bluuebunny/crossref_metadata_2025_split huggingface dataset:
Laparoscopic Large Hiatal Hernia Repair With RefluxStop: Outcomes of Six Months Follow-up in Thirty Patients
Authors: Fringeli Yannick , Linas Ioannis , Kessler Ulf , Zehetner Joerg 
Published: February 2024

Objective:
The antireflux surgical technique with the RefluxStop device is one of the latest approaches to treating patients with gastroesophageal reflux disease (GERD). The aim of this study was to assess the safety and feasibility of laparoscopic hiatal hernia (HH) repair with the RefluxStop device in patients with GERD and concurrent large HH (≥4 cm).

Patients and Methods:
A retrospective chart review was performed for the first 30 patients with a large HH who consented and underwent HH surgery with the RefluxStop device. The operative technique and outcomes were evaluated to assess safety and feasibility, HH recurrence, dysphagia, and patient satisfaction.

Results:
Between May 2020 and April 2022, 30 patients underwent laparoscopic HH repair with the RefluxStop device. All patients had typical symptoms of GERD, such as heartburn and regurgitation, and 15 patients (50%) had preoperative dysphagia. Median HH size was 5 cm (interquartile range, 4 to 5). Median operating time was 56 minutes (interquartile range, 52 to 63), with no intra and postoperative complications related to the device. One patient required laparotomy due to adhesions and associated bleeding when accessing the abdomen. All patients had postoperative imaging (video fluoroscopy) on postoperative day 1 and at 3 months, confirming the correct location of the RefluxStop device. One patient (3.3%) needed postoperative balloon dilatation due to severe dysphagia. Reflux symptoms (heartburn and acid regurgitation) resolved significantly in all patients (P < 0.001) at 6 months. One episode of recurrence of HH (3.3%) occurred during the follow-up period of 6 months.

Conclusion:
This study demonstrates the short-term safety and feasibility of laparoscopic HH repair with the RefluxStop device in patients with large HH, with a low rate of postoperative dysphagia and subsequent improvement or resolution of reflux symptoms in all patients.
Transmission and Non-transmission of Melanoma From Deceased Solid Organ Donors to Transplant Recipients: Risks and Missed Opportunities
Authors: Rosales Brenda Maria , Hedley James , De La Mata Nicole , Cavazzoni Elena , Vajdic Claire M. , Thompson John F. , Kelly Patrick J. , Wyburn Kate , Webster Angela C. 
Published: February 2024

Background.
Biovigilance concerns are in tension with the need to increase organ donation. Cancer transmission risk from donor to recipient may be overestimated, as non-transmission events are rarely reported. We sought to estimate melanoma transmission risk in deceased organ donation and identify missed opportunities for donation in an Australian cohort with high melanoma prevalence.

Methods.
We used a population-based approach and linked deceased organ donors, transplant recipients, and potential donors forgone, 2010–2018, with the Central Cancer Registry (CCR), 1976–2018. We identified melanomas using ICD-O-3 classification, assessed the probability of transmission, and compared suspected melanoma history in potential donors forgone with melanoma notifications in the CCR.

Results.
There were 9 of 993 donors with melanoma in CCR; 4 in situ low-risk and 5 invasive high-to-unacceptable risk. Four were unrecognized before donation. Of 16 transplant recipients at risk, we found 0 of 14 transmission events (2 recipients had insufficient follow-up). Of 35 of 3588 potential donors forgone for melanoma risk alone, 17 were otherwise suitable for donation; 6 of 35 had no melanoma in CCR, 2 of 35 had in situ melanomas and 9 of 35 had thin invasive melanomas (localized, ≤0.8 mm thickness).

Conclusions.
Our findings contribute to current evidence that suggests donors with melanomas of low metastatic potential may provide an opportunity to safely increase organ donation and so access to transplantation.
Effect of Behavioral Health Disorders on Surgical Outcomes in Cancer Patients
Authors: Katayama Erryk S , Woldesenbet Selamawit , Munir Muhammad Musaab , Endo Yutaka , Rawicz-Pruszyński Karol , Khan Muhammad Muntazir Mehdi , Tsilimigras Diamantis , Dillhoff Mary , Cloyd Jordan , Pawlik Timothy M 
Published: February 2024

BACKGROUND:
Behavioral health disorders (BHDs) can often be exacerbated in the setting of cancer. We sought to define the prevalence of BHD among cancer patients and characterize the association of BHD with surgical outcomes.

STUDY DESIGN:
Patients diagnosed with lung, esophageal, gastric, liver, pancreatic, and colorectal cancer between 2018 and 2021 were identified within Medicare Standard Analytic Files. Data on BHD defined as substance abuse, eating disorder, or sleep disorder were obtained. Postoperative textbook outcomes (ie no complications, prolonged length of stay, 90-day readmission, or 90-day mortality), as well as in-hospital expenditures and overall survival were assessed.

RESULTS:
Among 694,836 cancer patients, 46,719 (6.7%) patients had at least 1 BHD. Patients with BHD were less likely to undergo resection (no BHD: 23.4% vs BHD: 20.3%; p < 0.001). Among surgical patients, individuals with BHD had higher odds of a complication (odds ratio [OR] 1.32 [1.26 to 1.39]), prolonged length of stay (OR 1.36 [1.29 to 1.43]), and 90-day readmission (OR 1.57 [1.50 to 1.65]) independent of social vulnerability or hospital-volume status resulting in lower odds to achieve a TO (OR 0.66 [0.63 to 0.69]). Surgical patients with BHD also had higher in-hospital expenditures (no BHD: $16,159 vs BHD: $17,432; p < 0.001). Of note, patients with BHD had worse long-term postoperative survival (median, no BHD: 46.6 [45.9 to 46.7] vs BHD: 37.1 [35.6 to 38.7] months) even after controlling for other clinical factors (hazard ratio 1.26 [1.22 to 1.31], p < 0.001).

CONCLUSIONS:
BHD was associated with lower likelihood to achieve a postoperative textbook outcome, higher expenditures, as well as worse prognosis. Initiatives to target BHD are needed to improve outcomes of cancer patients undergoing surgery.
Evaluating the effect of rapamycin treatment in Alzheimer's Disease and aging usingin vivoimaging: the ERAP phase IIa clinical study protocol
Authors: Svensson Jonas E. , Bolin Martin , Thor Daniel , Williams Pete A. , Brautaset Rune , Carlsson Marcus , Sörensson Peder , Marlevi David , Spin-Neto Rubens , Probst Monika , Hagman Göran , Morén Anton Forsberg , Kivipelto Miia , Plavén-Sigray Pontus 
Published: February 2024

ABSTRACTBackgroundRapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and pre-clinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatment in humans. Results from mouse models of Alzheimer’s disease have shown beneficial effects of rapamycin including preventing or reversing cognitive deficits, reducing amyloid oligomers and tauopathies and normalizing synaptic plasticity and cerebral glucose uptake. The “Evaluating rapamycin treatment in Alzheimer’s disease using positron emission tomography” (ERAP) trial aims to test if these results translate to humans through evaluating the change in cerebral glucose uptake following six months of rapamycin treatment in participants with early-stage Alzheimer’s disease.MethodsERAP is a six month long, single-arm, open-label, phase IIa biomarker driven study evaluating if the drug rapamycin can be repurposed to treat Alzheimer’s disease. Fifteen patients will be included and treated with a weekly dose of 7 mg rapamycin for six months. The primary endpoint will be change in cerebral glucose uptake, measured using [18F]FDG positron emission tomography. Secondary endpoints will be change in cognitive measures, markers in cerebrospinal fluid as well as cerebral blood flow measured using magnetic resonance imaging. As exploratory outcomes, the study will assess change in multiple age-related pathological processes, such as periodontal inflammation, retinal degeneration, bone mineral density loss, atherosclerosis and decreased cardiac function.DiscussionThe ERAP study is a clinical trial usingin vivoimaging biomarkers to assess the repurposing of rapamycin for the treatment of Alzheimer’s disease. If successful, the study would provide a strong rationale for large-scale evaluation of mTOR-inhibitors as a potential disease modifying treatment in Alzheimer’s disease.Trial RegistrationClinicalTrials.govIDNCT06022068, date of registration 2023-08-30
Pharmacodynamic evaluation of AUM001/tinodasertib, an oral inhibitor of mitogen-activated protein kinase (MAPK)-interacting protein kinase 1, 2 (MNK1/2) in preclinical models and tissues from a Phase 1 clinical study
Authors: Gan Bong Hwa , Lee Lay Hoon , Takeda Reika , Yasin Maryam , Teneggi Vincenzo , Ethirajulu Kantharaj , Yeo Pauline , Umrani Dhananjay , Pendharkar Vishal , Lim Darren Wan Teck , Li Greg , Lu Qingshu , Cao Yang , Nellore Ranjani , Blanchard Stephanie , Hentze Hannes , Novotny-Diermayr Veronica 
Published: February 2024

AbstractMitogen-activated protein kinase (MAPK) interacting kinase (MNK) inhibitors affect cap-dependent mRNA translation by blocking the phosphorylation of RNA-binding proteins such as the eukaryotic initiation factor 4E (eIF4E). Phosphorylation on serine (Ser) 209 of eIF4E causes hyperactivation and dysregulation of mRNA translation, which is a hallmark of numerous malignancies. AUM001/Tinodasertib (ETC-206) is a selective and potent oral kinase inhibitor of MNK1 and MNK2 (IC50of 64 and 86 nM, respectively), inducing dose-dependent inhibition of eIF4E phosphorylation on Ser209 (p-eIF4E) with an IC50of 0.8 µM in K562-eIF4E cells. In mice, single oral doses of ∼12.5 mg/kg led to rapid (1-2 h post-dose) ∼70% inhibition of p-eIF4E in different normal or tumor tissues at a plasma concentration of 8.6 μM. However, in peripheral blood mononuclear cells (PBMCs), obtained from human healthy volunteers (HVs) in a Ph1 study, single oral doses of 10 or 20 mg ETC-206 did not show inhibitory activity up to 12 h post-dose, instead ETC-206 caused a statistically significant (p=0.0037) p-eIF4E inhibition in PBMCs of 24% at 24 h post-dose with 10 mg, and an inhibition of ≥27 % up to 52% was seen in 11/14 subjects in the 20 mg group where ETC-206 plasma concentrations remained above the IC50for p-eIF4E (1.7 µM) for 30 h. While in mouse pharmacodynamic (PD) activity was also shown in tumor, skin, and hair follicles (HFs), in human tissues, PBMCs showed a trend for delayed PD inhibition and skin was not a suitable surrogate. Analysis of pharmacokinetic (PK) and PD relationships shown herein demonstrate excellent pharmaceutical properties of ETC-206 which has now advanced to Ph2 clinical trials (NCT05462236).
A new look at functional beta diversity
Authors: Ricotta Carlo , Pavoine Sandrine 
Published: February 2024

AbstractThe variability in species composition among a set of sampling sites, or beta diversity, is considered a key signature of the ecological processes that shape the spatial structure of species assemblages.In this paper, we propose to decompose this variability into three additive components: i) the standard compositional similarity between individuals of the same species among sites, ii) the degree of functionaldissimilaritybetween individuals of distinct species among sites, and iii) the degree of functionalsimilaritybetween individuals of distinct species among sites. These three components can be used to portray the functional resemblance among sites on a ternary diagram.The potential of this method is shown with real data on the functional turnover of Alpine species along a primary succession on glacial deposits in northern Italy.Synthesis. With the resulting ternary diagram of ‘functional resemblance’ we can relate various aspects of taxonomic and functional variability among sites to community assembly processes more completely than just looking at individual components.
Evaluation of commonin vitroassays for the prediction of oral bioavailability and hepatic metabolic clearance in humans
Authors: Fagerholm Urban 
Published: February 2024

ABSTRACTIntroductionIntrinsic hepatic metabolic clearance (CLint) measured with human hepatocytes, apparent intestinal permeability (Papp) obtained using the Caco-2 model, unbound fraction in plasma (fu) and blood-to-plasma concentration ratio (Cbl/Cpl) are commonly used for predicting the hepatic clearance (CLH) and oral bioavailability (F) of drug candidates in humans. The primary objective was to select drugs whosein vitrohepatocyte CLint, Caco-2 Papp, fuand Cbl/Cplhave been measured in various laboratories and studies, and estimate correlation coefficients (R2) for predicted and observed F and log plasma CLH. Secondary aims were to estimate the laboratory/study variability and its impact on predictions and to compare results toin silicoand animal model-based predictions.Materials and MethodsA literature search was done in order to find unbound hepatocyte CLint, (and corresponding predictedin vivoCLint), Caco-2 Papp, fuand Cbl/Cpldata. Compounds with multiple measurements for the four assays, without significantin vivosolubility/dissolution limitations and with knownin vivoCLHand F, were selected. Min, max and mean estimates were used in the analysis.Results and DiscussionThirty-two compounds with data (in total 561 estimates) produced by 21 major pharmaceutical companies and universities met the inclusion criteria. The predicted vs observed R2for log mean CLint, log mean CLHand mean F were 0.32, 0.08 and 0.20, respectively. Exclusion of atenolol increased the R2for CLHto 0.20. R2-values were considerably lower than those presented in many studies, which seems to be explained by selection bias (choosing favorable reference values). There was considerable interstudy variability for measured and predicted CLint(80- and 1,476-fold mean and max differences, respectively) and measured fu(6.6- and 50-fold mean and max differences, respectively). For F, higher predictive performance was found forin silico(Q2=0.58; head-to-head) and animalin vivomodels (R2=0.30).ConclusionThe combination of data from many laboratories and the use of mean values resulted in reduced selection bias and predictive accuracy. Overall, the predictive accuracy (here R2) for log CLint, log CLHand F was low to moderately low (0.08-0.32). The halved R2compared to individual studies where high performance was demonstrated seems to be explained be selection bias (enabled by large data variability). Animalin vivomodels, and in particular,in silicomethodology, outperformedin vitromethodology for the prediction of F in man.
Perinatal Brain Injury Triggers Niche-Specific Changes to Cellular Biogeography
Authors: Tahmasian Nareh , Feng Min Yi , Arbabi Keon , Rusu Bianca , Cao Wuxinhao , Kukreja Bharti , Lubotzky Asael , Wainberg Michael , Tripathy Shreejoy J. , Kalish Brian T. 
Published: February 2024

SUMMARYPreterm infants are at risk for brain injury and neurodevelopmental impairment due, in part, to white matter injury following chronic hypoxia exposure. However, the precise molecular mechanisms by which perinatal hypoxia disrupts early neurodevelopment are poorly understood. Here, we constructed a brain-wide map of the regenerative response to newborn brain injury using high-resolution imaging-based spatial transcriptomics to analyze over 1.3 million cells in a mouse model of chronic neonatal hypoxia. Additionally, we developed a new method for inferring condition-associated differences in cell type spatial proximity, enabling the identification of niche-specific changes in cellular architecture. We observed hypoxia-associated changes in region-specific cell states, cell type composition, and spatial organization. Importantly, our analysis revealed mechanisms underlying reparative neurogenesis and gliogenesis, while also nominating pathways that may impede circuit rewiring following perinatal hypoxia. Altogether, our work provides a comprehensive description of the molecular response to newborn brain injury.
Evoked Resonant Neural Activity Long-Term Dynamics can be Reproduced by a Computational Model with Vesicle Depletion
Authors: Sermon James J. , Wiest Christoph , Tan Huiling , Denison Timothy , Duchet Benoit 
Published: February 2024

AbstractSubthalamic deep brain stimulation (DBS) robustly generates high-frequency oscillations known as evoked resonant neural activity (ERNA). Recently the importance of ERNA has been demonstrated through its ability to predict the optimal DBS contact in the subthalamic nucleus in patients with Parkinson’s disease. However, the underlying mechanisms of ERNA are not well understood, and previous modelling efforts have not managed to reproduce the wealth of published data describing the dynamics of ERNA. Here, we therefore aim to present a minimal model capable of reproducing the characteristics of the slow ERNA dynamics published to date. We make biophysically-motivated modifications to the Kuramoto model and fit its parameters to the slow dynamics of ERNA obtained from data. We further validate the model against experimental data from Parkinson’s disease patients by simulating variable stimulation and medication states, as well as the response of individual neurons. Our results demonstrate that it is possible to reproduce the slow dynamics of ERNA with a single neuronal population, and, crucially, with vesicle depletion as the key mechanism behind the ERNA frequency decay. We provide a series of predictions from the model that could be the subject of future studies for further validation.Author SummaryERNA is a high amplitude response to stimulation of deep brain structures, with a frequency over twice that of the frequency of stimulation. While the underlying mechanisms of ERNA are still unclear, recent findings have demonstrated its importance as the best indicator of which stimulation contact to select for DBS therapy in patients with Parkinson’s disease. Previous modelling studies of ERNA focus on the immediate responses to stimulation (<200ms) and rely on interconnected neural structures and delays. Our work shows that the long-term (on the scale of one or more seconds) ERNA response to continuous stimulation can be modelled using a single neural structure. The proposed model also captures the long-term frequency and amplitude characteristics of ERNA with variable stimulation and medication paradigms. The key features of the model, in particular the depletion of vesicles carrying neurotransmitters between neurons by high-frequency stimulation, may provide insights into the underlying mechanisms of ERNA and inform future investigations into this neural response.
Dynamic Clinical Success Rates for Drugs in the 21st Century
Authors: Zhou Ying , Zhang Yintao , Chen Zhen , Huang Shijie , Li Yinghong , Fu Jianbo , Zhang Hongning , Zhao Donghai , Lian Xichen , Zhou Yuan , Shen Xinyi , Qiu Yunqing , Han Lianyi , Zhu Feng 
Published: February 2024

AbstractIn clinical drug development, two fundamental questions remain unanswered: what is the success rate of drugs in clinical trial? how does such rate change over time? Herein, a systematic analysis on the dynamic change of drugs’clinical success rates(ClinSRs) using data from 20,398 clinical trial pipelines of 9,682 unique molecular entities during the past two decades was presented. Our analysis discovered that ClinSRs had been declining since the beginning of 21st century, and hit the bottom in recent years even substantially lower than previous estimates. In-depth assessments further reported great variation among the ClinSRs of various diseases, developmental strategies, and drug modalities. A platform ‘ClinSR.org’ (http://ClinSR.idrblab.org/) was finally constructed online to enable the illustration of how ClinSR dynamically changes over time, automated update of ClinSR for the coming decade, and customized calculation of ClinSRs for any drug group of interest. In sum, this study met the critical demand for accurate, timely and persistent assessment of ClinSR, for now and the future, to aid pharmaceutical and economic decision making.
A Curated Compendium of Transcriptomic Data for the Exploration of Neocortical Development
Authors: Sonthalia Shreyash , Adkins Ricky S. , Orvis Joshua , Li Guangyan , Blanco Xoel Mato , Casella Alex , Liu Jinrui , Stein-O’Brien Genevieve , Caffo Brian , Hertzano Ronna , Mahurkar Anup , Gillis Jesse , Werner Jonathan , Ma Shaojie , Micali Nicola , Sestan Nenad , Rakic Pasko , Santpere Gabriel , Ament Seth A. , Colantuoni Carlo 
Published: February 2024

AbstractVast quantities of multi-omic data have been produced to characterize the development and diversity of cell types in the cerebral cortex of humans and other mammals. To more fully harness the collective discovery potential of these data, we have assembled gene-level transcriptomic data from 188 published studies of neocortical development, including the transcriptomes of ∼30 million single-cells, extensive spatial transcriptomic experiments and RNA sequencing of sorted cells and bulk tissues:nemoanalytics.org/landing/neocortex. Applying joint matrix decomposition (SJD) to mouse, macaque and human data in this collection, we defined transcriptome dynamics that are conserved across mammalian neurogenesis and which elucidate the evolution of outer, or basal, radial glial cells. Decomposition of adult human neocortical data identified layer-specific signatures in mature neurons and, in combination with transfer learning methods in NeMO Analytics, enabled the charting of their early developmental emergence and protracted maturation across years of postnatal life. Interrogation of data from cerebral organoids demonstrated that while broad molecular elements ofin vivodevelopment are recapitulatedin vitro, many layer-specific transcriptomic programs in neuronal maturation are absent. We invite computational biologists and cell biologists without coding expertise to use NeMO Analytics in their research and to fuel it with emerging data (carlocolantuoni.org).