bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experimental investigation for nonalcoholic fatty pancreas management using probiotics
Authors: Matboli Marwa , Al-Amodi Hiba S. , Hamady Shaimaa , Ali Marwa , Roushdy Marian MS , Hasanin Amany Helmy , Aboul-Ela Yasmin M. , Albadawy Reda , Gomaa Eman , Kamel Hala F. M. , ELsawi Hind A , Farid Laila M. , Abouelkhair Mariam B. , Elmakromy Gena M , Fawzy Nesma Mohamed 
Published: July 2024

Abstract
Background
Nonalcoholic fatty pancreatitis (NAFP) presents a pressing challenge within the domain of metabolic disorders, necessitating further exploration to unveil its molecular intricacies and discover effective treatments. Our focus was to delve into the potential therapeutic impact of ZBiotic, a specially engineered strain of probiotic B. subtilis, in managing NAFP by targeting specific genes linked with necroptosis and the TNF signaling pathway, including TNF, ZBP1, HSPA1B, and MAPK3, along with their upstream epigenetic regulator, miR-5192, identified through bioinformatics.

Methods
Rats were subjected to either a standard or high-fat, high-sucrose diet (HFHS) for eight weeks. Subsequently, they were divided into groups: NAFP model, and two additional groups receiving daily doses of ZBiotic (0.5 ml and 1 ml/kg), and the original B. subtilis strain group (1 ml/kg) for four weeks, alongside the HFHS diet.

Results
ZBiotic exhibited remarkable efficacy in modulating gene expression, leading to the downregulation of miR-5192 and its target mRNAs (p < 0.001). Treatment resulted in the reversal of fibrosis, inflammation, and insulin resistance, evidenced by reductions in body weight, serum amylase, and lipase levels (p < 0.001), and decreased percentages of Caspase and Nuclear Factor Kappa-positive cells in pancreatic sections (p < 0.01). Notably, high-dose ZBiotic displayed superior efficacy compared to the original B. subtilis strain, highlighting its potential in mitigating NAFP progression by regulating pivotal pancreatic genes.

Conclusion
ZBiotic holds promise in curbing NAFP advancement, curbing fibrosis and inflammation while alleviating metabolic and pathological irregularities observed in the NAFP animal model. This impact was intricately linked to the modulation of necroptosis/TNF-mediated pathway-related signatures.
Identifying longitudinal cognitive resilience from cross-sectional amyloid, tau, and neurodegeneration
Authors: Boyle Rory , Townsend Diana L. , Klinger Hannah M. , Scanlon Catherine E. , Yuan Ziwen , Coughlan Gillian T. , Seto Mabel , Shirzadi Zahra , Yau Wai-Ying Wendy , Jutten Roos J. , Schneider Christoph , Farrell Michelle E. , Hanseeuw Bernard J. , Mormino Elizabeth C. , Yang Hyun-Sik , Papp Kathryn V. , Amariglio Rebecca E. , Jacobs Heidi I. L. , Price Julie C. , Chhatwal Jasmeer P. , Schultz Aaron P. , Properzi Michael J. , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. , Hohman Timothy J. , Donohue Michael C. , Buckley Rachel F. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: July 2024

Abstract
Background
Leveraging Alzheimer’s disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR.

Methods
We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aβ, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women).

Results
The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline.

Conclusion
These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity.
Nutrition guidance within a multimodal intervention improves diet quality in prodromal Alzheimer’s disease: Multimodal Preventive Trial for Alzheimer’s Disease (MIND-ADmini)
Authors: Levak Nicholas , Lehtisalo Jenni , Thunborg Charlotta , Westman Eric , Andersen Pia , Andrieu Sandrine , Broersen Laus M. , Coley Nicola , Hartmann Tobias , Irving Gerd Faxén , Mangialasche Francesca , Ngandu Tiia , Pantel Johannes , Rosenberg Anna , Sindi Shireen , Soininen Hilkka , Solomon Alina , Wang Rui , Kivipelto Miia 
Published: July 2024

Abstract
Background
Multimodal lifestyle interventions can benefit overall health, including cognition, in populations at-risk for dementia. However, little is known about the effect of lifestyle interventions in patients with prodromal Alzheimer’s disease (AD). Even less is known about dietary intake and adherence to dietary recommendations within this population making it difficult to design tailored interventions for them.

Method
A 6-month MIND-ADmini pilot randomized controlled trial (RCT) was conducted among 93 participants with prodromal AD in Sweden, Finland, Germany, and France. Three arms were included in the RCT: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management, and social stimulation); 2) multimodal lifestyle intervention + medical food product; and 3) regular health advice (control group). Adherence to dietary advice was assessed with a brief food intake questionnaire by using the Healthy Diet Index (HDI) and Mediterranean Diet Adherence Screener (MEDAS). The intake of macro- and micronutrients were analyzed on a subsample using 3-day food records.

Results
The dietary quality in the intervention groups, pooled together, improved compared to that of the control group at the end of the study, as measured with by HDI (p = 0.026) and MEDAS (p = 0.008). The lifestyle-only group improved significantly more in MEDAS (p = 0.046) and almost significantly in HDI (p = 0.052) compared to the control group, while the lifestyle + medical food group improved in both HDI (p = 0.042) and MEDAS (p = 0.007) during the study. There were no changes in macro- or micronutrient intake for the intervention groups at follow-up; however, the intakes in the control group declined in several vitamins and minerals when adjusted for energy intake.

Conclusion
These results suggest that dietary intervention as part of multimodal lifestyle interventions is feasible and results in improved dietary quality in a population with prodromal AD. Nutrient intakes remained unchanged in the intervention groups while the control group showed a decreasing nutrient density.

Trial registration
ClinicalTrials.gov NCT03249688, 2017–07-08.
Association between tobacco smoke exposure and depression: the NHANES 2005–2018 and Mendelian randomization study
Authors: Guo Yikun , Yan Jun 
Published: July 2024

Abstract
Objective
The relationship between tobacco smoke exposure (TSE) and depression is controversial. This study combined observational research and Mendelian randomization (MR) to explore the relationship of depression with both smoking status and cotinine levels.

Method
We collected relevant data from the National Health and Nutrition Examination Survey (NHANES) database from 2005 to 2018, and used weighted multifactorial logistic regression modelling to assess the correlation between TSE and depression, and assessed the causal relationship of depression with both smoking status and cotinine levels by MR.

Result
Current smokers had the highest risk of depression (OR 1.94; P < 0.01); there was a positive trend for correlation between daily smoking and depression (OR 1.66; P for trend < 0.01). Serum ketamine levels above 3.00 ng/ml had a higher risk of depression (OR 2.13; P < 0.001). MR results showed that current smoking (OR = 4.66; P < 0.001) and previous smoking (OR 2.09; P < 0.01) were risk factors for the onset of depression, and that there was no causal association between cotinine levels and depression.

Conclusion
Smoking is significantly associated with depression and plays a potential causal role in the development of depression. Cotinine was significantly associated with depression, however MR results showed no causal relationship between cotinine and depression.
Predictive modeling of perioperative patient deterioration: combining unanticipated ICU admissions and mortality for improved risk prediction
Authors: Bakkes Tom H.G.F. , Mestrom Eveline H.J. , Ourahou Nassim , Kaymak Uzay , de Andrade Serra Paulo J. , Mischi Massimo , Bouwman Arthur R. , Turco Simona 
Published: July 2024

Abstract
Objective
This paper presents a comprehensive analysis of perioperative patient deterioration by developing predictive models that evaluate unanticipated ICU admissions and in-hospital mortality both as distinct and combined outcomes.

Materials and Methods
With less than 1% of cases resulting in at least one of these outcomes, we investigated 98 features to identify their role in predicting patient deterioration, using univariate analyses. Additionally, multivariate analyses were performed by employing logistic regression (LR) with LASSO regularization. We also assessed classification models, including non-linear classifiers like Support Vector Machines, Random Forest, and XGBoost.

Results
During evaluation, careful attention was paid to the data imbalance therefore multiple evaluation metrics were used, which are less sensitive to imbalance. These metrics included the area under the receiver operating characteristics, precision-recall and kappa curves, and the precision, sensitivity, kappa, and F1-score. Combining unanticipated ICU admissions and mortality into a single outcome improved predictive performance overall. However, this led to reduced accuracy in predicting individual forms of deterioration, with LR showing the best performance for the combined prediction.

Discussion
The study underscores the significance of specific perioperative features in predicting patient deterioration, especially revealed by univariate analysis. Importantly, interpretable models like logistic regression outperformed complex classifiers, suggesting their practicality. Especially, when combined in an ensemble model for predicting multiple forms of deterioration. These findings were mostly limited by the large imbalance in data as post-operative deterioration is a rare occurrence. Future research should therefore focus on capturing more deterioration events and possibly extending validation to multi-center studies.

Conclusions
This work demonstrates the potential for accurate prediction of perioperative patient deterioration, highlighting the importance of several perioperative features and the practicality of interpretable models like logistic regression, and ensemble models for the prediction of several outcome types. In future clinical practice these data-driven prediction models might form the basis for post-operative risk stratification by providing an evidence-based assessment of risk.
Genomic characterization of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) strains circulating in three university hospitals in Northern Italy over three years
Authors: Fox Valeria , Mangioni Davide , Renica Silvia , Comelli Agnese , Teri Antonio , Zatelli Michela , Orena Beatrice Silvia , Scuderi Cristina , Cavallero Annalisa , Rossi Marianna , Casana Maddalena , Mela Ludovica , Bielli Alessandra , Scutari Rossana , Morelli Paola , Cariani Lisa , Casari Erminia , Vismara Chiara Silvia , Matinato Caterina , Callegaro Annapaola , Bottazzi Barbara , Cassani Barbara , Perno Carlo Federico , Gori Andrea , Muscatello Antonio , Bandera Alessandra , Alteri Claudia 
Published: July 2024

Abstract
Objectives
Genomic surveillance of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) is crucial for virulence, drug-resistance monitoring, and outbreak containment.

Methods
Genomic analysis on 87 KPC-Kp strains isolated from 3 Northern Italy hospitals in 2019-2021 was performed by whole genome sequencing (WGS), to characterize resistome, virulome, and mobilome, and to assess potential associations with phenotype resistance and clinical presentation. Maximum Likelihood and Minimum Spanning Trees were used to determine strain correlations and identify potential transmission clusters.

Results
Overall, 15 different STs were found; the predominant ones included ST307 (35, 40.2%), ST512/1519 (15, 17.2%), ST20 (12, 13.8%), and ST101 (7, 8.1%). 33 (37.9%) KPC-Kp strains were noticed to be in five transmission clusters (median number of isolates in each cluster: 5 [3-10]), four of them characterized by intra-hospital transmission. All 87 strains harbored Tn4401a transposon, carrying blaKPC-3 (48, 55.2%), blaKPC-2 (38, 43.7%), and in one case (1.2%) blaKPC-33, the latter gene conferred resistance to ceftazidime/avibactam (CZA). Thirty strains (34.5%) harbored porin mutations; of them, 7 (8.1%) carried multiple Tn4401a copies. These strains were characterized by significantly higher CZA minimum inhibitory concentration compared with strains with no porin mutations or single Tn4401a copy, respectively, even if they did not overcome the resistance breakpoint of 8 ug/mL. Median 2 (IQR:1-2) virulence factors per strain were detected. The lowest number was observed in ST20 compared to the other STs (p<0.001). While ST307 was associated with infection events, a trend associated with colonization events could be observed for ST20.

Conclusions
Integration of genomic, resistance score, and clinical data allowed us to define a relative diversification of KPC-Kp in Northern Italy between 2019 and 2021, characterized by few large transmission chains and rare inter-hospital transmission. Our results also provided initial evidence of correlation between KPC-Kp genomic signatures and higher MIC levels to some antimicrobial agents or colonization/infection status, once again underlining WGS's importance in bacterial surveillance.
Differences in the pupillary responses to evening light between children and adolescents
Authors: Hartstein Lauren E. , LeBourgeois Monique K. , Durniak Mark T. , Najjar Raymond P. 
Published: July 2024

Abstract
Background
In the mammalian retina, intrinsically-photosensitive retinal ganglion cells (ipRGC) detect light and integrate signals from rods and cones to drive multiple non-visual functions including circadian entrainment and the pupillary light response (PLR). Non-visual photoreception and consequently non-visual sensitivity to light may change across child development. The PLR represents a quick and reliable method for examining non-visual responses to light in children. The purpose of this study was to assess differences in the PLRs to blue and red stimuli, measured one hour prior to bedtime, between children and adolescents.

Methods
Forty healthy participants (8–9 years, n = 21; 15–16 years, n = 19) completed a PLR assessment 1 h before their habitual bedtime. After a 1 h dim-light adaptation period (< 1 lx), baseline pupil diameter was measured in darkness for 30 s, followed by a 10 s exposure to 3.0 × 1013 photons/cm2/s of either red (627 nm) or blue (459 nm) light, and a 40 s recovery in darkness to assess pupillary re-dilation. Subsequently, participants underwent 7 min of dim-light re-adaptation followed by an exposure to the other light condition. Lights were counterbalanced across participants.

Results
Across both age groups, maximum pupil constriction was significantly greater (p < 0.001, ηp2 = 0.48) and more sustained (p < 0.001, ηp2 = 0.41) during exposure to blue compared to red light. For adolescents, the post-illumination pupillary response (PIPR), a hallmark of melanopsin function, was larger after blue compared with red light (p = 0.02, d = 0.60). This difference was not observed in children. Across light exposures, children had larger phasic (p < 0.01, ηp2 = 0.20) and maximal (p < 0.01, ηp2 = 0.22) pupil constrictions compared to adolescents.

Conclusions
Blue light elicited a greater and more sustained pupillary response than red light in children and adolescents. However, the overall amplitude of the rod/cone-driven phasic response was greater in children than in adolescents. Our findings using the PLR highlight a higher sensitivity to evening light in children compared to adolescents, and continued maturation of the human non-visual photoreception/system throughout development.
A phase 1 study evaluating the safety, pharmacokinetics, and efficacy of fadraciclib, an oral CDK2/9 inhibitor, in patients with advanced solid tumors and lymphoma.
Authors: Villalona-Calero Miguel Angel , Oh Do-Youn , Garralda Elena , Vieito Maria , Huang Julius , Piha-Paul Sarina A. 
Published: July 2024

3125 Background: Fadraciclib (formerly CYC065)is a highly selective inhibitor of CDK2 (IC50= 5 nM) and CDK9 (IC50=26 nM) causing mitotic catastrophe and apoptotic death of cancer cells at sub-micromolar concentrations. In a previous Phase 1 study of intravenous fadraciclib monotherapy, a heavily pretreated endometrial cancer patient with CDNK2A, CDKN2B and PRMT5 loss achieved confirmed CR. This is the first study to evaluate oral fadraciclib monotherapy. Methods: A global Phase 1/2, open-label, dose-escalation study in subjects with advanced solid tumors or lymphoma (NCT04983810). The Phase 1 portion is exploring both schedule and dose of oral fadraciclib monotherapy in 28-day cycles to identify MTD and/or RP2D using a standard 3+3 design. Results: As of January 31, 2024, 45 subjects have received fadraciclib at 8 dose levels (DL1-6a: 50-150 mg, bid given 3-5 days per week for 3-4 out of 4 weeks or DL6b: 125 mg, daily for 4/4 weeks). Heavily pretreated patients with breast, colorectal, gynecological cancers, and T cell lymphoma with ECOG PS 0:1 (9:36) were enrolled. Fadraciclib was well tolerated at dose levels 1 to 5 (up to 100 mg bid). Adverse events reported were nausea (n=31), vomiting (n=23), thrombocytopenia (n=6). Grade 3 DLT of hyperglycemia (1/2 DL6 and 2/6 DL6a) and nausea (1/2 DL6) was observed at doses above 125mg bid M-F, 4/4 weeks. Hyperglycemia was controlled after dose interruption and blood glucose levels returned to normal range after treatment. Preliminary PK analysis suggests dose dependent exposure. At DL5 and above, plasma concentration was above target concentration from CDK2 and CDK9 target engagement studies. Preliminary PD analysis of treated patient samples showed suppression of expression in multiple target genes, including MYC, MCL1, CCNE/cyclin E, CDKN2A, CDKN2B, and PRMT5. Preliminary efficacy data are available for 31 evaluable patients. Two PRs after the first cycle were observed in one patient with CTCL and one with angioimmunoblastic T-Cell Lymphoma (AITL). Twenty patients showed SD. Tumor size reduction was observed in 10 patients. A squamous NSCLC patient harboring a CDK2NB loss of function mutation and prior chemo- and immunotherapy achieved reduction of 22% in the sum of all target lesions after 1 cycle of treatment. Conclusions: Based on data from the CYC065-101 study, fadraciclib appears well tolerated from DL1 to 5. The MTD for the bid dosing schedule is 100mg bid, M-F, 4/4 weeks. The trial is ongoing with evaluation of a daily dosing schedule. Clinical trial information: NCT04983810 .
A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors.
Authors: Gouda Mohamed Alaa , Shunyakova Jenny , Naing Aung , Dumbrava Ecaterina Elena , Hong David S. , Yuan Ying , Yang Peiying , Myers Alan , Liang Yulong , Ping Jing , Karp Daniel D. , Tsimberidou Apostolia Maria , Rodon Ahnert Jordi , Yap Timothy A. , Piha-Paul Sarina A. , Meric-Bernstam Funda , Fu Siqing 
Published: July 2024

3152 Background: Paclitaxel resistance in patients is a clinical challenge that limits the durability of clinical benefit in patients with taxane-responsive advanced solid tumors. One proposed mechanism for this resistance is overexpression of spleen tyrosine kinase (SYK); which can be inhibited with new molecules including TAK-659. In this phase I study, we have investigated the combination of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors; hypothesizing that use of TAK-659 would help to overcome resistance to prior taxane-based therapy. Methods: We included patients with advanced solid tumors who received and progressed on prior taxane-based therapy. Patients received treatment with intravenous paclitaxel on day 1,8, and 15 in addition of daily TAK-659 in 28-day cycles. Six cohorts were treated during dose escalation at different dose levels followed by a dose expansion phase in patients with advanced ovarian cancer. We used the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for evaluation of toxicity and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for assessment of preliminary efficacy. Results: We included 49 patients with advanced solid tumors. The maximum tolerated dose was not reached in this study; and no patients experienced treatment-related deaths. Most adverse events were either grade 1 or 2. Grade 3 or more adverse events were reported in 47% of patients (n=23). The most common grade ≥3 adverse events were decreased neutrophil count (n=7; 14%), elevated lipase (n=6; 12%), anemia (n=5; 10%), increased amylase (n=4; 8%), and decreased white blood cell counts (n=4; 8%). In 44 patients with taxane-refractory tumors who were evaluable for efficacy, 9% (n=4) had RECIST partial response and 27% (n=12) had RECIST stable disease, including 3 patients with prolonged stable disease for at least 6 months. Conclusions: The combination of paclitaxel and TAK-659 was well tolerated and showed preliminary modest efficacy which could be possibly overcoming resistance to taxane-based therapy in patients with advanced solid tumors. Clinical trial information: NCT03756818 .