bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetic/target engagement modelling of tozorakimab in healthy volunteers and patients with chronic obstructive pulmonary disease
Authors: Sadiq Muhammad Waqas , Yu Hongtao , Åstrand Magnus , Scott Ian C. , Williams Adam , Hewitt Lisa , White Nicholas , Killick Helen , Gavala Monica , Cohen E. Suzanne , Reid Fred , Kell Chris , Pandya Hitesh , Jimenez Eulalia 
Published: August 2024

AbstractAimsThis study describes the pharmacokinetic (PK)/target engagement (TE) relationship of tozorakimab, an anti‐interleukin (IL)‐33 antibody, by building a mechanistic population PK/TE model using phase 1 biomarker data.MethodsThe analysis included tozorakimab PK and TE in serum assessed in 60 tozorakimab‐treated participants, including healthy adults and patients with mild chronic obstructive pulmonary disease. Scenarios evaluated three dose frequencies (once every 2, 4 or 6 weeks) administered subcutaneously at seven doses of tozorakimab (30, 60, 90, 120, 150, 300 or 600 mg). For each dose, simulations were performed with 5000 virtual individuals to predict systemic TE. Inhibition of IL‐33/soluble ST2 (sST2) complex levels at trough PK at steady state was assessed in each dosing scenario. The PK/TE modelling analyses were performed using a nonlinear mixed‐effect modelling approach.ResultsThe final two‐compartment PK model with tozorakimab binding IL‐33 in the central compartment adequately described the systemic PK and TE of tozorakimab at population and individual levels. The mean PK parameter estimates of absorption rate, central volume of distribution and clearance were 0.48 (90% confidence interval [CI]: 0.40–0.59, 1/day), 12.64 (90% CI: 8.60–18.62, L) and 0.87 (90% CI: 0.65–1.16, L/day), respectively. Consistent with the observed value, tozorakimab bioavailability was 45%. For all three dose frequencies, predicted inhibition of systemic IL‐33/sST2 levels was more than 95% at doses greater than 90 mg.ConclusionsThe PK/TE model reliably quantified the relationship between PK and systemic TE of tozorakimab, with potential utility for predicting clinical dose–response relationships and supporting clinical dose selection.
Early therapeutic drug monitoring helps to identify inflammatory bowel disease patients with a high risk to fail thiopurine treatment
Authors: Deben Debbie S. , Winkens Bjorn , van Moorsel Sofia A. W. , van Oijen Brigit P. C. , Bus Paul , Pierik Marieke J. , Simsek Melek , de Boer Nanne K. H. , Leers Mathie P. G. , Wong Dennis R. , van Bodegraven Adriaan A. 
Published: August 2024

AbstractAimsConventional thiopurines (azathioprine and mercaptopurine) remain standard therapy to maintain steroid sparing remission in inflammatory bowel disease (IBD), but are regularly discontinued due to adverse drug reactions (ADRs). Measurement of the metabolites 6‐thioguanine nucleotides (6‐TGN), 6‐methylmercaptopurine ribonucleotides (6‐MMPR) and the 6‐MMPR/6‐TGN ratio, may predict the development of these ADRs. Our aim was to evaluate whether early thiopurine metabolite measurements were associated with clinical outcomes.MethodsA post‐hoc analysis was conducted of a multicentre, prospective, observational study on thiopurine‐induced hepatotoxicity. IBD patients who initiated thiopurine therapy were included and thiopurine metabolite concentrations were assessed after 7 days (±1) (T1). Patients were monitored for 12 weeks to document the occurrence of ADRs, early treatment discontinuation and effectiveness.ResultsIn total, 181 patients were evaluated. At T1, 6‐MMPR concentrations and 6‐TGN/6‐MMPR ratios were independently related to treatment discontinuation within 12 weeks after correction for sex, age and body mass index (BMI) (P = .034 and .002, respectively). The largest effects were observed for 6‐MMPR ≥3000 pmol/8 × 108 RBC and 6‐TGN/6‐MMPR ratio ≥17. Furthermore, 6‐MMPR concentrations and 6‐TGN/6‐MMPR ratios at T1 were independently related to skewed metabolism at steady state (Week 8, 6‐MMPR/‐6TGN ratio ≥11 and ≥20) (both P < .001). The occurrence of ADRs and effectiveness were not independently related to T1 thiopurine metabolite concentrations.ConclusionsThiopurine metabolite concentrations at T1 were related to early treatment discontinuation and skewed metabolism at steady state, but not to effectiveness, helping to identify patients with a high risk of thiopurine treatment failure.
Mechanisms of resistance to daratumumab in patients with multiple myeloma
Authors: Iversen Katrine Fladeland 
Published: August 2024

AbstractMultiple myeloma (MM) is an incurable cancer in the bone marrow. The treatment of MM has developed significantly during the last 20 years, which has resulted in increased survival. Daratumumab is the first CD38 antibody approved for the treatment of MM. It has improved the treatment of MM even further. This is an evaluation of the modes of action of daratumumab and a description of the development of resistance with a focus on inhibitory checkpoint receptors on CD8+ T‐cells, complement activation and extracellular vesicles.
Long‐term outcomes of bladder‐sparing therapy vs radical cystectomy in BCG‐unresponsive non‐muscle‐invasive bladder cancer
Authors: Taylor Jacob I. , Kamat Ashish M. , O'Donnell Michael A. , Annapureddy Drupad , Howard Jeffrey , Tan Wei Shen , McElree Ian , Davaro Facundo , Yim Kendrick , Harrington Stephen , Dyer Elizabeth , Black Anna J. , Kanabur Pratik , Roumiguié Mathieu , Lerner Seth , Black Peter C. , Raman Jay D. , Preston Mark A. , Steinberg Gary , Huang William , Li Roger , Packiam Vignesh T. , Woldu Solomon L , Lotan Yair 
Published: August 2024

ObjectiveTo quantify the oncological risks of bladder‐sparing therapy (BST) in patients with Bacillus Calmette–Guérin (BCG)‐unresponsive non‐muscle‐invasive bladder cancer (NMIBC) compared to upfront radical cystectomy (RC).Patients and MethodsPre‐specified data elements were collected from retrospective cohorts of patients with BCG‐unresponsive NMIBC from 10 international sites. After Institutional Review Board approval, patients were included if they had BCG‐unresponsive NMIBC meeting United States Food and Drug Administration criteria. Oncological outcomes were collected following upfront RC or BST. BST regimens included re‐resection or surveillance only, repeat BCG, intravesical chemotherapy, systemic immunotherapy, and clinical trials.ResultsAmong 578 patients, 28% underwent upfront RC and 72% received BST. The median (interquartile range) follow‐up was 50 (20–69) months. There were no statistically significant differences in metastasis‐free survival, cancer‐specific survival, or overall survival between treatment groups. In the BST group, high‐grade recurrence rates were 37% and 52% at 12 and 24 months and progression to MIBC was observed in 7% and 13% at 12 and 24 months, respectively. RC was performed in 31.7% in the BST group and nodal disease was found in 13% compared with 4% in upfront RC (P = 0.030).ConclusionIn a selected cohort of patients, initial BST offers comparable survival outcomes to upfront RC in the intermediate term. Rates of recurrence and progression increase over time especially in patients treated with additional lines of BST.
Practical approaches to diagnosing PitNETs/adenomas based on cell lineage
Authors: Goyal‐Honavar Abhijit , Chacko Geeta 
Published: August 2024

AbstractThe evolution of classification systems of pituitary adenomas (now PitNETs) has culminated in the use of transcription factor (TF) immunohistochemistry (IHC), forming a cell lineage‐based system. However, several issues remain to be addressed, including the additional financial and logistic burden of undertaking the complete array of anterior pituitary hormones and TF IHC. To that end, several groups have suggested algorithms to minimise the number of tests performed, with varying levels of diagnostic accuracy. Although the proportion of null cell tumours has decreased following the use of TFs, “multilineage” tumours have been reported and characterised using transcriptomic signatures, most prominently the PIT1‐SF1 co‐expressing PitNETs, which do not bear a position in the present system of classification. In this review, we examine the proposed practical approaches to the diagnosis of PitNETs. We review the literature on reported PitNET types that challenge the existing classification system, such as those that express multiple TFs, with their potential clinical implications. Finally, we assess limitations in the present system, such as the lack of a standardised system for IHC interpretation, that need to be addressed in the future.
Distinct brain network patterns in complete and incomplete spinal cord injury patients based on graph theory analysis
Authors: Yang Beining , Xin Haotian , Wang Ling , Qi Qunya , Wang Yu , Jia Yulong , Zheng Weimin , Sun Chuchu , Chen Xin , Du Jubao , Hu Yongsheng , Lu Jie , Chen Nan 
Published: August 2024

AbstractAimsTo compare the changes in brain network topological properties and structure–function coupling in patients with complete spinal cord injury (CSCI) and incomplete spinal cord injury (ICSCI), to unveil the potential neurobiological mechanisms underlying the different effects of CSCI and ICSCI on brain networks and identify objective neurobiological markers to differentiate between CSCI and ICSCI patients.MethodsThirty‐five SCI patients (20 CSCI and 15 ICSCI) and 32 healthy controls (HCs) were included in the study. Here, networks were constructed using resting‐state functional magnetic resonance imaging to analyze functional connectivity (FC) and diffusion tensor imaging for structural connectivity (SC). Then, graph theory analysis was used to examine SC and FC networks, as well as to estimate SC‐FC coupling values.ResultsCompared with HCs, CSCI patients showed increased path length (Lp), decreased global efficiency (Eg), and local efficiency (Eloc) in SC. For FC, ICSCI patients exhibited increased small‐worldness, clustering coefficient (Cp), normalized clustering coefficient, and Eloc. Also, ICSCI patients showed increased Cp and Eloc than CSCI patients. Additionally, ICSCI patients had reduced SC‐FC coupling values compared to HCs. Moreover, in CSCI patients, the SC network's Lp and Eg values were significantly correlated with motor scores, while in ICSCI patients, the FC network's Cp, Eloc, and SC‐FC coupling values were related to sensory/motor scores.ConclusionsThese results suggest that CSCI patients are characterized by decreased efficiency in the SC network, while ICSCI patients are distinguished by increased local connections and SC‐FC decoupling. Moreover, the differences in network metrics between CSCI and ICSCI patients could serve as objective biological markers, providing a basis for diagnosis and treatment strategies.
Coronary heart disease increases the risk of perioperative ischemic stroke after noncardiac surgery: A retrospective cohort study
Authors: Wang Rui , Wang Han , Liu Siyuan , Yang Lujia , Ma Libin , Liu Fengjin , Li Yingfu , Li Peng , Shi Yizheng , Sun Miao , Song Yuxiang , Hou Wugang , Mi Weidong , Ma Yulong 
Published: August 2024

AbstractObjectiveTo investigate the association between coronary heart disease (CHD) and the risk of perioperative ischemic stroke in patients undergoing noncardiac surgery.MethodsThis retrospective study evaluated the incidence of ischemic stroke within 30 days after a noncardiac surgery. A cohort of 221,541 patients who underwent noncardiac surgery between January 2008 and August 2019 was segregated according to whether they were diagnosed with CHD. Primary, sensitivity, and subgroup logistic regression analyses were conducted to confirm that CHD is an independent risk factor for perioperative ischemic stroke. Propensity score matching analysis was used to account for the potential residual confounding effect of covariates.ResultsAmong the 221,541 included patients undergoing noncardiac surgery, 484 patients (0.22%) experienced perioperative ischemic stroke. The risk of perioperative ischemic stroke was higher in patients with CHD (0.7%) compared to patients without CHD (0.2%), and multivariate logistic regression analysis showed that CHD was associated with a significantly increased risk of perioperative ischemic stroke (odds ratio (OR), 3.7943; 95% confidence interval (CI) 2.865–4.934; p < 0.001). In a subset of patients selected by propensity score matching (PSM) in which all covariates between the two groups were well balanced, the association between CHD and increased risk of perioperative ischemic stroke remained significantly significant (OR 1.8150; 95% CI, 1.254–2.619; p = 0.001). In the subgroup analysis stratified by age, preoperative β‐blockers, and fibrinogen‐to‐albumin ratio (FAR), the association between CHD and perioperative ischemic stroke was stable (p for interaction >0.05). Subgroup analyses also showed that CHD was significantly increased the risk of perioperative ischemic stroke in the preoperative mean arterial pressure (MAP) ≥94.2 mmHg subgroups (p for interaction <0.001).ConclusionCHD is significantly associated with an increased risk of perioperative ischemic stroke and is an independent risk factor for perioperative ischemic stroke after noncardiac surgery. Strict control of preoperative blood pressure may reduce the risk of perioperative ischemic stroke for patients with CHD undergoing noncardiac surgery.
The first surveillance report for Xylella fastidiosa in olive and stone fruit orchards in Palestine
Authors: Alabdallah Osama , Alkowni Raed , Radwan Jehad , Ghzayal Suha , Jaradat Shatella , Shubib Salameh , Jarrar Samer , Valentini Franco 
Published: August 2024

AbstractXylella fastidiosa has been identified as the causal agent of several horticultural plant diseases that have resulted in major economic and cultural heritage losses. In the last decade, X. fastidiosa emerged as a destructive phytopathogen on olive trees in the Apulia region, Italy, prompting widespread surveillance throughout the Mediterranean basin. The present paper reports monitoring efforts for X. fastidiosa in Palestine on olive for 5 years (2017–2022) and 1 year (2022) on stone fruit trees, as a result of international collaboration projects. No signs of olive quick decline syndrome were observed on olive trees in all the Palestinian olive‐growing lands. This observation was confirmed by molecular tests using LAMP technology and PCR. In addition, 500 leaf samples from stone fruit trees (almond, apricot, peach, nectarine and plum) were tested using LAMP and PCR. All of these samples were negative for X. fastidiosa, even though few of the samples from almond trees in Idna (Hebron governorate) and apricot trees in Bal'a (Tulkarm governorate) showed leaf scorch‐like symptoms. This study provides confirmation that these important horticultural crops in Palestine (olive and stone fruits) are still free of X. fastidiosa. Preventive measures and surveillance of these and other horticultural crops such as grapevine and citrus trees are strongly recommended.
Immunological and virological response to fostemsavir in routine US clinical care: An OPERA cohort study
Authors: Hsu Ricky K. , Brunet Laurence , Lackey Philip C. , Pierone Gerald , Levis Brooke , Fusco Jennifer S. , Henegar Cassidy , Vannappagari Vani , Clark Andrew , Fusco Gregory P. 
Published: August 2024

AbstractObjectivesFostemsavir is a novel attachment inhibitor used with other antiretrovirals in heavily treatment‐experienced (HTE) adults with multidrug‐resistant HIV‐1. Real‐world immunological and virological responses were assessed in individuals starting fostemsavir in the OPERA cohort.MethodsAmong adults with HIV‐1 starting fostemsavir between 2 July 2020 and 1 September 2022, 6‐month and 12‐month changes in CD4 T‐cell count and CD4%, and maintenance/achievement of viral load (VL) <50 copies/mL were described and stratified by baseline VL (suppressed: <50 copies/mL; viraemic: ≥50 copies/mL) and CD4 count (high: ≥350 cells/μL; low: <350 cells/μL).ResultsOf 182 individuals starting fostemsavir, 64% were viraemic (34% low CD4, 30% high CD4) and 36% were suppressed (16% low CD4, 20% high CD4). The suppressed/low CD4 group had the largest median increases in CD4 count (6‐month: 30 cells/μL [interquartile range {IQR} 9–66], 12‐month: 66 cells/μL [IQR 17–125]), and CD4% (6‐month: 1.0% [IQR −0.3–2.8], 12‐month: 1.9% [IQR 1.3–3.9]). Regardless of baseline VL, those with a high baseline CD4 count experienced a greater variability in immunological response than those with low CD4 counts (12‐month standard deviation range 172–231 cells/μL vs. 69–90 cells/μL). VL <50 copies/mL was maintained in most suppressed individuals; nearly half of the viraemic/high CD4 group and a third of the viraemic/low CD4 group achieved a VL <50 copies/mL at either timepoint.ConclusionsAfter 6 or 12 months of fostemsavir use, virological response was low in viraemic individuals, although most suppressed individuals did maintain suppression. While immunological response varied across individuals, virologically suppressed HTE individuals with low CD4 counts may benefit from immunological improvements with fostemsavir.
Assessment of targeted intervention programme under the National AIDS Control Program among men who have sex with men in India
Authors: Vashisht Shruti , Thakur Nishakar , Kant Shashi , Rai Sanjay , Jha Shreya 
Published: August 2024

AbstractIntroductionThe population of men who have sex with men (MSM) in India is vulnerable to HIV/AIDS. India instituted a targeted intervention (TI) programme to reduce this vulnerability. We aimed to measure the assessment of the TI programme for MSM.Materials and MethodsThe national Integrated Biological and Behavioural Survey (IBBS) was carried out in 2014–2015. We analysed MSM data from the IBBS and used bivariate and multivariate logistic regression to calculate the unadjusted and adjusted odds ratios with 95% confidence intervals. The use of a condom during their last sexual intercourse and consistent condom use during the previous month were considered indicators of programme effectiveness. The propensity score matching method was used to assess the effectiveness of the TI programme.ResultsThe matched‐samples estimate (i.e., average treatment effect on treated) for the use of condoms during their last sexual intercourse increased by 10.0% (0.10; 95% confidence interval [CI] 0.08–0.12), and consistent condom use during the previous month increased by 9.0% (0.09; 95% CI 0.07–0.10) among those who had received condoms from the peer educator/outreach worker compared with those who had not received condoms.ConclusionsThe TI programme intervention among MSM was effective in reducing HIV risk behaviours, as evidenced by an increase in the use of condoms during their last sexual intercourse and consistent condom use during the last month.
Bioactive properties, phytochemicals, fatty acids, mineral contents and sensory characteristics of the breads prepared using wheat flour and nutmeg powders at different concentrations
Authors: Qasem Akram A. , Ahmed Isam A. Mohamed , Mohammed Belal M. , Özcan Mehmet Musa , Albakry Zainab 
Published: August 2024

SummaryIn this study, bioactive compounds, antioxidant activity, phytochemicals, fatty acid compositions, elements and sensory characteristics of the breads prepared using wheat flour and nutmeg powders at different concentrations were investigated. The results obtained regarding the physical and chemical properties of nutmeg breads exhibited some changes based on the nutmeg amounts added in bread production. Also, ‘L*’ results of the breads changed between 70.85 (1.0%) and 76.09 (0.5%). In addition, ‘a*’ and ‘b*’ results of breads with nutmeg powder were assigned to be between 0.47 (0.5%) and 1.93 (2.0%) to 18.44 (2.0%) and 20.42 (0.5%) and 1.93 (0.5%), respectively. Total phenol and flavonoid amounts of breads were established between 24.64 (0.5%) and 47.58 mg GAE per 100 g (2.0%) to 10.71 (control) and 177.38 mg per 100 g (2.0%), respectively. An increase in the redness value was monitored in nutmeg bread added at the rate of 1% and 2%. The amounts of phenolic constituents in the breads fluctuated depending on the added nutmeg concentrations. Gallic acid and 3,4‐dihydroxybenzoic acid values of the breads were stated to be between 2.66 (2.0%) and 6.66 mg per 100 g (1.0%) to 1.48 (2.0%) and 2.71 mg per 100 g (control), respectively. Phosphorus and potassium quantities of the breads were found between 743.60 (control) and 810.50 mg kg−1 (0.5%) to 2077.37 (1.5%) and 2345.42 mg kg−1 (0.5%), respectively. The dominant fatty acids in bread oils were myristic, palmitic, oleic and linoleic acids. It can be seen that the addition of nutmeg in high concentration decreased the consumer's taste. In addition, the added nutmeg increased the colour value of the bread and corrected the textural structure.
Unravelling the nexus between structure, texture, and acoustic traits of fried chicken nuggets
Authors: Liberty Jacob Tizhe , Bhuiyan Md. Hafizur Rahman , Ngadi Michael 
Published: August 2024

SummaryTexture is a multi‐parameter attribute and one of the prime quality attributes of fried products. This study explored the nexus between microstructure and texture of fried breaded chicken nuggets. Chicken nuggets were deep‐fat fried (2, 4, 6, and 8 min) in canola oil at different frying temperature (170, 180, and 190 °C). Microstructure and texture of fried samples were assessed by scanning electron microscopy (SEM) and acoustic‐mechanical texture analyser, respectively. Maximum force (Fmax), number of force peaks (NFP), area under force‐deformation plots (FA), sound pressure level (SPL), number of sound peaks (AUX), and area under amplitude‐time curves (SA) were used to describe the textural parameters. Microstructural indices (porosity, number of pores, average pore area, polydispersity index, and average shape factor) were estimated from the SEM images. Results revealed that, both the frying time and temperature were positively correlated with the mechanical (Fmax: 25–55 N, NFP: 05–74 N, FA: 6500–15 000 N.sec) and acoustic (SPL: 88–97 dB, AUX: 650–810 dB, SA: 380–405 dB.sec) parameters. Frying time and temperature significantly (P < 0.05) impacted the formation of micropores in fried chicken nuggets. Crust microporosity showed strong positive correlations (r = 0.82) with the AUX value. The NFP, SPL, and SA of the fried nuggets were significantly (P < 0.05) impacted by the crust microporosity. Crust porosity (10–30%), number of pores (8–400), average pore area (10–4000 μm2), polydispersity index (0.05–0.2), and average shape factor (0.8–1.1) of fried nuggets were significantly (P < 0.05) influenced by both the frying time and temperature. Findings from this study would be useful in quality improvement and process monitoring including modelling of coated fried products.