentiation, associated with a decrease in the IL12/IL23 pathway signalling. The immune response was stronger in response to the evolutionarily derived MG isolate compared to the original one, consistent with known increases in MG virulence over time. The host populations differed namely in pre-activation immune gene expression, suggesting population-specific adaptations. Compared to other populations, finches from Virginia, which have the longest co-evolutionary history with MG, showed significantly higher expression of anti-inflammatory genes and Th1 mediators. This may explain the evolution of disease tolerance to MG infection in VA birds. We also show a potential modulating role of BCL10, a positive B- and T-cell regulator activating the NFKB signalling. Our results illuminate potential mechanisms of house finch adaptation to MG-induced immunopathology, contributing to understanding of the host evolutionary responses to pathogen-driven shifts in immunity-immunopathology trade-offs.

Fate of transgenic soybean DNA and immune response of broilers fed genetically modified DP-3Ø5423-1 soybean.

Increased use of genetically modified (GM) plants in the food and feed industry has raised several concerns about the presence of unwanted genes in the food chain and potential associated health risks. In recent years, several studies have compared the nutrient contents of GM crops to conventional counterparts, and some have also tracked the fate of novel DNA fragments and proteins in the gastrointestinal (GIT) and their presence in several tissues. This study was conducted to investigate the fate of transgenic PHP19340A DNA fragment containing gm-fad2-1 (Soybean Event DP-3Ø5423-1) gene in digestive tract contents, blood, internal organs, and muscle tissues. The effects of feeding DP-3Ø5423-1 full-fat soybean meal (FFSBM) to broiler chickens on immune response and blood profiles were also evaluated on d 35. Day-old Ross 308 birds (n = 480) were randomly allocated to 24 floor pens in a 2 × 2 factorial arrangement with diet and gender as main factors. Birds were fed diets containing 20% of either DP-3Ø5423-1 or non-GM FFSBM for 35 d. Data were subjected to a 2-way ANOVA using the GLM procedure of JMP (Pro13). Based on PCR analysis, transgenic PHP19340A DNA fragment containing gm-fad2-1 gene was degraded throughout the digestive system to reach undetectable level in the cecal digesta. Moreover, there was no transgenic gene translocation to blood, organs, or muscle tissue. Feeding DP-3Ø5423-1 FFSBM to broilers had no effect on mRNA abundance of IL-1ß, IL-2, IL-6, IL-12B, IL-17A, IFNγ, TNFα, and NF-κB in the spleen or on blood profile. In conclusion, these findings indicate that the examined transgenic fragment in DP-3Ø5423-1 FFSBM progressively degraded in the GIT and did not translocate into blood or tissues. Along with the immune response and blood profile findings, it can be assumed that DP-3Ø5423-1 soybean is safe and unlikely to pose any health risks to broilers or consumers.

Future is Brighter: New Potential Paradigm-Shifting Medications and Regimens for Diabetes and Obesity.

Diabetes is a chronic illness that can become debilitating owing to its microvascular and macrovascular complications. Its prevalence is increasing and so is its cost. Diabetes, particularly type 2, appears to have a very close relationship with obesity. While lifestyle modifications, exercises, and current therapeutics have substantially improved clinical outcomes, the need for new therapeutics and regimens continue to exist. Several new medications and regimens for diabetes, obesity, and diabesity are showing promising results in advanced clinical trials. For type 1 diabetes mellitus (T1DM), they include teplizumab, ustekinumab, jakinibs, and cell therapies, whereas for type 2 diabetes mellitus (T2DM), they include once-weakly insulin, tirzepatide, high oral dose of semaglutide, orforglipron, retatrutide, CagriSema, and survodutide. Given their structural and mechanistic diversity as well as their substantial efficacy and safety profiles, these medications and regimens are paradigm shifting and promise a brighter future. They will likely enable better disease prevention and management. This review will provide details about each of the above strategies to keep the scientific community up to date about progress in the fields of diabetes and obesity.

Triple Action of Lignosulfonic Acid Sodium: Anti-protease, Antioxidant, and Anti-inflammatory Effects of a Polymeric Heparin Mimetic.

BACKGROUND: Heparins are sulfated glycosaminoglycans that are used as anticoagulants to treat thrombosis. Heparins exhibit other potential therapeutic effects, such as anti-inflammatory, anti-viral, and anti-malarial effects. However, the strong anticoagulant activity of heparins poses a risk of life-threatening bleeding, limiting their therapeutic use for other diseases beyond thrombosis. To exploit the other effects of heparins and eliminate the bleeding risk, we explored an alternative polymer called lignosulfonic acid sodium (LSAS), which acts as a sulfonated heparin mimetic. LSAS targets factor XIa to exert an anticoagulant effect, and thus, unlike heparins, it is unlikely to cause bleeding. METHODS: This study investigated the multiple effects of LSAS to identify potential leads for complex pathologies treatment. A series of chromogenic substrate hydrolysis assays were used to evaluate the inhibition of three inflammation-related proteases by LSAS. Its chemical antioxidant activity against the system of ABTS/hydrogen peroxide/metmyoglobin was also determined. Lastly, the effect of LSAS on TNFα-induced activation of the NF-κB pathway in HEK-293 cells was also tested to determine its cellular anti-inflammatory activity. RESULTS: The results showed that LSAS effectively inhibited human neutrophil elastase, cathepsin G, and plasmin, with IC50 values ranging from 0.73 to 212.5 µg/mL. Additionally, LSAS demonstrated a significant chemical antioxidant effect, with an IC50 value of 44.1 µg/mL. Furthermore, at a concentration of approximately 530 µg/mL, LSAS inhibited the TNFα-induced activation of the NF-κB pathway in HEK-293 cells, indicating a substantial anti-inflammatory effect. An essential advantage of LSAS is its high water solubility and virtual non-toxicity, making it a safe and readily available polymer. CONCLUSION: Based on these findings, LSAS is put forward as a polymeric heparin mimetic with multiple functions, serving as a potential platform for developing novel therapeutics to treat complex pathologies.

Bielectrode Strategy for Determination of CYP2E1 Catalytic Activity: Electrodes with Bactosomes and Voltammetric Determination of 6-Hydroxychlorzoxazone.

We describe a bielectrode system for evaluation of the electrocatalytic activity of cytochrome P450 2E1 (CYP2E1) towards chlorzoxazone. One electrode of the system was employed to immobilize Bactosomes with human CYP2E1, cytochrome P450 reductase (CPR), and cytochrome b5 (cyt b5). The second electrode was used to quantify CYP2E1-produced 6-hydroxychlorzoxazone by its direct electrochemical oxidation, registered using square-wave voltammetry. Using this system, we determined the steady-state kinetic parameters of chlorzoxazone hydroxylation by CYP2E1 of Bactosomes immobilized on the electrode: the maximal reaction rate (Vmax) was 1.64 ± 0.08 min-1, and the Michaelis constant (KM) was 78 ± 9 µM. We studied the electrochemical characteristics of immobilized Bactosomes and have revealed that electron transfer from the electrode occurs both to the flavin prosthetic groups of CPR and the heme iron ions of CYP2E1 and cyt b5. Additionally, it has been demonstrated that CPR has the capacity to activate CYP2E1 electrocatalytic activity towards chlorzoxazone, likely through intermolecular electron transfer from the electrochemically reduced form of CPR to the CYP2E1 heme iron ion.