bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of High-Potency Synthetic Opioids on Pharmacotherapies for Opioid Use Disorder: A Scoping Review
Authors: Jegede Oluwole , De Aquino Joao P. , Hsaio Connie , Caldwell Ebony , Funaro Melissa C. , Petrakis Ismene , Muvvala Srinivas B.
Published: August 2024

Background

The clinical implications of high potency synthetic opioids (HPSO) on medications for opioid use disorder (MOUDs) are not well understood. Although pharmacological interactions are plausible, the clinical significance of such interaction has not been systematically elucidated. This scoping review investigates the relationship between HPSO exposure and various MOUD treatment outcomes.

Methods

We followed PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews) for scoping reviews with extensive a priori search strategy of databases: MEDLINE, EMBASE, PsycINFO, Web of Science, CINAHL, and Cochrane.

Results

From 9149 studies, 34 fulfilled the inclusion criteria. Synthesized data reveal several critical insights: First, there is a variable but high occurrence (38%–80%) of HPSO usage among individuals with MOUDs. Second, MOUDs are linked to a decreased risk of overdoses and deaths associated with HPSO. Third, HPSO consumption is correlated with the risk of precipitated withdrawal when starting buprenorphine. Fourth, low-dose buprenorphine is being recognized as one method to avoid moderate withdrawal symptoms prior to treatment. Lastly, significant gaps exist in human experimental data concerning the effects of HPSO on key factors critical for treating OUD-craving, withdrawal symptoms, and pain.

Conclusions

Current evidence supports MOUD safety and effectiveness in reducing nonmedical opioid use. Further research is needed to explore HPSO’s influence on the acute factors preceding nonmedical opioid use, such as cravings, withdrawal symptoms, and pain. This research could inform the optimization of MOUD dosing strategies. Achieving consensus and harmonizing data across clinical and research protocols could diminish variability, enhancing our understanding of HPSOs effect on MOUD treatment outcomes.
Management of Femoral and Tibial Shaft Fractures in Patients With Chronic Spinal Cord Injury
Authors: Moreno-Diaz Andres Fidel , Morris Cade A. , Obudzinski Sarah , Taylor Patrick R. , Pazik Marissa , Kakalecik Jaquelyn , Talerico Michael , Lins Laura , Kuhn Gabrielle , Whiting Paul , Chen Andrew , Tyler Andrew Farley , Mitchell Phillip M. , Obremskey William T. ,   on behalf of Southeastern Fracture Consortium
Published: August 2024

OBJECTIVES:

To compare outcomes and complications between nonoperative and operative management of femur and tibia fractures in patients with paraplegia or quadriplegia from chronic spinal cord injury (SCI).

METHODS:

Design:

Retrospective cohort study.

Setting:

Three Level-1 Trauma centers.

Patient Selection Criteria:

All adult patients with paraplegia or quadriplegia due to a chronic SCI with operative or nonoperative treatment of a femoral or tibial shaft fracture from January 1, 2009 through December 31, 2019 were included.

Outcome Measures and Comparisons:

Outcomes collected included range of motion, pain, return to baseline activity, extent of malunion, and treatment complications (infection, pressure ulcers, nonunion, deep vein thrombosis/pulmonary emobolus, stroke, amputation, death). Comparison between operative and nonoperative treatment were made for each outcome.

RESULTS:

Fifty-nine patients with acute lower extremity fracture in the setting of chronic SCI fulfilled inclusion criteria with a median age of 46 years in the operative group and 47 years in the nonoperative group. Twelve patients (70.6%) in the nonoperative group were male with 32 (76.2%) male patients in the operative group. Forty-six patients (78%) presented as low energy trauma. Differences were seen between operative and nonoperative management for pressure ulcers (19% vs. 52.9%, P = 0.009) and mean Visual Analog Scale pain score at first follow-up (1.19 vs. 3.3, P = 0.03). No difference was seen for rates of infection, nonunion, deep vein thrombosis/pulmonary emobolus, stroke, amputation, death, return to baseline activity, and range of motion.

CONCLUSIONS:

Tibial and femoral shaft fractures commonly resulted from low energy mechanisms in patients with chronic SCI. Operative treatment seemed to decrease morbidity in these patients via lowered rates of pressure ulcers and decreased pain compared with nonoperative management.

LEVEL OF EVIDENCE:

Therapeutic, Level III. See Instructions for Authors for a complete description of levels of evidence.
The 100 Most-cited Articles in Autologous Breast Reconstruction: A Bibliometric Analysis
Authors: Ruccia Francesca , Elmorsi Rami , Dhandapani Karthikeyan , Alzaid Mohammad , Bailón-Valdez Zaira , Tammasse Iin , Khajuria Ankur
Published: August 2024

Background:

Autologous breast reconstruction has continued to increase in popularity and witnessed significant advancements in aesthetic outcomes, patient satisfaction, and improved quality of life. We performed the first bibliometric analysis focused only on the 100 most-cited autologous breast reconstruction articles to characterize any emerging trends and assess the methodological quality of these studies.

Methods:

The 100 most-cited articles in autologous breast reconstruction were identified on Web of Science, across all available journals and years. Study details, including the citation count, main subject, and outcome measures, were extracted from each article, and the level of evidence was also assessed.

Results:

The 100 most-cited articles in autologous breast reconstruction were cited by a total of 21,194 articles. Citation per article ranged significantly from 112 to 1123 (mean, 211.9). Overall, most of the top-cited articles are case reports/series (n = 32, mean citations = 243.2) and cohort studies (n = 30, mean citations = 211.2). This is closely followed by case-control studies (n = 29, mean citations = 183.6). Only four studies achieved level 1 status, underscoring a lack of high-quality methodological research in the field. Most studies (n = 72) highlighted autologous breast reconstruction outcomes, whereas 12 focused on its indications. There were nine studies exploring surgical techniques, and seven studies addressing the autologous breast reconstruction surgical anatomy.

Conclusions:

Overall, most of the influential articles in autologous breast reconstruction literature are of lower-level evidence. Contemporary research should focus on enhancing the study designs and measure clinical and patient-reported outcomes with validated tools, such as BREAST-Q.
Long-Term Prognosis of Anterior Blepharitis After Topical Antibiotics Treatment
Authors: Sakimoto Tohru , Sugiura Takeshi
Published: August 2024

Objective:

We conducted a retrospective evaluation of the long-term prognosis associated with anterior blepharitis subsequent to topical antibiotic intervention.

Methods:

Inclusion criteria encompassed 92 eyes of 92 patients who exhibited clinical manifestations of anterior blepharitis and undergone a regimen of topical azithromycin. The follow-up duration extended to a minimum of one year within our medical facility. The diagnostic framework for anterior blepharitis, along with the evaluation of both objective and subjective manifestations, adhered to the Blepharitis Preferred Practice Pattern as promulgated by the American Academy of Ophthalmology. Relapse denoted the resurgence of blepharitis symptoms subsequent to the primary treatment, necessitating the instigation of either topical or oral therapeutic measures.

Results:

Of 92 cases of anterior blepharitis, 48 showed recurrence, with a recurrence rate of 52.2%. During the follow-up period, 2 patients experienced 5 relapses, 2 patients experienced 4 relapses, 5 patients experienced 3 relapses, 13 patients experienced 2 relapses, and 26 patients experienced 1 relapse. When the patients were divided into three groups: multiple recurrence group (22 patients), single recurrence group (26 patients), and no recurrence group (44 patients), there were no significant differences in the blepharitis finding score before and after the initial treatment among three groups. However, significantly fewer patients in the no recurrence group required further treatment after initial treatment, and the percentage of patients with residual blepharitis during follow-up was significantly lower in the no recurrence group.

Conclusions:

Our data suggest that patients with residual findings after blepharitis treatment are at a risk of recurrence.
Intracameral Enoxaparin for Descemet Membrane Endothelial Keratoplasty: A Pilot Safety Study
Authors: Mulpuri Lakshman , Ouano Dean P. , Riaz Kamran M. , Warner Evan J. , Stone Donald U. , Cheung Albert Y. , Gomez Angela , Rangu Neal , Sabater Alfonso L. , Tonk Rahul S.
Published: August 2024

Purpose:

The purpose of this study was to investigate the safety and outcomes of Descemet membrane endothelial keratoplasty (DMEK) performed with intracameral enoxaparin.

Methods:

Two arms were used: a clinical multicenter retrospective cohort arm (CA) and an ex vivo basic science arm (BSA). In CA, DMEKs were performed by 6 experienced corneal surgeons at multiple sites. Intracameral enoxaparin (40 mg/500 mL) was added to the irrigation fluid for all cases. Primary outcomes were measured at 6 and 12 months. In BSA, mated graft pairs were randomized to control or enoxaparin exposure (0.8 mg/mL × 1 hour) and assessed for endothelial cell death count at 0-, 1-, and 24-hour intervals and cellular stress by ELISA Annexin V protein quantification.

Results:

In the cohort arm, the mean age of 159 eyes of 134 patients was 69.3 years with Fuchs dystrophy as the primary diagnosis. Mean BCVA improved from 0.42 ± 0.3 logMAR preoperatively to 0.13 ± 0.1 logMAR postoperatively at 6 months (P  < 0.001) and to 0.1 ± 0.1 logMAR at 12 months (P < 0.001). At 6 months, 58.4% of patients achieved a final BCVA of 20/25 or better and 91% improved to 20/40 or better. Rebubble rate was 13% (n = 21), with 6 of these 21 eyes requiring more than 1 rebubble. One total graft detachment was noted with no reports of intraoperative or postoperative hemorrhage. PGF occurred in 0 of 159 eyes. In BSA, enoxaparin had no significant effect on endothelial cell death count or cellular apoptosis compared with control.

Conclusions:

Enoxaparin can safely be used in DMEK surgery without apparent increased risk of intraoperative hemorrhage, graft detachment/failure, or endothelial cell toxicity.
Systematic Review of Volume and Methodological Quality of Randomized Trials in Acute Pancreatitis
Authors: Joseph Nejo , Liu Gordon , Varghese Chris , Lim Wei , Xu William , Wells Cameron I. , Tobias Shayne , Capurso Gabriele , de Madaria Enrique , Drewes Asbjørn , Besselink Marc G. , Windsor John , Pandanaboyana Sanjay
Published: August 2024

Background

This systematic review assessed the volume and methodological quality of randomized controlled trials (RCTs) in relation to management of acute pancreatitis (AP).

Materials and Methods

The PubMed, MEDLINE, and CENTRAL databases were systematically searched for RCTs published across 3 time periods: <1996 (P1), 1996–2008 (P2), and >2008 (P3). RCT quality was assessed using the Cochrane Risk of Bias (RoB) 2 tool and sample size recalculation, and for spin (interpretation of nonstatistically significant results as relevant, making the study appear to be positive).

Results

Overall, 263 RCTs with 23,232 patients with AP were included. The average number of RCTs per year increased from 1.4, 6.0, to 10.6 in P1, P2, and P3, respectively. The RoB assessment showed low, some, and high concerns in overall RoB in 21%, 56%, and 24% of all RCTs. Selective reporting bias improved over time. Sample size calculation reporting significantly increased through the 3 time periods (17%, 38%, and 47%; P < 0.001). Spin was identified in 68 RCTs (26% of all RCTs).

Conclusion

The quantity and quality of published RCTs relating AP management has increased over time, however significant shortcomings of methodological quality persist. Significant improvements in the conduct and reporting of randomized trials in AP are required to improve the evidence base in this field.
Effect of Radiotherapy in Neoadjuvant Treatment of Borderline Resectable and Locally Advanced Pancreatic Cancer
Authors: Tang Peng , Zhang Junfeng , Zhou Qiang , Yi Wenmin , Wang Huaizhi
Published: August 2024

Background

Pancreatic cancer is a malignant tumor with poor prognosis and bad curative effect. Previous studies did not confirm the role of radiotherapy in neoadjuvant treatment of borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC). By reviewing new findings reported in recent years, we conducted this study to evaluate the survival impact by comparing chemoradiotherapy (CRT) with chemotherapy alone.

Materials and Methods

PubMed, Embase, MEDLINE, Web of Science, Scopus, and Cochrane Library were searched for studies reporting median overall survival (OS) in patients with BRPC or LAPC treated with neoadjuvant treatment. Secondary outcomes included progression-free survival (PFS) or disease-free survival (DFS) or recurrence-free survival (RFS) and R0 resection rate.

Results

A total of 18 studies were included in the meta-analysis. OS (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.64–0.91, I2 = 61.7%) and PFS/DFS/RFS (HR = 0.72, 95% CI: 0.58–0.91, I2 = 52.3%) are both favored CRT. Although R0 resection rate was increased in CRT group, significant survival benefit of radiotherapy was found in LAPC and low resection rate subgroup in stratification analysis. Regression analysis showed that only tumor resectability was associated with OS.

Conclusions

For patients with LAPC and who are unlikely to receive resection, neoadjuvant radiotherapy seems to improve OS and PFS/DFS/RFS.
Prevalence of S-methyl-5′-thioadenosine Phosphorylase (MTAP) Deficiency in Human Cancer
Authors: Gorbokon Natalia , Wößner Niklas , Lennartz Maximilian , Dwertmann Rico Sebastian , Kind Simon , Reiswich Viktor , Viehweger Florian , Lutz Florian , Fraune Christoph , Luebke Andreas M. , Hube-Magg Claudia , Menz Anne , Schlichter Ria , Krech Till , Hinsch Andrea , Burandt Eike , Sauter Guido , Simon Ronald , Steurer Stefan , Marx Andreas H. , Lebok Patrick , Dum David , Minner Sarah , Jacobsen Frank , Clauditz Till S. , Hackert Thilo , Uzunoǧlu Faik G. , Bubendorf Lukas , Bernreuther Christian , Kluth Martina
Published: August 2024

Loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression is a common event in cancer leading to a critical vulnerability of cancer cells towards anti-cancer drugs. Homozygous MTAP deletions result in a complete expression loss that can be detected by immunohistochemistry (IHC). In this study, a tissue microarray containing 17,078 samples from 149 different tumor entities was analyzed by IHC, and complete MTAP loss was validated by fluorescence in situ hybridization. MTAP loss was observed in 83 of 149 tumor categories, including neuroendocrine neoplasms (up to 80%), Hodgkin lymphoma (50.0%), mesothelioma (32.0% to 36.8%), gastro-intestinal adenocarcinoma (4.0% to 40.5%), urothelial neoplasms (10.5% to 36.7%), squamous cell carcinomas (up to 38%), and various types of sarcomas (up to 20%) and non-Hodgkin lymphomas (up to 14%). Homozygous MTAP deletion was found in 90% to 100% of cases with MTAP expression loss in most tumor categories. However, neuroendocrine tumors, Hodgkin lymphomas, and other lymphomas lacked MTAP deletions. MTAP deficiency was significantly linked to unfavorable tumor phenotype in selected tumor entities and the presence of PD-L1 expression on tumor cells, absence of PD-L1 expression on immune cells, and a low density of CD8+ lymphocytes. In summary, MTAP deficiency can occur in various tumor entities and is linked to unfavorable tumor phenotype and noninflamed tumor microenvironment, but is not always related to deletions. MTAP IHC is of considerable diagnostic value for the detection of neoplastic transformation in multiple different applications.
Efficacy of Neuroendoscopy Surgery Combined With Postoperative Lokomat Rehabilitation Training in Patients With Hypertensive Intracerebral Hemorrhage
Authors: Zhang Lizhuang , Xu Lifeng , Jing Shanquan , Liang Liping
Published: August 2024

Objective:

To explore the effects of neuroendoscopy surgery combined with postoperative Lokomat rehabilitation training on patients with hypertensive cerebral hemorrhage.

Methods:

A total of 88 patients with hypertensive cerebral hemorrhage who underwent surgical treatment in our hospital were retrospectively analyzed. They were divided into a study group and a conventional group with 44 patients in each group. The patients in the 2 groups were compared regarding operation-related conditions, hospital stay, preoperative and postoperative functional status scores, and postoperative complications.

Results:

The operation time, intraoperative blood loss, hospital stays, and hematoma clearance rate of the study group were significantly better than those of the conventional group (P<0.001). Regarding scores of related functional status, there was no significant difference between the 2 groups before operation (P>0.05). The different scores of the study group were significantly better than those of the conventional group 1 month after the operation (P<0.05). Regarding complications, the study group also has significant advantages, with only one case of rebleeding.

Conclusion:

Compared to the traditional approach of small bone window craniotomy followed by postoperative Lokomat rehabilitation training, the combination of neuroendoscopy surgery and Lokomat training proves to be more efficient. This approach can effectively reduce the operating time and hospital stay of patients with hypertensive intracerebral hemorrhage, minimize intraoperative blood loss, improve the hematoma clearance rate, and lower the incidence of postoperative complications.
Wave transmission in quasi-periodic lattices
Authors: Moscatelli Marco , Comi Claudia , Marigo Jean-Jacques
Published: August 2024

Structural lattices with quasi-periodic patterns possess interesting dynamic features that can be exploited to control, localize and redirect propagating waves. In this work, we show that the properties of a large class of quasi-periodic locally resonant systems (approximated as periodic, with arbitrarily large period) can be performed by defining an equivalent discrete system. Several properties of wave propagation can
a priori
be demonstrated with reference to this system. Results in terms of bulk spectrum, showing the Hofstadter butterfly pattern, and of topological modes are then discussed in detail with reference to a simple example of quasi-periodic lattice.

This article is part of the theme issue ‘Current developments in elastic and acoustic metamaterials science (Part 2)’.
Wave propagation in tailored metastructures consisting of elastic beams and rigid bodies
Authors: Rosić N. , Karličić D. , Cajić M. , Adhikari S. , Lazarević M.
Published: August 2024

This paper presents a study of wave propagation through an infinite periodic structure that consists of elastic Timoshenko beams interconnected with rigid bodies. This is a generalized approach in which the beams are not coaxial and the centre of mass of each rigid body is placed away from the intersection of their neutral axes. An analytical approach is used by applying the transfer matrix method (TMM), along with the Floquet–Bloch theorem for elastic wave propagation. Subsequent parametric analysis is performed with visualization of resulting band diagrams of a representative structure. These results are verified through comparison with solutions obtained using the finite-element method (FEM). In this manner, a comprehensive dynamical analysis of tailored metastructures is provided.

This article is part of the theme issue ‘Current developments in elastic and acoustic metamaterials science (Part 2)’.
Genomic characterization of prophage elements in Clostridium clostridioforme: an understudied component of the intestinal microbiome
Authors: Humphrey Suzanne , Marouli Angeliki , Thümmler Katja , Mullin Margaret , Pritchard Leighton , Wall Daniel M.
Published: August 2024

Genome sequencing of Clostridium clostridioforme strain LM41 revealed the presence of an atypically high proportion of mobile genetic elements for this species, with a particularly high abundance of prophages. Bioinformatic analysis of prophage sequences sought to characterize these elements and identify prophage-linked genes contributing to enhanced fitness of the host bacteria in the dysbiotic gut. Using PHASTER, PhageScope and manual curation, this work has identified 15 prophages: 4 predicted to be intact, 2 predicted to be defective and 9 which are unclassified. Quantitative PCR (qPCR) analysis revealed spontaneous release of four of the LM41 prophages (φ1, φ2, φ4 and φ10) into the culture supernatant, with virion-like particles visualized using transmission electron microscopy. The majority (12/14) of these particles had morphology akin to podoviruses, which is consistent with morphology predictions for φ1 and φ4. We observed diversity in the lysogeny mechanisms utilized by the prophages, with examples of the classical λ-like CI/Cro system, the ICEBs1 ImmR/ImmA-like system and the Mu-like C/Ner system. Classical morons, such as toxins or immune evasion factors, were not observed. We did, however, identify a variety of genes with roles in mediating restriction modification and genetic diversity, as well as some candidate genes with potential roles in host adaptation. Despite being the most abundant entities in the intestine, there is a dearth of information about phages associated with members of the microbiome. This work begins to shed light on the contribution of these elements to the lifestyle of C. clostridioforme LM41.
HCM-associated mutations in MYH6/7 drive pathologic expression of TGF-β1 in cardiomyocytes within weeks of developmental specification
Authors: Hsieh Jeanne , Hall Megan A. L. , Shameem Mohammad , Ernst Patrick J. , Kamdar Forum , Singh Bhairab N. , Meisel Robert L. , Ogle Brenda M.
Published: August 2024

Hypertrophic cardiomyopathy (HCM) is characterized by myocyte hypertrophy, sarcomere disarray, and myocardial fibrosis, leading to significant morbidity and mortality. As the most common inherited cardiomyopathy, HCM largely results from mutations in sarcomeric protein genes. Current treatments for HCM primarily focus on alleviating late-stage symptoms, with a critical gap in the detailed understanding of early-stage deficiencies that drive disease progression. We recently showed, in monolayers of cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) withMYH7R723C andMYH6R725C mutations, altered expression of several extracellular matrix (ECM)-related genes with associated defects in cardiomyocyte-ECM adhesion. To better evaluate the cardiomyocyte-ECM interface and pathological ECM dynamics in early-stage HCM, here we adopted a 3D engineered heart tissue (EHT) model containing both cardiomyocytes and fibroblasts, the primary contributor to ECM remodeling. Mutant EHTs showed aberrant cardiomyocyte distribution, augmented calcium handling, and force generation compared to controls. Altered proteoglycan deposition and increased phosphorylated focal adhesion kinase (pFAK) further indicated changes in ECM composition and connectivity. Elevated transforming growth factor beta-1 (TGF-β1) secretion and a higher proportion of activated fibroblasts were identified in mutant EHTs, along with sustained TGF-β1 transcription specifically in mutant cardiomyocytes. Remarkably, blocking TGF-β1 receptor signaling reduced fibroblast activation and contraction force to control levels. This study underscores the early interplay of mutant hiPSC-CMs with fibroblasts, wherein mutant cardiomyocytes initiate fibroblast activation via TGF-β1 overexpression, independent of the immune system. These findings provide a promising foundation for developing and implementing novel strategies to treat HCM well before the manifestation of clinically detectable fibrosis and cardiac dysfunction.
MAJOR AETIOLOGIES OF MALE INFERTILITY AMONG COUPLES ATTENDING FERTILITY CLINICS IN OSUN STATE, NIGERIA: FINDINGS FROM A MIXED METHOD STUDY
Authors: Awodele Kehinde , Adeyemo Sunday Charles , Olabode Eniola Dorcas , Fasanu Adeniyi Olaonipekun , Akindele Akintunde Rasaq , Afolabi Olusegun Adegboyega , Olagunju Olufunso Abidemi , Oyerinde Olusegun , Olaitan Lanre
Published: August 2024

Male infertility accounts for nearly half of the infertility cases globally. Seminal fluid analysis (SFA) is a critical diagnostic tool in the evaluation of male infertility. This study aimed to assess the implications of seminal fluid analysis on male infertility among patients attending fertility clinics in Osogbo, Nigeria.

The study employed mixed-method approach of both qualitative (Key informant interview) among 10 participants and quantitative method (cross-sectional survey) using pre-tested structured questionnaire among 305 respondents. The respondents in the cross-sectional survey were also made to undergo seminal fluid analysis. The data from the qualitative study was analysed using Atlas ti while data from the quantitative study were analysed using IBM Statistical Product for Service Solution (SPSS) version 27. 0. Descriptive statistics was carried out for all variables. The univariate, bivariate and multivariate analysis were done using p<0.05 as level of significance.

The seminal fluid analysis of the respondents revealed that 241 (79.0%) had Normal sperm count (>32 million per ejaculation) while 64 (21.0%) had abnormal sperm count. Only 101 (33.1%) had normal progressive motility (>32 percent) while 204 (66.9%) had abnormal (Athenospermia) progressive motility. 195 (63.9%) were found to have abnormal morphology (Teratospermia i.e., <4%). The qualitative analysis further analysed the implications of SFA parameters on infertile males and these were substantial, extending beyond physical health to encompass psychological, emotional, and social well-being.

The study concluded that lifestyle modifications and early diagnosis as well as prompt treatment of medical conditions can curb high prevalence abnormality of SFA, hence reduce male infertility in our environment. The study recommends that advocacy program, early screening and public health education will further reduce the burden of infertility among the female folks.
Predictive Modeling of Novel Somatic Mutation Impacts on Cancer Prognosis: A Machine Learning Approach Using the COSMIC Database
Authors: Mansoor Masab A
Published: August 2024

Abstract Background Somatic mutations play a crucial role in cancer initiation, progression, and treatment response. While high-throughput sequencing has vastly expanded our understanding of cancer genomics, interpreting the functional impact of novel somatic mutations remains challenging. Machine learning approaches show promise in predicting mutation impacts, but robust models for accurate prognosis across different cancer types are still needed. Objective This study aimed to develop and validate a machine learning model using the Catalogue of Somatic Mutations in Cancer (COSMIC) database to predict the functional impact of novel somatic mutations on cancer prognosis across various cancer types. Methods We extracted data on 6,573,214 coding point mutations across 1,391 cancer types from COSMIC v95. We engineered 47 features for each mutation, including sequence context, protein domain information, evolutionary conservation scores, and frequency data. We developed and compared Random Forest, XGBoost, and Deep Neural Network models, selecting XGBoost based on performance. The model was evaluated using standard metrics and externally validated using data from The Cancer Genome Atlas (TCGA). Results The XGBoost model achieved an area under the Receiver Operating Characteristic curve (AUC-ROC) of 0.89 on the test set and 0.86 on the TCGA validation set. The model demonstrated consistent performance across major cancer types (AUC-ROC range: 0.85-0.92). Key predictive features included evolutionary conservation score, protein domain disruption, and mutation frequency. The model correctly identified 87% of known driver mutations and predicted 3,241 potentially high-impact novel mutations. Model predictions significantly correlated with patient survival in the TCGA dataset (HR = 1.8, 95% CI: 1.6-2.0, p < 0.001). Conclusions Our machine learning model shows strong predictive power in assessing the functional impact of somatic mutations on cancer prognosis across various cancer types. This approach has potential applications in research prioritization and clinical decision support, contributing to the advancement of precision oncology. Keywords cancer genomics; somatic mutations; machine learning; prognosis prediction; COSMIC database; precision oncology
Genome-wide association study of COVID-19 Breakthrough Infections and genetic overlap with other diseases: A study of the UK Biobank
Authors: Feng Yaning , Wong Kenneth Chi-Yin , Tsui Wai Kai , Zhang Ruoyu , Xiang Yong , So Hon-Cheong
Published: August 2024

Background

The COVID-19 pandemic has led to substantial health and financial burden worldwide, and vaccines provide hope to reduce the burden of this pandemic. However, vaccinated people remain at risk for SARS-CoV-2 infection. Genome-wide association studies (GWAS) may allow for the identification of potential genetic factors involved in the development of COVID-19 breakthrough infections (BI), however very few or no GWAS have been conducted for COVID-19 BI so far.

Methods

We conducted a GWAS and detailed bioinformatics analysis on COVID-19 BI in a European population based on the UK-Biobank (UKBB). We conducted a series of analyses at different levels, including SNP-based, gene-based, pathway, and transcriptome-wide association analyses, to investigate genetic factors associated with COVID-19 BI and hospitalized infection. Polygenic risk score (PRS) and Hoeffding’s test were performed to reveal genetic relationships between BI and other medical conditions.

Results

Two independent loci (LD-clumped at r2=0.01) reached genome-wide significance (p<5e-08), including rs36170929 mapped toLOC102725191/VWDE,and rs28645263 mapped toRETREG1. Pathway enrichment analysis highlighted pathways such as viral myocarditis, Rho-selective guanine exchange factor AKAP13 signaling, and lipid metabolism. PRS analyses showed significant genetic overlap between COVID-19 BI and heart failure, HbA1c and type 1 diabetes. Genetic dependence was also observed between COVID-19 BI and asthma, lung abnormalities, schizophrenia, and type 1 diabetes, based on the Hoeffding’s test.

Conclusions

This GWAS study revealed two significant loci that may be associated with COVID-19 BI, and a number of genes and pathways that may be involved in BI. Genetic overlap with other diseases was identified. Further studies are warranted to replicate the findings and elucidate the mechanisms involved.
Mechanism of Co-Transcriptional Cap-Snatching by Influenza Polymerase
Authors: Rotsch Alexander Helmut , Li Delong , Dupont Maud , Krischuns Tim , Oberthuer Christiane , Stelfox Alice , Lukarska Maria , Fianu Isaac , Lidschreiber Michael , Naffakh Nadia , Dienemann Christian , Cusack Stephen , Cramer Patrick
Published: August 2024

Influenza virus mRNA is stable and competent for nuclear export and translation because it receives a 5′ cap(1) structure in a process called cap-snatching1. During cap-snatching, the viral RNA-dependent RNA polymerase (FluPol) binds to host RNA polymerase II (Pol II) and the emerging transcript2,3. The FluPol endonuclease then cleaves a capped RNA fragment that sub-sequently acts as a primer for the transcription of viral genes4,5. Here, we present the cryo-EM structure of FluPol bound to a transcribing Pol II in complex with the elongation factor DSIF in the pre-cleavage state. The structure shows that FluPol directly interacts with both Pol II and DSIF, which position the FluPol endonuclease domain near the RNA exit channel of Pol II. These interactions are important for the endonuclease activity of FluPol and FluPol activity in cells. A second structure trapped after cap-snatching shows that cleavage rearranges the capped RNA primer within the FluPol, directing the capped RNA 3′-end towards the FluPol polymerase active site for viral transcription initiation. Altogether, our results provide the molecular mechanisms of co-transcriptional cap-snatching by FluPol.
Methods for detection of cardiac glycogen-autophagy
Authors: Koutsifeli Parisa , Daniels Lorna J. , Neale Joshua , Fong Sarah , Varma Upasna , Annandale Marco , Li Xun , Nursalim Yohanes , Bell James R. , Weeks Kate L. , Stotland Aleksandr , Taylor David J. , Gottlieb Roberta A. , Delbridge Lea M.D. , Mellor Kimberley M.
Published: August 2024

Glycogen-autophagy (‘glycophagy’) is a selective autophagy process involved in delivering glycogen to the lysosome for bulk degradation. Glycophagy protein intermediaries include STBD1 as a glycogen tagging receptor, delivering the glycogen cargo into the forming phagosome by partnering with the Atg8 homolog, GABARAPL1. Glycophagy is emerging as a key process of energy metabolism and development of reliable tools for assessment of glycophagy activity is an important priority. Here we show that antibodies raised against the N-terminus of the GABARAPL1 protein (but not the full-length protein) detected a specific endogenous GABARAPL1 immunoblot band at 18kDa. A stable GFP-GABARAPL1 cardiac cell line was used to quantify GABARAPL1 lysosomal flux via measurement of GFP puncta in response to lysosomal inhibition with bafilomycin. Endogenous glycophagy flux was quantified in primary rat ventricular myocytes by the extent of glycogen accumulation with bafilomycin combined with chloroquine treatment (no effect observed with bafilomycin or chloroquine alone). In wild-type isolated mouse hearts, bafilomycin alone and bafilomycin combined with chloroquine (but not chloroquine alone) elicited a significant increase in glycogen content signifying basal glycophagy flux. Collectively, these methodologies provide a comprehensive toolbox for tracking cardiac glycophagy activity to advance research into the role of glycophagy in health and disease.
Nasal colonizing vancomycin-resistant and intermediateStaphylococcus aureusamong admitted patients
Authors: Mengistu Biniyam Kijineh , Alemayehu Tsegaye , Mengesha Techilo Habtemariam , Ali Musa Mohammed
Published: August 2024

Background

Staphylococcus aureuscolonizing the nasal cavity is a potential source of infections. Vancomycin is a mainstay for treating invasive infections caused by penicillin and methicillin-resistantS. aureus(MRSA). Some reports indicate the emergence of vancomycin-resistantS. aureus(VRSA) making it a high-priority pathogen that needs attention. There is a limited report on the epidemiology of VRSA and vancomycin-intermediateS. aureus(VISA) from the Sidama regional state.

Objective

The objective of this study was to determine VRSA and VISA amongS. aureuscolonizing patients admitted at Hawassa University Comprehensive Specialized Hospital (HUCSH), associated factors, and antimicrobial susceptibility profile.

Methods

A hospital-based prospective cross-sectional study was conducted from April to June 2023. Socio-demographic and clinical data were collected using an interviewer-administered questionnaire. Nasal swabs were collected from 378 admitted patients. Identification ofS. aureuswas made using standard bacteriological methods. VRSA was determined by the Epsilometer test (E-test). The antimicrobial susceptibility profile was determined according to the Kirby-Bauer disk diffusion method. Data was analyzed using SPSS version 22. Ap<0.05 was taken as a cut point to determine a statistically significant association.

Results

Out of the total 92S. aureusisolated 12 (13.04%), 27(29.3%), 15(16.3%) were VRSA, VISA, and MRSA respectively. The carriage rate of VRSA and VISA among admitted patients were 12(3.2%) with 95% CI: 1.7%−5.5% and 27(7.14%) with 95% CI: 4.8%−10.2% respectively. The overall nasal carriage rate ofS. aureusand MRSA was 92(24.3%) with 95% CI: 20.1%−29% and 15(3.97%) with 95% CI: 2.2%−6.5% respectively. Of the VRSA isolates, 11(91.7%) were susceptible to tigecycline. Forty (43.5%) ofS. aureuswere positive for inducible clindamycin resistance. Participants with a history of hospitalization at the intensive care unit were 37 times more likely to be colonized with VRSA (p=0.001). Participants who have domestic animals were 22 times more likely to be colonized with VRSA (p=0.021).

Conclusions

This study indicated a high proportion of VRSA and VISA amongS. aureusisolated from hospitalized patients in the study area. More than 80% of VRSA were susceptible to tigecycline. History of hospitalization at the intensive care unit and having domestic animals at home could increase the odds of VRSA colonization.
A gene regulatory network–aware graph learning method for cell identity annotation in single-cell RNA-seq data
Authors: Zhao Mengyuan , Li Jiawei , Liu Xiaoyi , Ma Ke , Tang Jijun , Guo Fei
Published: August 2024

Cell identity annotation for single-cell transcriptome data is a crucial process for constructing cell atlases, unraveling pathogenesis, and inspiring therapeutic approaches. Currently, the efficacy of existing methodologies is contingent upon specific data sets. Nevertheless, such data are often sourced from various batches, sequencing technologies, tissues, and even species. Notably, the gene regulatory relationship remains unaffected by the aforementioned factors, highlighting the extensive gene interactions within organisms. Therefore, we propose scHGR, an automated annotation tool designed to leverage gene regulatory relationships in constructing gene-mediated cell communication graphs for single-cell transcriptome data. This strategy helps reduce noise from diverse data sources while establishing distant cellular connections, yielding valuable biological insights. Experiments involving 22 scenarios demonstrate that scHGR precisely and consistently annotates cell identities, benchmarked against state-of-the-art methods. Crucially, scHGR uncovers novel subtypes within peripheral blood mononuclear cells, specifically from CD4+T cells and cytotoxic T cells. Furthermore, by characterizing a cell atlas comprising 56 cell types for COVID-19 patients, scHGR identifies vital factors like IL1 and calcium ions, offering insights for targeted therapeutic interventions.
Measurement of the fluorescence decay rate of
2 PJ3
positronium
Authors: Daly R. J. , Sheldon R. E. , Cassidy D. B.
Published: August 2024

The fluorescence decay rate of 2 PJ3 positronium (Ps) atoms [Γfl] has been experimentally determined using a Stark-mixing technique. Ground-state Ps atoms were optically excited in an electric field to states containing both 2 PJ3 and 23S1 components. The relative state populations were controlled via an applied mixing electric field, and a larger, pulsed, electric field was used to induce rapid quenching of the system after a fixed time delay. The dependence of the quenching signal on the mixing field strength was used to determine the relative and populations of the mixed states, whose decay rates are determined by the intrinsic self-annihilation and fluorescence decay rates. The measurements were compared to a trajectory simulation and Stark-mixing model, using the fluorescence decay rate as a free parameter. By finding the best agreement between the data and simulations we obtain Γfl=299±25µs−1, which is consistent with the mean theoretical value of 313.343±0.003µs−1.

Published by the American Physical Society
2024
Bottom quark dynamics from nonprompt
D0
and
J/ψ
production in
Pb+Pb
collisions at
sNN=5.02
TeV
Authors: Xing Wen-Jing , Li Shu-Qing , Cao Shanshan , Qin Guang-You
Published: August 2024

We study bottom quark energy loss via the nuclear modification factor (RAA) and elliptic flow (v2) of nonprompt D0 and J/ψ in relativistic heavy-ion collisions at the Large Hadron Collider (LHC). The space-time profile of quark-gluon plasma is obtained from the hydrodynamics simulation, the dynamical evolution of heavy quarks inside the color deconfined QCD medium is simulated using a linear Boltzmann transport model that combines Yukawa and string potentials of heavy-quark-medium interactions, the hadronization of heavy quarks is performed using a hybrid coalescence-fragmentation model, and the decay of B mesons is simulated via . Using this numerical framework, we calculate the transverse momentum (pT) dependent RAA and v2 of direct D mesons, B mesons, and nonprompt D0 and J/ψ from B meson decay in Pb+Pb collisions at

s

N

N

=

5.02

TeV. We find the mass hierarchy of the nuclear modification of prompt D and B mesons depends on their pT. Both RAA and v2 of heavy flavor particles show strong pT and centrality dependences due to the interplay between parton energy loss, medium geometry and flow, and hadronization of heavy quarks. Nonprompt D0 and J/ψ share similar patterns of RAA and v2 to B mesons except for a pT shift during the decay processes. Therefore, future more precise measurements on nonprompt D0 and J/ψ can help further pin down the bottom quark dynamics inside the quark-gluon plasma.

Published by the American Physical Society
2024
Open charm tetraquarks in broken
SU(3)F
symmetry
Authors: Maiani L. , Polosa A. D. , Riquer V.
Published: August 2024

Prompted by a recent lattice QCD calculation, we review the SU(3) light quark flavor structure of charmed tetraquarks with spin 0 diquarks. Fermi statistics forces the three light quarks to be in the representation 3¯⊗3¯=3⊕6¯. This agrees with the weak repulsion in the 15 of the 3⊗8 in D¯K scattering studied on the lattice. We analyze the 3⊕6¯ multiplet broken by the strange quark mass and determine the five independent masses from the known masses of diquarks. The mass of Ds0*(2317) is predicted within 50 MeV accuracy. The recently observed D¯s−−(2900) and D¯s0(2900), likely part of a I=1 multiplet, with flavor composition c¯q¯q′s, and X0(2900), an isosinglet with flavor composition c¯s¯ud, fit naturally in a 3⊕6¯ structure as the first radial excitations. We discuss also the decay modes of Ds0*(2317), of the radial excitations and of the predicted particles.

Published by the American Physical Society
2024
Hamiltonian formulation of the Rothe-Stamatescu model and field mixing
Authors: Chen Qi , Tu Kaixun , Wang Qing
Published: August 2024

While neutrino oscillations have led to attention and research on field mixing arising from quadratic interactions, the field mixing inherent in clothed particles is more fundamental, serving as a significant source of complexity and nonperturbative challenges in quantum field theory. We present an example of an analytical solution for field mixing involving a three-point interaction between a bosonic field and a fermionic field. Specifically, we study the Rothe-Stamatescu (RS) model and utilize lattice regularization to provide a well-defined Hamiltonian that is absent in the original continuous RS model. Because of the complexity introduced by three-point interactions compared to quadratic interactions, the Fock representation commonly used in discussions of field mixing does not work well; instead, we define a representation based on real space to investigate the physical vacuum and clothed particles. These eigenstates not only reveal the field mixing between the bosonic and fermionic fields but also allow us to directly observe the spatial entanglement structure.

Published by the American Physical Society
2024
Reviving MeV-GeV indirect detection with inelastic dark matter
Authors: Berlin Asher , Krnjaic Gordan , Pinetti Elena
Published: August 2024

Thermal relic dark matter below ∼10  GeV is excluded by cosmic microwave background data if its annihilation to visible particles is unsuppressed near the epoch of recombination. Usual model-building measures to avoid this bound involve kinematically suppressing the annihilation rate in the low-velocity limit, thereby yielding dim prospects for indirect detection signatures at late times. In this work, we investigate a class of cosmologically viable sub-GeV thermal relics with late-time annihilation rates that are detectable with existing and proposed telescopes across a wide range of parameter space. We study a representative model of inelastic dark matter featuring a stable state χ1 and a slightly heavier excited state χ2 whose abundance is thermally depleted before recombination. Since the kinetic energy of dark matter in the Milky Way is much larger than it is during recombination, χ1χ1→χ2χ2 upscattering can efficiently regenerate a cosmologically long-lived Galactic population of χ2, whose subsequent coannihilations with χ1 give rise to observable gamma-rays in the ∼1  MeV−100  MeV energy range. We find that proposed MeV gamma-ray telescopes, such as e-ASTROGAM, AMEGO, and MAST, would be sensitive to much of the thermal relic parameter space in this class of models and thereby enable both discovery and model discrimination in the event of a signal at accelerator or direct detection experiments.

Published by the American Physical Society
2024
Lepton and baryon numbers as local gauge symmetries
Authors: Fileviez Pérez Pavel
Published: August 2024

A simple theory where the total lepton number is a local gauge symmetry is proposed. In this context, the gauge anomalies are canceled with the minimal number of extra fermionic fields and one predicts that the neutrinos are Majorana fermions. The properties of the neutrino sector are discussed, showing that this theory predicts a 3+2 light neutrino sector. We show that using the same fermionic fields one can gauge the baryon number and define a simple theory where the lepton and baryon numbers can be spontaneously broken at the low scale in agreement with experiments.

Published by the American Physical Society
2024
Deepest sensitivity to wavelike dark photon dark matter with superconducting radio frequency cavities
Authors: Cervantes R. , Aumentado J. , Braggio C. , Giaccone B. , Frolov D. , Grassellino A. , Harnik R. , Lecocq F. , Melnychuk O. , Pilipenko R. , Posen S. , Romanenko A.
Published: August 2024

Wavelike, bosonic dark matter candidates like axions and dark photons can be detected using microwave cavities known as haloscopes. Traditionally, haloscopes consist of tunable copper cavities operating in the TM010 mode, but ohmic losses have limited their performance. In contrast, superconducting radio frequency (SRF) cavities can achieve quality factors of ∼1010, perhaps 5 orders of magnitude better than copper cavities, leading to more sensitive dark matter detectors. In this paper, we first derive that the scan rate of a haloscope experiment is proportional to the loaded quality factor QL, even if the cavity bandwidth is much narrower than the dark matter halo line shape. We then present a proof-of-concept search for dark photon dark matter using a nontunable ultrahigh-quality SRF cavity. We exclude dark photon dark matter with kinetic mixing strengths of χ>1.5×10−16 for a dark photon mass of mA′=5.35  μeV, achieving the deepest exclusion to wavelike dark photons by almost an order of magnitude.

Published by the American Physical Society
2024
Embedded domain walls and electroweak baryogenesis
Authors: Schröder Tobias , Brandenberger Robert
Published: August 2024

Embedded walls are domain wall solutions which are unstable in the vacuum but stabilized in a plasma of the early Universe. We show how embedded walls in which the electroweak symmetry is restored can lead to an efficient scenario of electroweak baryogenesis. We construct an extension of the Standard Model of particle physics in which embedded walls exist and are stabilized in an electromagnetic plasma.

Published by the American Physical Society
2024