bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Evolution of Ultraconserved Elements in Vertebrates
Authors: Cummins Mitchell , Watson Cadel , Edwards Richard J , Mattick John S 
Published: July 2024

Abstract
Ultraconserved elements were discovered two decades ago, arbitrarily defined as sequences that are identical over a length ≥ 200 bp in the human, mouse, and rat genomes. The definition was subsequently extended to sequences ≥ 100 bp identical in at least three of five mammalian genomes (including dog and cow), and shown to have undergone rapid expansion from ancestors in fish and strong negative selection in birds and mammals. Since then, many more genomes have become available, allowing better definition and more thorough examination of ultraconserved element distribution and evolutionary history. We developed a fast and flexible analytical pipeline for identifying ultraconserved elements in multiple genomes, dedUCE, which allows manipulation of minimum length, sequence identity, and number of species with a detectable ultraconserved element according to specified parameters. We suggest an updated definition of ultraconserved elements as sequences ≥ 100 bp and ≥97% sequence identity in ≥50% of placental mammal orders (12,813 ultraconserved elements). By mapping ultraconserved elements to ∼200 species, we find that placental ultraconserved elements appeared early in vertebrate evolution, well before land colonization, suggesting that the evolutionary pressures driving ultraconserved element selection were present in aquatic environments in the Cambrian–Devonian periods. Most (&gt;90%) ultraconserved elements likely appeared after the divergence of gnathostomes from jawless predecessors, were largely established in sequence identity by early Sarcopterygii evolution—before the divergence of lobe-finned fishes from tetrapods—and became near fixed in the amniotes. Ultraconserved elements are mainly located in the introns of protein-coding and noncoding genes involved in neurological and skeletomuscular development, enriched in regulatory elements, and dynamically expressed throughout embryonic development.
Inhibition of PERK-mediated unfolded protein response acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma
Authors: Ketkar Madhura , Desai Sanket , Rana Pranav , Thorat Rahul , Epari Sridhar , Dutt Amit , Dutt Shilpee 
Published: July 2024

Abstract

Background
Glioblastoma due to recurrence is clinically challenging with 10–15 months overall survival. Previously we showed that therapy-induced senescence (TIS) in glioblastoma reverses causing recurrence. Here, we aim to delineate the TIS reversal mechanism for potential therapeutic intervention to prevent glioblastoma (GBM) recurrence.

Methods
Residual senescent (RS) and end of residual senescence (ERS) cells were captured from GBM patient-derived primary-cultures and cell lines mimicking clinical scenarios. RNA-sequencing, transcript/protein validations, knock-down/inhibitor studies, ChIP RT-PCR, biochemical assays, and IHCs were performed for the mechanistics of TIS reversal. In vivo validations were conducted in GBM orthotopic mouse model.

Results
Transcriptome analysis showed co-expression of endoplasmic reticulum (ER) stress-unfolded protein response (UPR) and senescence-associated secretory phenotype (SASP) with TIS induction and reversal. Robust SASP production and secretion by RS cells could induce senescence, Reactive oxygen specis (ROS), DNA damage, and ER stress in paracrine fashion independent of radiation. Neutralization of most significantly enriched cytokine from RS-secretome IL1β, suppressed SASP, and delayed senescence reversal. Mechanistically, with SASP and massive protein accumulation in ER, RS cells displayed stressed ER morphology, upregulated ER stress markers, and PERK pathway activation via peIF2α-ATF4-CHOP which was spontaneously resolved in ERS. ChIP RT-PCR showed CHOP occupancy at CXCL8/IL8, CDKN1A/p21, and BCL2L1/BCLXL aiding survival. PERK knockdown/inhibition with GSK2606414 in combination with radiation led to sustained ER stress and senescence without SASP. PERKi in RS functioned as senolytic via apoptosis and prevented recurrence in vitro and in vivo ameliorating overall survival.

Conclusion
We demonstrate that PERK-mediated UPR regulates senescence reversal and its inhibition can be exploited as a potential seno-therapeutic option in glioblastoma.
Oral Preexposure Prophylaxis Uptake and Discontinuation in the HIV Vaccine Trials Network 704/HIV Prevention Trials Network 085 Study: Implications for Biomedical Human Immunodeficiency Virus Prevention Trials
Authors: Cantos Valeria D , Neradilek Moni , Huang Yunda , Roxby Alison C , Gillespie Kevin , deCamp Allan C , Karuna Shelly T , Edupuganti Srilatha , Gallardo-Cartagena Jorge , Sanchez Jorge , del Rio Carlos , Veloso Valdilea , Cohen Myron S , Donnell Deborah J , Corey Lawrence , Kelley Colleen F 
Published: July 2024

Abstract

Background
HIV Vaccine Trials Network (HVTN) 704/085, a placebo-controlled clinical trial assessing the efficacy of VRC01 broadly neutralizing antibody infusion for HIV prevention, offered oral preexposure prophylaxis (PrEP) as the standard of prevention at no cost to participants.

Methods
We characterized features of- identified factors associated with- PrEP initiation and discontinuation, and the effects of PrEP initiation on HIV incidence.

Results
Of 2221 participants, 31.8% initiated oral PrEP during study follow-up, with the highest proportion of PrEP initiations in Brazil (83.2%) and the United States (US) (54.2%). Prior PrEP use was associated with PrEP initiation (hazard ratio [HR], 2.22 [95% confidence interval {CI}, 1.25–3.95]). Participants from Switzerland (HR, 0.5 [95% CI, .3–1.0]) and Peru (HR, 0.08 [95% CI, .06–.1]) had lower likelihood of PrEP initiation compared to the US, while participants from Brazil had higher likelihood (HR, 2.6 [95% CI, 2.0–3.3]). In the US, PrEP initiation was lower in areas with higher unmet need for PrEP (HR, 0.9 per 5 units [95% CI, 0.8–1.0]). PrEP initiators had 58% less risk of acquiring HIV than PrEP noninitiators. Among PrEP initiators, 34.4% discontinued PrEP during study follow-up. Brazil had 63% less likelihood of PrEP discontinuation than the US (HR, 0.37 [95% CI, .22–.60]).

Conclusions
When included as standard of prevention in HVTN 704/085, oral PrEP utilization patterns mirrored those observed in real-life settings. Variable effects of oral PrEP on HIV outcomes in clinical trials may be expected based on regional differences in oral PrEP use.
Incorporating boron distribution variations in microdosimetric kinetic model-based relative biological effectiveness calculations for boron neutron capture therapy
Authors: Li Mingzhu , Geng Changran , Han Yang , Guan Fada , Liu Yuanhao , Shu Diyun , Tang Xiaobin 
Published: July 2024

Abstract
This study introduces the MKM_B model, an approach derived from the MKM model, designed to evaluate the biological effectiveness of Boron Neutron Capture Therapy (BNCT) in the face of challenges from varying microscopic boron distributions. The model introduces a boron compensation factor, allowing for the assessment of compound Biological Effectiveness (CBE) values for different boron distributions. Utilizing the TOPAS simulation platform, the lineal energy spectrum of particles in BNCT was simulated, and the sensitivity of the MKM_B model to parameter variations and the influence of cell size on the model were thoroughly investigated. The CBE values for 10B-boronphenylalanine (BPA) and 10B-sodium (BSH) were determined to be 3.70 and 1.75, respectively. These calculations were based on using the nucleus radius of 2.5 μm and the cell radius of 5 μm while considering a 50% surviving fraction. It was observed that as cell size decreased, the CBE values for both BPA and BSH increased. Additionally, the model parameter rd was identified as having the most significant impact on CBE, with other parameters showing moderate effects. The development of the MKM_B model enables the accurate prediction of CBE under different boron distributions in BNCT. This model offers a promising approach to optimize treatment planning by providing increased accuracy in biological effectiveness.
Comprehensive metabolic modulations of sphingolipids are promising severity indicators in COVID‐19
Authors: Uranbileg Baasanjav , Isago Hideaki , Nakayama Hitoshi , Jubishi Daisuke , Okamoto Koh , Sakai Eri , Kubota Masayuki , Tsutsumi Takeya , Moriya Kyoji , Kurano Makoto 
Published: July 2024

AbstractThe COVID‐19 pandemic, caused by SARS‐CoV‐2, has had a significant worldwide impact, affecting millions of people. COVID‐19 is characterized by a heterogenous clinical phenotype, potentially involving hyperinflammation and prolonged tissue damage, although the exact underlying mechanisms are yet to be fully understood. Sphingolipid metabolites, which govern cell survival and proliferation, have emerged as key players in inflammatory signaling and cytokine responses. Given the complex metabolic pathway of sphingolipids, this study aimed to understand their potential role in the pathogenesis of COVID‐19. We conducted a comprehensive examination of sphingolipid modulations across groups classified based on disease severity, incorporating a time‐course in serum and urine samples. Several sphingolipids, including sphingosine, lactosylceramide, and hexosylceramide, emerged as promising indicators of COVID‐19 severity, as validated by correlation analyses conducted on both serum and urine samples. Other sphingolipids, such as sphingosine 1‐phosphate, ceramides, and deoxy‐dihydroceramides, decreased in both COVID‐19 patients and individuals with non‐COVID infectious diseases. This suggests that these sphingolipids are not specifically associated with COVID‐19 but rather with pathological conditions caused by infectious diseases. Our analysis of urine samples revealed elevated levels of various sphingolipids, with changes dependent on disease severity, potentially highlighting the acute kidney injury associated with COVID‐19. This study illuminates the intricate relationship between disturbed sphingolipid metabolism, COVID‐19 severity, and clinical factors. These findings provide valuable insights into the broader landscape of inflammatory diseases.
Perioperative care of patients with recent stroke undergoing nonemergent, nonneurological, noncardiac, nonvascular surgery: a systematic review and meta-analysis
Authors: Lele Abhijit V. , Moreton Elizabeth Olive , Sundararajan Jayashree , Blacker Samuel Neal 
Published: July 2024

Purpose of review
To systematically review and perform a meta-analysis of published literature regarding postoperative stroke and mortality in patients with a history of stroke and to provide a framework for preoperative, intraoperative, and postoperative care in an elective setting.

Recent findings
Patients with nonneurological, noncardiac, and nonvascular surgery within three months after stroke have a 153-fold risk, those within 6 months have a 50-fold risk, and those within 12 months have a 20-fold risk of postoperative stroke. There is a 12-fold risk of in-hospital mortality within three months and a three-to-four-fold risk of mortality for more than 12 months after stroke. The risk of stroke and mortality continues to persist years after stroke. Recurrent stroke is common in patients in whom anticoagulation/antiplatelet therapy is discontinued. Stroke and time elapsed after stroke should be included in the preoperative assessment questionnaire, and a stroke-specific risk assessment should be performed before surgical planning is pursued.

Summary
In patients with a history of a recent stroke, anesthesiology, surgery, and neurology experts should create a shared mental model in which the patient/surrogate decision-maker is informed about the risks and benefits of the proposed surgical procedure; secondary-stroke-prevention medications are reviewed; plans are made for interruptions and resumption; and intraoperative care is individualized to reduce the likelihood of postoperative stroke or death.
Harnessing artificial intelligence for predicting and managing postoperative pain: a narrative literature review
Authors: Sajdeya Ruba , Narouze Samer 
Published: July 2024

Purpose of review
This review examines recent research on artificial intelligence focusing on machine learning (ML) models for predicting postoperative pain outcomes. We also identify technical, ethical, and practical hurdles that demand continued investigation and research.

Recent findings
Current ML models leverage diverse datasets, algorithmic techniques, and validation methods to identify predictive biomarkers, risk factors, and phenotypic signatures associated with increased acute and chronic postoperative pain and persistent opioid use. ML models demonstrate satisfactory performance to predict pain outcomes and their prognostic trajectories, identify modifiable risk factors and at-risk patients who benefit from targeted pain management strategies, and show promise in pain prevention applications. However, further evidence is needed to evaluate the reliability, generalizability, effectiveness, and safety of ML-driven approaches before their integration into perioperative pain management practices.

Summary
Artificial intelligence (AI) has the potential to enhance perioperative pain management by providing more accurate predictive models and personalized interventions. By leveraging ML algorithms, clinicians can better identify at-risk patients and tailor treatment strategies accordingly. However, successful implementation needs to address challenges in data quality, algorithmic complexity, and ethical and practical considerations. Future research should focus on validating AI-driven interventions in clinical practice and fostering interdisciplinary collaboration to advance perioperative care.
Kratom: a primer for pain physicians
Authors: Emerick Trent , Durbhakula Shravani , Eibel Maria R. , Kohan Lynn 
Published: July 2024

Purpose of review
Kratom is used commonly in the United States, usually to mitigate pain, opioid withdrawal, or fatigue. A comprehensive discussion on kratom, tailored to pain management physicians, is needed, given its associated risks and potential interactions.

Recent findings
Kratom and its main metabolites, mitragynine and 7-OH-mitragynine, bind to a variety of receptors including mu opioid receptors. Still, kratom cannot be described as a classic opioid. Kratom has been utilized without FDA approval as an alternative to traditional medications for opioid use disorder and opioid withdrawal. Lower doses of kratom typically cause opioid-like effects while higher doses can have sedating effects. Tolerance, dependence and withdrawal still occur, although kratom withdrawal appears to be more moderate than opioid withdrawal. Contamination with heavy metals and biological toxins is concerning and there is potential for serious complications, including seizures and death.

Summary
The use of kratom as an opioid-sparing alternative as a part of a multimodal pain regimen is not without significant risks. It is of utmost importance for pain physicians to be aware of the risks and adverse effects associated with kratom use.
Resting-State Functional Connectivity Predicts Cochlear-Implant Speech Outcomes
Authors: Esmaelpoor Jamal , Peng Tommy , Jelfs Beth , Mao Darren , Shader Maureen J. , McKay Colette M. 
Published: July 2024

Objectives:
Cochlear implants (CIs) have revolutionized hearing restoration for individuals with severe or profound hearing loss. However, a substantial and unexplained variability persists in CI outcomes, even when considering subject-specific factors such as age and the duration of deafness. In a pioneering study, we use resting-state functional near-infrared spectroscopy to predict speech-understanding outcomes before and after CI implantation. Our hypothesis centers on resting-state functional connectivity (FC) reflecting brain plasticity post-hearing loss and implantation, specifically targeting the average clustering coefficient in resting FC networks to capture variation among CI users.

Design:
Twenty-three CI candidates participated in this study. Resting-state functional near-infrared spectroscopy data were collected preimplantation and at 1 month, 3 months, and 1 year postimplantation. Speech understanding performance was assessed using consonant-nucleus-consonant words in quiet and Bamford-Kowal-Bench sentences in noise 1-year postimplantation. Resting-state FC networks were constructed using regularized partial correlation, and the average clustering coefficient was measured in the signed weighted networks as a predictive measure for implantation outcomes.

Results:
Our findings demonstrate a significant correlation between the average clustering coefficient in resting-state functional networks and speech understanding outcomes, both pre- and postimplantation.

Conclusions:
This approach uses an easily deployable resting-state functional brain imaging metric to predict speech-understanding outcomes in implant recipients. The results indicate that the average clustering coefficient, both pre- and postimplantation, correlates with speech understanding outcomes.
Concurrent Use of Trastuzumab Deruxtecan and Radiation Therapy in HER2-positive and HER2-low Metastatic Breast Cancer
Authors: Bouziane Jihane , Loap Pierre , Cao Kim , Allali Sofiane , Gounane Yacine , Loganadane Gokoulakrichenane , Escalup Laurence , Pierga Jean-Yves , Kirova Youlia 
Published: July 2024

Objectives:
Recent DESTINY-Breast trials have demonstrated trastuzumab deruxtecan’s effectiveness in HER2-positive and HER2-low metastatic breast cancer. However, safety concerns remain regarding its combination with radiation therapy (RT). The purpose of this work is to assess the toxicity profile of combining trastuzumab deruxtecan and RT in patients with HER2-positive and HER2-low metastatic breast cancer to address these concerns.

Methods:
We conducted a retrospective study which included patients treated at Institut Curie Paris between November 2020 and January 2024. Patients with HER2-positive and HER2-low metastatic breast cancer who received concurrent trastuzumab deruxtecan and RT were identified. Data on patient demographics, treatment regimens, radiation doses, toxicity profiles, and treatment discontinuations were collected. Follow-up was conducted from the last day of radiotherapy until death or the last examination and toxicities were graded using the CTCAE V5.0.

Results:
The studied population includes all 33 patients with HER2-positive and HER2-low metastatic breast cancer who underwent concurrent treatment with trastuzumab deruxtecan and radiotherapy. The median follow-up was 11 months. The most common acute grade 1 toxicity was nausea. Grade 2 toxicities affected 21.2% of patients, including asthenia, mucositis, cardiac decompensation, and diarrhea. Trastuzumab deruxtecan discontinuation occurred in 5 patients due to systemic treatment-related toxicities, including nausea, thrombocytopenia, neutropenia, and cardiac decompensation. There were 21.2% reported with late toxicities, with nausea being the most prevalent.

Conclusions:
Our series of patients who received concurrent treatment of radiotherapy and trastuzumab deruxtecan are showing acceptable toxicity. Larger prospective studies are needed to evaluate the toxicity and efficacy of this combination.
Evolving Trends in the Diagnosis and Management of Keratoconus Over 3 Decades
Authors: Deshmukh Rashmi S. , Das Anthony Vipin , Vaddavalli Pravin Krishna 
Published: July 2024

Purpose:
To report the trends in the clinical presentation, diagnosis, and management of keratoconus (KC) in patients presenting to a multitier hospital network over 33 years.

Methods:
This retrospective study included patients with KC presenting from 1987 to 2020. Patients with KC in at least 1 eye were included. The data of 20,576 patients included in this study were retrieved from the electronic medical record database. Data on patient demographics, ocular diagnosis, contact lens usage, and surgical history were collected and exported for analysis. Descriptive statistics and chi square test were used for statistical analysis.

Results:
A total of 20,576 KC cases were seen from 1987 to 2020. Mean age at diagnosis reduced from 29.3 years (1987–1991) to 22.2 years (2016–2020). Adults (76.64%) were commonly affected with a majority being male (61.25%). Use of contact lenses increased from 4.34% (2002–2006) to 11.23% (2016–2020). Of the total number of surgical interventions, collagen crosslinking (CXL) constituted more than 1/5th (22.28%) between 2007 and 2011, which increased to more than half between 2012 and 2016 (53.61%) and almost 3/4th (72.53%) between 2017 and 2020. Advances in lamellar surgery have led to more patients undergoing deep anterior lamellar keratoplasty (DALK) as compared with penetrating keratoplasty. In the last 8 years, 17.2% patients underwent surgery and the most common was CXL (14.77%) followed by DALK (1.72%) and penetrating keratoplasty (1.04%).

Conclusions:
We report the trends in the clinical presentation and management of KC over 3 decades. In the last 33 years, advances in diagnostics have helped diagnose KC earlier. Contact lenses and advances in CXL have reduced the number of keratoplasties in KC, DALK being more common.
Relationships of Psychosocial Factors to Diabetes Self-efficacy
Authors: Heo Seongkum , Kang JungHee , Barbé Tammy , Kim JinShil , Slocumb Rhonda H. , Haley Brandy , Wright Nina 
Published: July 2024

Background
Self-care in people with diabetes is poor, which could be influenced by positive and negative psychosocial factors. Self-efficacy is an important factor affecting self-care, and depressive symptoms and diabetes distress may directly and indirectly affect self-efficacy.

Objective
The aim of this study was to examine the relationships of depressive symptoms, diabetes distress, age, sex, self-compassion, resilience, self-esteem, and social support to diabetes self-efficacy and the mediating roles of diabetes distress and depressive symptoms in the relationships among people with diabetes.

Methods
In this cross-sectional, correlational study, data on all the psychosocial and demographic factors were collected (N = 148; 57.6 years old) through Research Electronic Data Capture in 2023. The PROCESS macro for SPSS was used to address the purpose.

Results
The mean score of diabetes self-efficacy was 28.6 (range, 8–40). In 1 model, depressive symptoms were directly and indirectly associated with diabetes self-efficacy through diabetes distress (direct effect, −3.524; t = −3.020, P = .003; indirect effect, −2.089; 95% bootstrap confidence interval, −3.494 to −0.911). In another model, diabetes distress was directly and indirectly associated with diabetes self-efficacy through depressive symptoms (direct effect, −3.778; t = −3.638, P < .001; indirect effect, −0.785; 95% bootstrap confidence interval, −1.868 to −0.089). In addition, self-esteem was associated with both depressive symptoms and diabetes distress. Resilience was associated with diabetes self-efficacy in 1 model.

Conclusions
Negative psychological factors were directly and indirectly associated with diabetes self-efficacy. Depressive symptoms, diabetes distress, self-esteem, and resilience can be important targets of interventions to improve diabetes self-efficacy.