Cationic lignin as an efficient and sustainable homogenous catalyst for aqueous Knoevenagel condensation reactions.

Knoevenagel condensation is a chemical reaction between aldehydes and active methylene-containing compounds in the presence of heterogeneous, basic homogenous organic or inorganic catalysts and solvent or neat systems. Herein, we introduced a new strategy for this synthesis by using the aqueous solution of cationic kraft lignin (CKL) as a catalyst. The CKL was synthesized through the reaction of kraft lignin (KL) with glycidyltrimethylammonium chloride (GTMAC) in a basic medium. The optimal reaction conditions for the Knoevenagel reaction were 5% catalyst load (weight of catalyst to the weight of benzaldehyde), water as the solvent, and at room temperature, which generated the products with a yield of 97%, illustrating that the CKL was an effective homogenous and green catalyst. The results confirmed that the increase in CKL charge density improved the product yield. The water-insoluble products were easily separated by filtration, and the filtrate containing the catalysts was reused effectively for 5 cycles without a significant decrease in the production yield, which would confirm the advantages of this catalyst for this reaction system. The CKL catalyst exhibited biodegradability comparable to KL. This paper discusses a novel method for Knoevenagel condensation reactions for different aldehydes in a green system utilizing a sustainable, biodegradable catalyst at room temperature and in an aqueous system.

Effects of Partial Replacement of Corn Grains With Mango Seed Kernel on Nutrient Digestibility, Blood Metabolites and Rumen Parameters of Growing Calves.

Fruit by-products are a sustainable and cost-effective alternative to traditional grain feed for livestock. One of the most important by-products is mango seed kernel (MSK), which can be used as a valuable energy source for feeding growing calves in the tropical and subtropical productive regions of the world. This study investigated the effect of replacing corn grains (CGs) with MSK on intake, nutrient digestibility, blood metabolites and rumen parameters. Eighteen growing male Friesian calves (200 ± 6.55 kg of body weight and 9-11 months old) were randomly assigned to three treatment groups. Three concentrate feed mixtures were formulated such that MSK replaced CG at 0%, 25% and 50%. Dry matter intake was unaffected, whereas dry matter, organic matter and fibre digestibility increased linearly (p < 0.05) with increased inclusion of MSK. Ruminal pH (p = 0.053) and total volatile fatty acid (VFA) concentration (p = 0.041) increased linearly. There was a linear decrease in cholesterol (p = 0.029) and AST (p = 0.028) levels in the blood of calves. In conclusion, this study demonstrated the positive effect of replacing 50% of CG with MSK on rumen parameters, including a higher ruminal pH and total VFA concentration, alongside higher nutrient digestibility. The dietary inclusion of mango seed can serve as a valuable and sustainable dietary component for growing calves.

Endoplasmic reticulum stress is involved in mycotoxin zearalenone induced inflammatory response, proliferation, and apoptosis in goat endometrial stromal cells.

Zearalenone (ZEA) is an estrogen-like mycotoxin and is considered a secondary metabolite produced by Fusarium fungi, which are widely found in the surrounding environment. ZEA has been found to cause reproductive dysfunction in female and male animals, but the underlying mechanism remains unclear. Therefore, this study examined cell proliferation, cell apoptosis, autophagy protein expression, and some inflammatory cytokines such as IL-1ß and IL-8 of goat endometrial stromal cells (ESCs) induced by different concentrations (0, 15, 30, 60, and 90 µM) of ZEA. The apoptosis rate was detected by flow cytometry. Western Blot and ELISA assay were used to identify the ER stress signaling pathway and some inflammatory cytokines. Our results revealed that ZEA induced cell proliferation and inhibited cell apoptosis at low and middle concentrations, while at high concentrations of ZEA, cell apoptosis was induced in ESCs. Additionally, ZEA induced the ER stress protein markers such as ATF6, IRE1α, EIF2α, and ATF4. LC3 as a marker of autophagy was up-regulated at all concentrations of ZEA. Moreover, IL-1ß and IL-8 showed down-regulation at a low concentration of ZEA, but middle and high concentrations showed up-regulation. In the present study, Knockdown ERN1 can inhibit autophagy and the main markers of ER stress. These results suggest that the IRE1 pathway can reduce apoptosis protein markers, down activate IRE1, and unfolded protein response branches such as ATF6 and LC3 in ESCs. Additionally, IL-1ß and IL-8 achieve up-regulation under knockdown IRE1, which can block ER stress markers.

Risk of developing inflammatory arthritis in patients with psoriasis initiating treatment with biologics: A population-based analysis.

BACKGROUND: The relationship between biologic treatments for psoriasis (PsO) and the development of inflammatory arthritis in patients is not fully understood. OBJECTIVE: The objective of this study was to analyze the effects of biologic treatment on the development of inflammatory arthritis in patients with PsO. METHODS: This retrospective study assessed patients with PsO identified in the Optum Clinformatics Data Mart database from Jan 2007 to Mar 2023 with no baseline diagnosis of inflammatory arthritis. Patients were stratified based on the class of initial biologic treatment (interleukin [IL] 23, IL-12/23, IL-17, or tumor necrosis factor [TNF] inhibitor) and followed for up to 3 years or development of inflammatory arthritis. Risk of developing inflammatory arthritis was assessed using a multivariate Cox proportional hazard model using IL-23 inhibitors as reference. RESULTS: Incidence rates of developing inflammatory arthritis expressed as events/100 person-years were 4.99, 7.29, 6.06, and 9.39 for IL-23, IL-17, IL-12/23, and TNF inhibitors, respectively. Adjusted hazard ratios were significantly higher for patients receiving IL-17 (1.44; P = .0294) and TNF (1.90; P < .0001) inhibitors when compared with patients receiving IL-23 inhibitors. LIMITATIONS: Limitations include those associated with medical coding errors and the potential for protopathic bias. CONCLUSION: Patients receiving IL-23 inhibitors are at lower risk of developing inflammatory arthritis or psoriatic arthritis than those receiving IL-17 and TNF inhibitors.

An Investigation on the Potential of Utilizing Aluminum Alloys in the Production and Storage of Hydrogen Gas.

The interest in hydrogen is rapidly expanding because of rising greenhouse gas emissions and the depletion of fossil resources. The current work focuses on employing affordable Al alloys for hydrogen production and storage to identify the most efficient alloy that performs best in each situation. In the first part of this work, hydrogen was generated from water electrolysis. The Al alloys that are being examined as electrodes in a water electrolyzer are 1050-T0, 5052-T0, 6061-T0, 6061-T6, 7075-T0, 7075-T6, and 7075-T7. The flow rate of hydrogen produced, energy consumption, and electrolyzer efficiency were measured at a constant voltage of 9 volts to identify the Al alloy that produces a greater hydrogen flow rate at higher process efficiency. The influence of the electrode surface area and water electrolysis temperature were also studied. The second part of this study examines these Al alloys' resistance to hydrogen embrittlement for applications involving compressed hydrogen gas storage, whether they are utilized as the primary vessel in Type 1 pressure vessels or as liners in Type 2 or Type 3 pressure vessels. Al alloys underwent electrochemical charging by hydrogen and Charpy impact testing, after which a scanning electron microscope (SEM) was used to investigate the fracture surfaces of both uncharged and H-charged specimens. The structural constituents of the studied alloys were examined using X-ray diffraction analysis and were correlated to the alloys' performance. Sensitivity analysis revealed that the water electrolysis temperature, electrode surface area, and electrode material type ranked from the highest to lowest in terms of their influence on improving the efficiency of the hydrogen production process. The 6061-T0 Al alloy demonstrated the best performance in both hydrogen production and storage applications at a reasonable material cost.

A Complex Interplay of Tumor Microenvironment Could Enhance Cholangiocarcinoma Progression Even After Surgery: A Prospective Study.

Background: The current study was conducted to explore the impact of macrophages and programmed cell death protein 1 (PD-1) expression on tumor-infiltrating lymphocytes (TILs) on treatment outcomes and to define the interaction between these factors and the clinicopathologic features of advanced cholangiocarcinoma (CCA) patients. Methods: Twenty-five patients with metastatic CCA were recruited for the current study from El-Rajhi Hospital and the Clinical Oncology Department of Assiut University. Additionally, 19 healthy controls were included. Before the flow cytometric detection of immune cells, the diagnosis and staging of CCA were performed based on surgical intervention, imaging, carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) determinations. This was followed by flow cytometric detection of CD4+, CD8+, CD4+PD-1+, CD8+PD-1+, and CD11b+CD68+ macrophages in the peripheral blood of both patients and controls. Results: The current results revealed higher levels of CD4+, CD8+, and CD11b+CD68+ macrophages in controls compared to patients. At the same time, PD-1 expression was significantly higher in patients compared to controls. CD4+ was correlated with improved progression-free survival (PFS), while CD8+PD-1 was associated with shorter PFS. In general, CD4+ and CD8+ levels progressively increased with improved response to treatments, differentiation, single organ site metastasis, and surgical interventions. On the contrary, PD-1 expression and macrophages progressively increased with worsening response, dedifferentiation, multiple organ sites, and surgical interventions. The median PFS was 12 months, and the mean ± standard error (SE) was 13.1 ± 1.3. Conclusions: CCA has a desmoplastic microenvironment with complex immunologic topography and tumor-reactive stroma. The immune landscape of the peripheral blood mononuclear cells (PBMCs) in CCA patients before treatment could reflect the state of systemic immune function and response to treatments. Our results revealed that T-lymphocytes correlated with better prognosis while macrophages and PD-1+ expression were associated with poor outcomes.

Dose escalation and associated economic outcomes in patients with psoriasis treated with biologics: A retrospective analysis of German health claims data.

BACKGROUND: In Germany, several biologic therapies are available for the treatment of moderate-to-severe plaque psoriasis, with the option of exceeding recommended dosages if standard dosing does not achieve a satisfactory treatment response. OBJECTIVES: To examine dose escalation in patients with biologic-treated psoriasis and associated cost development for German statutory health insurance (SHI). METHODS: We conducted a retrospective, non-interventional cohort study using German SHI health claims data from 2016 to 2021. Adult patients initiating biologic treatment were included in drug-specific cohorts. The odds for dose escalation, defined as the exceedance of the individually received daily dose over the maintenance dose recommended by the European product information, was compared between cohorts using multivariate logistic regression. The impact of dose escalation on SHI expenditures was analyzed with a generalized linear model. RESULTS: The relative frequency of dose escalation varied between cohorts (range 1.1% [risankizumab] to 42.9% [infliximab]). Compared to risankizumab-treated patients, the odds for dose escalation were statistically significantly (p < 0.05) higher in patients treated with all other biologic drugs except tildrakizumab. Patients with dose escalation during the maintenance phase accrued on average €6,473 more in direct healthcare costs to the SHI over a one-year period compared to those without dose escalation, with statistical significance (p < 0.05) after controlling for differences in covariates. CONCLUSIONS: Compared to patients treated with other biologics, dose escalation during the maintenance phase was lowest among risankizumab-treated patients. Dose escalation was associated with higher costs and thus a higher economic burden for the German SHI.

Accuracy of self-reported treated hypertension in the women's health initiative: Comparisons with medication inventories.

Few studies have reported on the accuracy of self-reported hypertension history among older postmenopausal women, which was this study's objective. Participants were postmenopausal women enrolled in the Osteoporosis and Periodontal Disease (OsteoPerio) study, an ancillary investigation of the Women's Health Initiative Observational Study (WHI-OS) at the Buffalo, New York, clinical site. Participants self-reported their history of physician diagnosed hypertension treated with medication at WHI-OS enrollment (1993-1998; n = 1342, mean age 63 years), then 3 years later at OsteoPerio enrollment (1997-2001; n = 1342), and again at OsteoPerio Year 5 follow-up (2002-2005; n = 1020). At each time point, medication inventories were recorded and served as the criterion with which self-report was compared in the present study. Physician diagnosed-treated hypertension was also self-reported annually on mailed health update questionnaires in the WHI-OS and were compared against medication inventory at the subsequent clinic exam. Of those participants who self-reported a history of hypertension at WHI enrollment, OsteoPerio enrollment, and OsteoPerio Year 5 follow-up, 41.2%, 90.3%, and 94.4%, respectively, had anti-hypertensive pills in their medication inventory. Across the three time points, sensitivity and specificity ranged from 0.72 to 0.98 and from 0.85 to 0.95, and kappa coefficients ranged from 0.52 to 0.79 when comparing self-report with medication inventory. For self-reported newly physician-diagnosed and treated hypertension on the annual health update questionnaire, 88.4% and 95.2% of those reporting hypertension had anti-hypertensive pills in the subsequent medication inventory. In general, sensitivity and kappa were lower in women aged ≥70 versus < 70 years and in those with history of cardiovascular disease and diabetes compared to those without these comorbidities. In this cohort of postmenopausal women, self-reported physician diagnosed and treated hypertension demonstrated moderate to high accuracy when compared against anti-hypertensive medication use documented by pill inventory, particularly for those who were younger and managing fewer comorbidities.

How Intravesical Platelet-Rich Plasma Can Help Patients with Interstitial Cystitis/Bladder Pain Syndrome: A Comprehensive Scoping Review.

INTRODUCTION AND HYPOTHESIS: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition characterized by chronic inflammation that affects the bladder. The study was aimed at evaluating the effectiveness of intravesical platelet-rich plasma (PRP) injections in patients with IC/BPS. METHODS: We conducted a comprehensive search strategy to involve studies that investigate the efficacy of intravesical PRP injections or instillations over different time intervals. Various outcome measures were assessed, including pain scores, functional outcomes, urodynamic parameters, and surface expressions on the urothelium. RESULTS: Our search strategy revealed 1,125 studies. After screening, ten articles met the inclusion criteria. Intravesical PRP significantly reduced the visual analog scale (VAS) compared with baseline scores. Several clinical trials reported significant improvements in the global response rate (GRA), O'Leary-Sant Symptom (OSS) questionnaire, Interstitial Cystitis Symptom Index (ICSI), and Interstitial Cystitis Problem Index (ICPI). Urodynamic parameters such as maximum flow rate (Qmax) and post-voiding residual (PVR) showed significant improvements in some studies. CONCLUSION: The study concluded that intravesical PRP injections could be a promising effective treatment option for IC/BPS patients by their significant ability to reduce pain. However, improvement of urodynamic and functional outcomes is still not clear. Further large comparative trials are still warranted to assess the efficacy of PRP instillation.

Immune-Mediated and Psychiatric Comorbidities Among Patients Newly Diagnosed With Alopecia Areata.

Importance: Alopecia areata (AA) has been associated with multiple comorbidities, yet information regarding the timing of comorbidity development after AA diagnosis is limited. Objective: To evaluate the prevalence and new-onset incidence of psychiatric and autoimmune comorbidities in patients with AA in the US. Design, Setting, and Participants: This retrospective cohort analysis used data collected from January 1, 2007, to April 30, 2023, from the Merative MarketScan Research Databases, which contains medical and drug claims data from more than 46 million patients in the US. Data from adolescent and adult patients (aged 12-64 years) diagnosed with AA and patients without AA (ie, controls) were evaluated. For some analyses, patients with AA were matched (1:4) to controls based on sex, age, and geographic region. Main Outcomes and Measures: Prevalence (at the time of AA diagnosis) and incidence (new onset after AA diagnosis) of psychiatric and autoimmune diseases were reported as percentage of patients. Risk of developing a new-onset psychiatric or autoimmune disease after AA diagnosis was calculated as adjusted hazard ratios (AHRs) with 95% CIs. Results: At baseline, 63 384 patients with AA and 3 309 107 without AA were identified. After matching, there were 16 512 and 66 048 patients in the AA and control groups, respectively, with a mean (SD) age of 36.9 (13.4) years and 50.6% of whom were female. Compared with the unmatched controls, patients with AA had higher prevalence of psychiatric (30.9% vs 26.8%; P < .001) and autoimmune (16.1% vs 8.9%; P < .0001) comorbidities at AA diagnosis; incidence was also higher in patients with AA (without history of these comorbidities) vs the matched control group. Patients with AA vs controls had a significantly higher risk of developing a psychiatric (AHR, 1.3; 95% CI, 1.3-1.4) or autoimmune (AHR, 2.7; 95% CI, 2.5-2.8) comorbidity. Conclusions and Relevance: In this cohort study, patients with AA had a higher prevalence of autoimmune and psychiatric comorbidities at AA diagnosis and demonstrated an elevated risk of new-onset autoimmune and psychiatric comorbidities after their diagnosis. These data highlight the most common comorbidities among patients with AA and may help physicians counsel and monitor patients newly diagnosed with AA.

Green, facile synthesis and evaluation of unsymmetrical carbamide derivatives as antimicrobial and anticancer agents with mechanistic insights.

A very practical method for the synthesis of unsymmetrical carbamide derivatives in good to excellent yield was presented, without the need for any catalyst and at room temperature. Using a facile and robust protocol, fifteen unsymmetrical carbamide derivatives (9-23) bearing different aliphatic amine moieties were designed and synthesized by the reaction of secondary aliphatic amines with isocyanate derivatives in the presence of acetonitrile as an appropriate solvent in good to excellent yields. Trusted instruments like IR, mass spectrometry, NMR spectra, and elemental analyses were employed to validate the purity and chemical structures of the synthesized compounds. All the synthesized compounds were tested as antimicrobial agents against some clinically bacterial pathogens such as Salmonella typhimurium, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Compounds 15, 16, 17, 19 and 22 showed potent antimicrobial activity with promising MIC values compared to the positive controls. Moreover, compounds 15 and 22 provide a potent lipid peroxidation (LPO) of the bacterial cell wall. On the other hand, we investigated the anti-proliferative activity of compounds 9-23 against selected human cancerous cell lines of breast (MCF-7), colon (HCT-116), and lung (A549) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti- and pro-apoptotic protein markers. The results of MTT assay revealed that compounds 10, 13, 21, 22 and 23 possessed highly cytotoxic effects. Out of these, three synthesized compounds 13, 21 and 22 showed cytotoxicity with IC50 values (13, IC50 = 62.4 ± 0.128 and 22, IC50 = 91.6 ± 0.112 µM, respectively, on MCF-7), (13, IC50 = 43.5 ± 0.15 and 21, IC50 = 38.5 ± 0.17 µM, respectively, on HCT-116). Cell cycle and apoptosis/necrosis assays demonstrated that compounds 13 and 22 induced S and G2/M phase cell cycle arrest in MCF-7 cells, while only compound 13 had this effect on HCT-116 cells. Furthermore, compound 13 exhibited the greatest potency in inducing apoptosis in both cell lines compared to compounds 21 and 22. Docking studies indicated that compounds 10, 13, 21 and 23 could potentially inhibit enzymes and exert promising antimicrobial effects, as evidenced by their lower binding energies and various types of interactions observed at the active sites of key enzymes such as Sterol 14-demethylase of C. albicans, Dihydropteroate synthase of S. aureus, LasR of P. aeruginosa, Glucosamine-6-phosphate synthase of K. pneumenia and Gyrase B of B. subtilis. Moreover, 13, 21, and 22 demonstrated minimal binding energy and favorable affinity towards the active pocket of anticancer receptor proteins, including CDK2, EGFR, Erα, Topoisomerase II and VEGFFR. Physicochemical properties, drug-likeness, and ADME (absorption, distribution, metabolism, excretion, and toxicity) parameters of the selected compounds were also computed.

1 Million Segmented Red Blood Cells With 240 K Classified in 9 Shapes and 47 K Patches of 25 Manual Blood Smears.

Around 20% of complete blood count samples necessitate visual review using light microscopes or digital pathology scanners. There is currently no technological alternative to the visual examination of red blood cells (RBCs) morphology/shapes. True/non-artifact teardrop-shaped RBCs and schistocytes/fragmented RBCs are commonly associated with serious medical conditions that could be fatal, increased ovalocytes are associated with almost all types of anemias. 25 distinct blood smears, each from a different patient, were manually prepared, stained, and then sorted into four groups. Each group underwent imaging using different cameras integrated into light microscopes with 40X microscopic lenses resulting in total 47 K + field images/patches. Two hematologists processed cell-by-cell to provide one million + segmented RBCs with their XYWH coordinates and classified 240 K + RBCs into nine shapes. This dataset (Elsafty_RBCs_for_AI) enables the development/testing of deep learning-based (DL) automation of RBCs morphology/shapes examination, including specific normalization of blood smear stains (different from histopathology stains), detection/counting, segmentation, and classification. Two codes are provided (Elsafty_Codes_for_AI), one for semi-automated image processing and another for training/testing of a DL-based image classifier.

Molecular detection and characterization of Anaplasma marginale and Babesia canis vogeli infecting dogs in Luxor, Egypt.

Tick-borne diseases in animals are increasing rapidly worldwide, but there is insufficient information about tick-borne diseases infecting dogs in southern Egypt. Thus, in the current study, we detected the presence of Anaplasma marginale (A. marginale) and Babesia canis vogeli (B. canis vogeli) in the blood of dogs. The results revealed that 4/100 (4%) were positive, and a higher infection rate was found in males (75%), than females (25%). The phylogenetic analysis for the major surface protein 4 (msp4) gene in this study was compared with amplicons separate from other reported isolates with alignment by identity 100% with cattle and camels from Egypt, and the phylogenetic analysis for the B. canis vogeli small subunit ribosomal RNA (SSU rRNA) gene in this study identified identity by 99.89% with dogs from Egypt. This report is considered the first report in southern Egypt about A. marginale in dogs based on the sequence analysis of the msp4 gene, providing new data for the classification and identification of A. marginale in dogs compared to A. marginale isolated from other animals in southern Egypt.

A Core NRF2 Gene Set Defined Through Comprehensive Transcriptomic Analysis Predicts Selective Drug Resistance and Poor Multicancer Prognosis.

Aims: The nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (NRF2-KEAP1) pathway plays an important role in the cellular response to oxidative stress but may also contribute to metabolic changes and drug resistance in cancer. However, despite its pervasiveness and important role, most of nuclear factor erythroid 2-related factor 2 (NRF2) target genes are defined in context-specific experiments and analysis, making it difficult to translate from one situation to another. Our study investigates whether a core NRF2 gene signature can be derived and used to represent NRF2 activation in various contexts, allowing better reproducibility and understanding of NRF2. Results: We define a core set of 14 upregulated NRF2 target genes from 7 RNA-sequencing datasets that we generated and analyzed. This NRF2 gene signature was validated using analyses of published datasets and gene sets. An NRF2 activity score based on expression of these core target genes correlates with resistance to drugs such as PX-12 and necrosulfonamide but not to paclitaxel or bardoxolone methyl. We validated these findings in our Kelch-like ECH-associated protein 1 (KEAP1) knockout cancer cell lines. Finally, our NRF2 score is prognostic for cancer survival and validated in additional independent cohorts for lung adenocarcinoma and also novel cancer types not associated with NRF2-KEAP1 mutations such as clear cell renal carcinoma, hepatocellular carcinoma, and acute myeloid leukemia. Innovation and Conclusions: These analyses define a core NRF2 gene signature that is robust, versatile, and useful for evaluating NRF2 activity and for predicting drug resistance and cancer prognosis. Using this gene signature, we uncovered novel selective drug resistance and cancer prognosis associated with NRF2 activation.

Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: twelve months of an ongoing randomized phase 3 trial.

BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol/0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN: This ongoing, 48-month, phase 3 study consists of a 12-month double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The coprimary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy vs placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% vs 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% vs 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was <1% and was attenuated compared with bone loss observed with elagolix monotherapy.

Development of a small animal model replicating core characteristics of takotsubo syndrome in humans.

Aims: Adequate animal models are necessary to understand human conditions, such as takotsubo syndrome (TS) characterized by the heart's transient regional wall motion abnormalities. This study aims to develop a reproducible, low-mortality TS model that closely mimics the human condition and addresses the limitations of existing models. Methods and results: We conducted six experiments using 309 Sprague Dawley rats, each approximately 300 g and aged 7-8 weeks. Initially, we replicated an established model using intraperitoneal isoprenaline injections. Subsequent experiments varied the doses and infusion durations of intravenous isoprenaline and assessed the effects of sex, strain, and breeder on the development of reversible akinetic segments. High-resolution echocardiography monitored the regional wall motion over 30 days to correlate with histological changes. Increasing the isoprenaline dose and the infusion time significantly enhanced akinesia (P < 0.01), resulting in pronounced apical ballooning observed in three-dimensional imaging. Akinesia peaked at 6 h post-infusion, with recovery observed at 24 h; most rats recovered from akinetic segments within 48-72 h. Optimizing the mode of administration, dose, and duration achieved a TS-like phenotype in 90% of cases, with a 16.7% mortality rate. Histological examinations confirmed that myocardial injury occurred, independent of apical ballooning. Conclusion: This study presents a refined TS model that reliably replicates the syndrome's key features, including morphological and electrocardiographic changes, demonstrating its transient nature with high fidelity and reduced mortality. The model's reproducibility, evidenced by consistent results across trials, suggests its potential for broader application pending further validation.