bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bayesian Phylogenetic Analysis on Multi-Core Compute Architectures: Implementation and Evaluation of BEAGLE in RevBayes With MPI
Authors: Smith Killian , Ayres Daniel , Neumaier René , Wörheide Gert , Höhna Sebastian 
Published: January 2024

Abstract
Phylogenies are central to many research areas in biology and commonly estimated using likelihood-based methods. Unfortunately, any likelihood-based method, including Bayesian inference, can be restrictively slow for large datasets—with many taxa and/or many sites in the sequence alignment—or complex substitutions models. The primary limiting factor when using large datasets and/or complex models in probabilistic phylogenetic analyses is the likelihood calculation, which dominates the total computation time. To address this bottleneck, we incorporated the high-performance phylogenetic library BEAGLE into RevBayes, which enables multi-threading on multi-core CPUs and GPUs, as well as hardware specific vectorized instructions for faster likelihood calculations. Our new implementation of RevBayes+BEAGLE retains the flexibility and dynamic nature that users expect from vanilla RevBayes. In addition, we implemented native parallelization within RevBayes without an external library using the message passing interface (MPI); RevBayes+MPI. We evaluated our new implementation of RevBayes+BEAGLE using multi-threading on CPUs and 2 different powerful GPUs (NVidia Titan V and NVIDIA A100) against our native implementation of RevBayes+MPI. We found good improvements in speedup when multiple cores were used, with up to 20-fold speedup when using multiple CPU cores and over 90-fold speedup when using multiple GPU cores. The improvement depended on the data type used, DNA or amino acids, and the size of the alignment, but less on the size of the tree. We additionally investigated the cost of rescaling partial likelihoods to avoid numerical underflow and showed that unnecessarily frequent and inefficient rescaling can increase runtimes up to 4-fold. Finally, we presented and compared a new approach to store partial likelihoods on branches instead of nodes that can speed up computations up to 1.7 times but comes at twice the memory requirements.
Patient-centered precision care in anaesthesia – the PC-square (PC)2 approach
Authors: Berger-Estilita Joana , Marcolino Isabel , Radtke Finn M. 
Published: January 2024

Purpose of review
This review navigates the landscape of precision anaesthesia, emphasising tailored and individualized approaches to anaesthetic administration. The aim is to elucidate precision medicine principles, applications, and potential advancements in anaesthesia. The review focuses on the current state, challenges, and transformative opportunities in precision anaesthesia.

Recent findings
The review explores evidence supporting precision anaesthesia, drawing insights from neuroscientific fields. It probes the correlation between high-dose intraoperative opioids and increased postoperative consumption, highlighting how precision anaesthesia, especially through initiatives like Safe Brain Initiative (SBI), could address these issues. The SBI represents multidisciplinary collaboration in perioperative care. SBI fosters effective communication among surgical teams, anaesthesiologists, and other medical professionals.

Summary
Precision anaesthesia tailors care to individual patients, incorporating genomic insights, personalised drug regimens, and advanced monitoring techniques. From EEG to cerebral/somatic oximetry, these methods enhance precision. Standardised reporting, patient-reported outcomes, and continuous quality improvement, alongside initiatives like SBI, contribute to improved patient outcomes. Precision anaesthesia, underpinned by collaborative programs, emerges as a promising avenue for enhancing perioperative care.
Risk Factors for Stiffness After Surgical Treatment of Pediatric Humeral Lateral Condyle Fractures: Results of a Multicenter Study
Authors: Tippabhatla Abhishek , Torres-Izquierdo Beltran , Pereira Daniel E. , Goldstein Rachel , Sanders Julia , Neal Kevin , Bellaire Laura , Denning Jaime , Hosseinzadeh Pooya 
Published: January 2024

Introduction:
Pediatric humeral lateral condyle fractures are the second most common elbow fractures. Their treatment presents challenges due to physeal and intra-articular involvement. Postoperative stiffness is a common concern that can limit limb functionality. This study aims to identify risk factors for postoperative stiffness in a large cohort of these fractures across multiple institutions.

Methods:
A large, multicenter retrospective review of medical records from 6 level I trauma centers was conducted. Data from children aged 1 to 12 years with lateral condyle fractures treated between 2005 and 2019 were collected. Elbow stiffness was defined in the present study as having a limited elbow ROM that led to requiring a physical or occupational therapy referral or needing surgical treatment to address stiffness. Relevant patient demographics, fracture characteristics, treatment approaches, and complications were analyzed.

Results:
Six hundred sixty-five fractures were analyzed. The average patient age was 8.8 years with 21% experiencing stiffness. The stiffness group had older patients, a higher incidence of elbow dislocations, a higher rate of open reduction, and more severe fracture patterns. Multivariate regression analysis identified open reduction, increased age, and concurrent elbow dislocation as significant risk factors for stiffness. Patients with stiffness commonly utilized only physical or occupational therapy (96%), while a small percentage (4%) required surgical interventions.

Conclusions:
This study highlights the risk factors for postoperative stiffness in pediatric humeral lateral condyle fractures, namely increased age, concomitant elbow dislocation, and treatment with open reduction. Families of older patients or severe fracture patterns requiring open reduction and those with concurrent elbow instability should be counseled about their increased risk of stiffness. The authors recommend initially attempting a closed reduction in high-risk patients to help mitigate the risk of postoperative stiffness. Early initiation of range of motion exercises may also be beneficial for at-risk patients.

Level of Evidence:
Level III: Therapeutic studies—Investigating the results of treatment
Lumbar Total Disc Replacement Device Removals and Revisions Performed During a 20 Year Experience with 2,141 Patients
Authors: Guyer Richard D. , Blumenthal Scott L. , Shellock Jessica L. , Zigler Jack E. , Ohnmeiss Donna D. 
Published: January 2024

Study Design:
This was a retrospective study with prospective patient contact attempted to collect current data.

Objective:
The purpose was to investigate the incidence and reasons for lumbar total disc replacement (TDR) removal or revision.

Summary of Background Data:
A concern regarding lumbar TDR was safety, particularly the need for device removal or revision. This may be particularly important considering removal/revision requires repeat anterior exposure with increased risk of vascular injury.

Methods:
Data were collected for a series of 2,141 lumbar TDR patients beginning with the first case experience in 2000. Mean follow-up was 78.6 months. For each case of device removal/revision, the reason, duration from index surgery, and procedure performed were recorded.

Results:
Of 2,141 patients, 27 (1.26%) underwent TDR removal or revision. Device removal was performed in 24 patients (1.12%) while 3 patients underwent revision (0.14%). Of the 24 removals: 12 were due to migration and/or loosening, 3 developed problems post-trauma, 2 developed lymphocytic reaction to device materials, 2 had ongoing pain, and there was one case of each: TDR was too large, vertebral body fracture (osteoporosis), lytic lesion, device subsidence and facet arthrosis, and infection seeded from a chest infection 146 months post-TDR. The 3 revisions were for: Core repositioning (technique error), device repositioning after displacement, and core replacement due to wear/failure. With respect to timing, 37.0% of removals/revisions occurred within one month post-implantation. Of note, 40.7% of removals/revisions occurred in the first 25 TDR cases performed by individual surgeons. There was one significant vascular complication, occurring in a patient whose TDR was removed due to trauma. This was also the only patient among 258 with >15-year follow-up who underwent removal/revision.

Conclusion:
In this large consecutive series, 1.26% of TDRs were removed/revised. The low rate over a 20 year period supports the safety of these devices.
Heterogeneity of treatment response to beta-blockers in the treatment of portal hypertension: A systematic review
Authors: Alsaeid Mohammad , Sung Shuen , Bai Wayne , Tam Matthew , Wong Yu Jun , Cortes Jordi , Cobo Erik , Gonzalez Jose Antonio , Abraldes Juan G. 
Published: January 2024

Background:
It has been suggested that a relevant proportion of patients do not respond to nonselective beta-blockers (NSBB)s, which raises questions regarding the need for individualized therapy. The existence of potential heterogeneity in the treatment response can be assessed using the variability ratio (VR) of the outcome measurement (in this case, HVPG) between the treated and placebo groups. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the potential heterogeneity in the portal pressure response to NSBBs.

Methods:
After a systematic search, we quantified the heterogeneity of treatment response with the VR between the treatment and control groups, with VR > 1 indicating potential heterogeneity. We used a similar approach to compare carvedilol with propranolol and statins with placebo.

Results:
We identified 18 studies that included 965 patients. A comparison between beta-blockers and placebo showed a pooled VR of 0.99 (95% CI:0.87–1.14), which suggests a homogeneous HVPG response to NSBB at the individual patient level (ie, no evidence to support that some patients responded to beta-blockers and others did not). For the comparison between carvedilol and propranolol, pooled VR was 0.97 (95% CI 0.82–1.14), suggesting that carvedilol achieves a greater average response (rather than an increase in the proportion of responders). There was no evidence of a heterogeneous response to statins.

Conclusion:
Our analysis did not support the existence of a heterogeneous patient-by-patient response to NSBBs in cirrhosis. These findings challenge the concept of personalized therapy based on portal pressure response and indicate that routine portal pressure measurement may not be necessary to guide NSBB therapy.
African American race does not confer an increased risk of clinical events in patients with primary sclerosing cholangitis
Authors: Yazdanfar Maryam , Zepeda Joseph , Dean Richard , Wu Jialin , Levy Cynthia , Goldberg David , Lammert Craig , Prenner Stacey , Reddy K. Rajender , Pratt Daniel , Forman Lisa , Assis David N. , Lytvyak Ellina , Montano-Loza Aldo J. , Gordon Stuart C. , Carey Elizabeth J. , Ahn Joseph , Schlansky Barry , Korzenik Joshua , Karagozian Raffi , Hameed Bilal , Chandna Shaun , Yu Lei , Bowlus Christopher L. 
Published: January 2024

Background:
The natural history of primary sclerosing cholangitis (PSC) among African Americans (AA) is not well understood.

Methods:
Transplant-free survival and hepatic decompensation–free survival were assessed using a retrospective research registry from 16 centers throughout North America. Patients with PSC alive without liver transplantation after 2008 were included. Diagnostic delay was defined from the first abnormal liver test to the first abnormal cholangiogram/liver biopsy. Socioeconomic status was imputed by the Zip code.

Results:
Among 850 patients, 661 (77.8%) were non-Hispanic Whites (NHWs), and 85 (10.0%) were AA. There were no significant differences by race in age at diagnosis, sex, or PSC type. Inflammatory bowel disease was more common in NHWs (75.8% vs. 51.8% p=0.0001). The baseline (median, IQR) Amsterdam-Oxford Model score was lower in NHWs (14.3, 13.4–15.2 vs. 15.1, 14.1–15.7, p=0.002), but Mayo risk score (0.03, −0.8 to 1.1 vs. 0.02, −0.7 to 1.0, p=0.83), Model for End-stage Liver Disease (5.9, 2.8–10.7 vs. 6.4, 2.6–10.4, p=0.95), and cirrhosis (27.4% vs. 27.1%, p=0.95) did not differ. Race was not associated with hepatic decompensation, and after adjusting for clinical variables, neither race nor socioeconomic status was associated with transplant-free survival. Variables independently associated with death/liver transplant (HR, 95% CI) included age at diagnosis (1.04, 1.02–1.06, p<0.0001), total bilirubin (1.06, 1.04–1.08, p<0.0001), and albumin (0.44, 0.33–0.61, p<0.0001). AA race did not affect the performance of prognostic models.

Conclusions:
AA patients with PSC have a lower rate of inflammatory bowel disease but similar progression to hepatic decompensation and liver transplant/death compared to NHWs.
Cellular origin and molecular mechanisms of lung metastases in patients with aggressive hepatoblastoma
Authors: Gulati Ruhi , Lutz Maggie , Hanlon Margaret , Cast Ashley , Karns Rebekah , Geller James , Bondoc Alex , Tiao Gregory , Timchenko Lubov , Timchenko Nikolai A. 
Published: January 2024

Background and Aims:
Lung metastases are the most threatening signs for patients with aggressive hepatoblastoma (HBL). Despite intensive studies, the cellular origin and molecular mechanisms of lung metastases in patients with aggressive HBL are not known. The aims of these studies were to identify metastasis-initiating cells in primary liver tumors and to determine if these cells are secreted in the blood, reach the lung, and form lung metastases.

Approach:
We have examined mechanisms of activation of key oncogenes in primary liver tumors and lung metastases and the role of these mechanisms in the appearance of metastasis-initiating cells in patients with aggressive HBL by RNA-Seq, immunostaining, chromatin immunoprecipitation, Real-Time Quantitative Reverse Transcription PCR and western blot approaches. Using a protocol that mimics the exit of metastasis-initiating cells from tumors, we generated 16 cell lines from liver tumors and 2 lines from lung metastases of patients with HBL.

Results:
We found that primary HBL liver tumors have a dramatic elevation of neuron-like cells and cancer-associated fibroblasts and that these cells are released into the bloodstream of patients with HBL and found in lung metastases. In the primary liver tumors, the ph-S675-β-catenin pathway activates the expression of markers of cancer-associated fibroblasts; while the ZBTB3-SRCAP pathway activates the expression of markers of neurons via cancer-enhancing genomic regions/aggressive liver cancer domains leading to a dramatic increase of cancer-associated fibroblasts and neuron-like cells. Studies of generated metastasis-initiating cells showed that these cells proliferate rapidly, engage in intense cell-cell interactions, and form tumor clusters. The inhibition of β-catenin in HBL/lung metastases–released cells suppresses the formation of tumor clusters.

Conclusions:
The inhibition of the β-catenin-cancer-enhancing genomic regions/aggressive liver cancer domains axis could be considered as a therapeutic approach to treat/prevent lung metastases in patients with HBL.
Sirtuin3 promotes the degradation of hepatic Z alpha-1 antitrypsin through lipophagy
Authors: Poole Brittney , Oshins Regina , Huo Zhiguang , Aranyos Alek , West Jesse , Duarte Sergio , Clark Virginia C. , Beduschi Thiago , Zarrinpar Ali , Brantly Mark , Khodayari Nazli 
Published: January 2024

Background:
Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by misfolding and accumulation of mutant alpha-1 antitrypsin (ZAAT) in the endoplasmic reticulum of hepatocytes. Hepatic ZAAT aggregates acquire a toxic gain-of-function that impacts the endoplasmic reticulum which is theorized to cause liver disease in individuals with AATD who present asymptomatic until late-stage cirrhosis. Currently, there is no treatment for AATD-mediated liver disease except liver transplantation. In our study of mitochondrial RNA, we identified that Sirtuin3 (SIRT3) plays a role in the hepatic phenotype of AATD.

Methods:
Utilizing RNA and protein analysis in an in vitro AATD model, we investigated the role of SIRT3 in the pathophysiology of AATD-mediated liver disease while also characterizing our novel, transgenic AATD mouse model.

Results:
We show lower expression of SIRT3 in ZAAT-expressing hepatocytes. In contrast, the overexpression of SIRT3 increases hepatic ZAAT degradation. ZAAT degradation mediated by SIRT3 appeared independent of proteasomal degradation and regular autophagy pathways. We observed that ZAAT-expressing hepatocytes have aberrant accumulation of lipid droplets, with ZAAT polymers localizing on the lipid droplet surface in a direct interaction with Perilipin2, which coats intracellular lipid droplets. SIRT3 overexpression also induced the degradation of lipid droplets in ZAAT-expressing hepatocytes. We observed that SIRT3 overexpression induces lipophagy by enhancing the interaction of Perilipin2 with HSC70. ZAAT polymers then degrade as a consequence of the mobilization of lipids through this process.

Conclusions:
In this context, SIRT3 activation may eliminate the hepatic toxic gain-of-function associated with the polymerization of ZAAT, providing a rationale for a potential novel therapeutic approach to the treatment of AATD-mediated liver disease.
Targeting G9a/DNMT1 methyltransferase activity impedes IGF2-mediated survival in hepatoblastoma
Authors: Demir Salih , Razizadeh Negin , Indersie Emilie , Branchereau Sophie , Cairo Stefano , Kappler Roland 
Published: January 2024

Background:
As the variable clinical outcome of patients with hepatoblastoma (HB) cannot be explained by genetics alone, the identification of drugs with the potential to effectively reverse epigenetic alterations is a promising approach to overcome poor therapy response. The gene ubiquitin like with PHD and ring finger domains 1 (UHRF1) represents an encouraging epigenetic target due to its regulatory function in both DNA methylation and histone modifications and its clinical relevance in HB.

Methods:
Patient-derived xenograft in vitro and in vivo models were used to study drug response. The mechanistic basis of CM-272 treatment was elucidated using RNA sequencing and western blot experiments.

Results:
We validated in comprehensive data sets that UHRF1 is highly expressed in HB and associated with poor outcomes. The simultaneous pharmacological targeting of UHRF1-dependent DNA methylation and histone H3 methylation by the dual inhibitor CM-272 identified a selective impact on HB patient-derived xenograft cell viability while leaving healthy fibroblasts unaffected. RNA sequencing revealed downregulation of the IGF2-activated survival pathway as the main mode of action of CM-272 treatment, subsequently leading to loss of proliferation, hindered colony formation capability, reduced spheroid growth, decreased migration potential, and ultimately, induction of apoptosis in HB cells. Importantly, drug response depended on the level of IGF2 expression, and combination assays showed a strong synergistic effect of CM-272 with cisplatin. Preclinical testing of CM-272 in a transplanted patient-derived xenograft model proved its efficacy but also uncovered side effects presumably caused by its strong antitumor effect in IGF2-driven tumors.

Conclusions:
The inhibition of UHRF1-associated epigenetic traces, such as IGF2-mediated survival, is an attractive approach to treat high-risk HB, especially when combined with the standard-of-care therapeutic cisplatin.
Influential Signs of Dry Eye–Related Ocular Symptoms in Participants With Unstable Tear Film
Authors: Shen Jiahui , Xu Zhiqiang , Wang Yuzhou , Ye Jingjian , Wei Linzhi , Xia Jiahui , Sun Yiran , Lu Fan , Hu Liang 
Published: January 2024

Purpose:
The aim of this study was to investigate the factors influencing dry eye disease (DED)-related ocular symptoms in participants with short fluorescein tear break-up time (FTBUT).

Methods:
This cross-sectional study included 82 participants with short FTBUT (<10 seconds). Examinations included Ocular Surface Disease Index (OSDI), FTBUT, average noninvasive tear break-up time (NIBUTave), lid wiper epitheliopathy, lipid layer thickness, blink rate, partial blink, tear meniscus height, and meibomian gland (MG) evaluation which included ratio of residual MG area (RMGA) and MG grade in tarsal plates. One-way analysis of variance was used to detect differences between symptomatic tear film instability group (FTBUT <5 s, OSDI ≥13), asymptomatic tear film instability group (FTBUT <5 s, OSDI <13), and control group (FTBUT ≥5 s, OSDI <13). A bivariate correlation, partial correlation, and multiple linear regression analyses were used to identify major factors. Only the right eye was included.

Results:
Among the participants with FTBUT <5 seconds, symptomatic group showed less upper RMGA (P < 0.001) and NIBUTave (P = 0.010). OSDI was negatively associated with upper RMGA (r = −0.450, P < 0.001) and NIBUTave (r = −0.414, P = 0.001), and positively associated with upper MG grade (r = 0.277, P = 0.027). Linear regression analysis showed that the upper RMGA significantly affected OSDI (B = −41.895, P = 0.001), while not significantly correlated with age, upper MG grade, and NIBUTave.

Conclusions:
The upper RMGA might be the main factor affecting DED-related discomfort in participants with unstable tear film, indicating an early ocular change in DED.
Risk Factors for Poor Outcomes in Children Hospitalized With Virus-associated Acute Lower Respiratory Infections: A Systematic Review and Meta-analysis
Authors: Trusinska Daira , Zin Si Thu , Sandoval Emmanuel , Homaira Nusrat , Shi Ting 
Published: January 2024

Background:
Acute lower respiratory infection (ALRI) caused by respiratory viruses is among the most common causes of hospitalization and mortality in children. We aimed to identify risk factors for poor outcomes in children <5 years old hospitalized with ALRI caused by respiratory syncytial virus (RSV), influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods:
We searched Embase, Medline and Global Health databases and included observational studies reporting risk factors for poor outcomes (defined as use of supplemental oxygen, mechanical ventilation, intensive care unit admission, prolonged hospital stay and mortality) published between January 2011 and January 2023. Two authors independently extracted data on study characteristics, outcomes and risk factors. Due to limited data, meta-analyses were only conducted for RSV-ALRI poor outcome risk factors using random effects model when there were at least 3 studies.

Results:
We included 30 studies. For RSV-related ALRI, significant risk factors based on meta-analysis were: neurological disease [odds ratio (OR): 6.14; 95% confidence intervals (CIs): 2.39–15.77], Down’s syndrome (5.43; 3.02–9.76), chronic lung disease (3.64; 1.31–10.09), immunocompromised status (3.41; 1.85–6.29), prematurity (2.98; 1.93–4.59), congenital heart disease (2.80; 1.84–4.24), underlying disease (2.45; 1.94–3.09), age <2 months (2.29; 1.78–2.94), age <6 months (2.08; 1.81–2.39), viral coinfection (2.01; 1.27–3.19), low birth weight (1.88; 1.19–2.95) and being underweight (1.80; 1.38–2.35). For influenza-related ALRI, chronic conditions and age 6–24 months were identified as risk factors for poor outcomes. Cardiovascular disease, immunosuppression, chronic kidney disease, diabetes and high blood pressure were reported as risk factors for mortality due to SARS-CoV-2 associated ALRI.

Conclusions:
These findings might contribute to the development of guidelines for prophylaxis and management of ALRI caused by RSV, influenza and SARS-CoV-2.