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Background: The present study aimed to investigate the effect of pre-admission Opioid Use Disorder (OUD) on in-hospital mortality and 6-month follow-up TBI outcomes., Design: This study included 2804 patients with TBI admitted to the Intensive Care Unit of Emtiaz (Rajaee) Hospital, a referral trauma center in Shiraz, Iran. Finally, 1087 eligible participants were selected from included patients. Then, 872 discharged patients were followed for six months. Subsequently, unfavorable neurological outcomes (Glasgow Outcome Scale-Extended ≤ 4) and the mortality rate were compared among the patients with and without OUD., Results: The mean age of the patients was 38.0 ± 18.9 years old (84.7% men). About 9.2% of patients had OUD. Opioid users had a slightly lower risk of in-hospital mortality (OR = 0.62, 95% CI = [0.328, 1.183], P-value = 0.148). In contrast, 6-month follow-up mortality significantly increased in the survived patients with a history of pre-admission OUD (OR = 2.49, 95%CI= [1.29, 2.80], P-value = 0.007). Moreover, 6-month unfavorable outcomes were raised in OUD, though it was not significant (OR = 1.59, 95%CI= [0.89, 2.84], P-value = 0.121)., Conclusions: Our results revealed that patients with OUD are at increased risk of 6-month follow-up complications and also death following moderate to severe TBI. Although OUD decreased in-hospital mortality, 6-month follow-up indicated that mortality and unfavorable outcomes were increased in the OUD group. Based on the existing evidence, this effect is probably not only due to the destructive impact of pre-admission OUD on brain physiology. However, it may also be due to an increase in opioid consumption to alleviate pain and withdrawal symptoms after hospital discharge., Competing Interests: Declarations Ethical approval The protocol of this study has been approved by the ethics committee of Fasa University of Medical Sciences (Code: IR.FUMS.REC.1401.032). All data used in the current study was extracted from the trauma registry database, which was established with the ethics code of IR.SUMS.REC.1401.183. Informed consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Patients or their visitors gave written informed consent for participation and dissemination at the time of admission. Competing interests The authors declare no competing interests. Conflict of interest Hosseinali Khalili, Maziyar Rismani, Hossein Pourmontaseri, Adib Valibeygi, Reza Taheri, Mohammad Sadegh Masoudi, and Amin Niakan declare they have no conflict of interest. This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Synthetic and natural carbons are widely used as carrier for electrodes in electrochemical applications. They need to have a controlled morphology in order to facilitate mass and charge transport, so the process of film formation is of uttermost importance. Here we show, how carbons (after proper preconditioning) can be codeposited with an ionomer by electrophoretic deposition, a method that does allow full control of deposition conditions during the process. In view of potential applications, we focus on the direct deposition on proton-conducting membranes. Ionomers and membranes applied are based on established per-fluorinated polyethylene with SO3H-terminated side chains (PFSA). Conditions for reproducible deposition are reported in terms of optimal charge on the carbon particles, field strength in the deposition cell and necessary deposition times for a given film thickness. Additionally, a horizontal cell arrangement is suggested to avoid gravitational effects., (© 2024 Wiley‐VCH GmbH.)

Cervical lymphadenopathy can indicate a range of diseases, including infections, inflammation, and neoplastic processes. Accurate diagnosis is crucial for identifying the underlying cause and determining appropriate treatment. Diagnostic procedures include clinical examination, ultrasound, fine needle aspiration, biopsy, and imaging techniques. While conventional imaging methods such as X-ray and computed tomography (CT) have proven useful, they exhibit limitations in sensitivity and specificity, especially for soft tissue structures. Magnetic resonance imaging (MRI) provides superior soft tissue contrast, offering additional critical information for differential diagnosis. This article presents a case study of a 29-year-old male with a cervical mass. Advanced dental MRI protocols, including DESS, SPACE-SPAIR, and SPACE-STIR sequences, have significantly enhanced the imaging capabilities of the den-tomaxillofacial region, enabling the generation of high-resolution images of both hard and soft tissues. Especially, MR OPGs have demonstrated the capacity to identify early signs of potential pathology. These protocols have the potential to enhance early detection, thereby con-tributing to accurate diagnosis and effective treatment planning., (Copyright 2024 . License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

Chest pain is a frequent complaint in emergency departments, with various differential diagnoses from benign to life-threatening. Hereby, we described a 60-year-old man presented with chest pain and hypotension who initially misdiagnosed as acute coronary syndrome, but was ultimately diagnosed with necrotizing fasciitis. This case highlights the importance of considering rare causes of chest pain., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Soft tissue lesions are among the most prevalent forms of tumors or tumor-like alterations within the oral cavity. They exhibit a wide spectrum of characteristics, ranging from benign, noninvasive lesions to malignant tumors, which collectively present a diagnostic challenge. A 67-year-old patient presented with an incidental finding of induration on the right cheek during dental hygiene. The intraoral examination revealed a soft, non-tender swelling measuring 20 mm in diameter. The sensitivity and percussion tests for the teeth in the fourth quadrant yielded unremarkable results. Panoramic radiography (OPG) revealed tip-ping of the premolars and an unclear apical finding in region 44. Cone-beam computed tomography (CBCT) revealed a sharply defined, lobulated hypodense lesion in the right buccal area. To clarify the diagnosis and optimize perioperative management, a 3 Tesla dental magnetic resonance imaging (MRI) scan was performed. This identified a 23×6×23 mm lipoma along the right mandibular ramus, causing detachment of the buccinator and de-pressor anguli oris muscles. A cinematic rendering reconstruction derived from the MRI data facilitated enhanced visualization for preoperative planning. The surgical excision was performed under local anesthesia, resulting in the successful removal of the neoplasm while preserving the mental nerve and submandibular gland. Histo-pathology confirmed the presence of a lobulated mature cell lipoma. The patient exhibited no complications during the removal of the sutures, with complete wound healing and no recurrence observed. This article highlights the efficacy of advanced MRI diagnostics and post-processing techniques in the management of ambiguous soft tissue neoplasms., (Copyright 2024 Adib Al-Haj Husain, Esra Salzer, Bernd Stadlinger. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

Genomic DNA breakages and the subsequent insertion and deletion mutations are important contributors to genome instability and linked diseases. Unlike the research in point mutations, the relationship between DNA sequence context and the propensity for strand breaks remains elusive. Here, by analyzing the differences and commonalities across myriads of genomic breakage datasets, we extract the sequence-linked rules and patterns behind DNA fragility. We show the overall deconvolution of the sequence influence into short-, mid- and long-range effects, and the stressor-dependent differences in defining the range and compositional effects on DNA fragility. We summarize and release our feature compendium as a library that can be seamlessly incorporated into genomic machine learning procedures, where DNA fragility is of concern, and train a generalized DNA fragility model on cancer-associated breakages. Structural variants (SVs) tend to stabilize regions in which they emerge, with the effect most pronounced for pathogenic SVs. In contrast, the effects of chromothripsis are seen across regions less prone to breakages. We find that viral integration may bring genome fragility, particularly for cancer-associated viruses. Overall, this work offers novel insights into the genomic sequence basis of DNA fragility and presents a powerful machine learning resource to further enhance our understanding of genome (in)stability and evolution., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background and Objectives: First-line therapy for most intracranial dural arteriovenous fistulas (dAVFs) is endovascular embolization, but some require microsurgical ligation due to limited endovascular accessibility, anticipated lower cure rates, or unacceptable risk profiles. We investigated the most common surgically treated dAVF locations and the approaches and outcomes of each., Methods: The Consortium for Dural Arteriovenous Fistula Outcomes Research database was retrospectively reviewed. Patients who underwent dAVF microsurgical ligation were included. Patient demographics, angiographic information, surgical details, and postoperative outcomes were collected. The 5 most common surgically treated dAVF locations were analyzed about used surgical approaches and postoperative outcomes. Univariate analyses were performed with statistical significance set at a threshold of P < .05., Results: In total, 248 patients in the Consortium for Dural Arteriovenous Fistula Outcomes Research database met inclusion criteria. The 5 most common surgically treated dAVF locations were tentorial, anterior cranial fossa (ACF), transverse-sigmoid sinus (TSS), convexity/superior sagittal sinus (SSS), and torcular. Most tentorial dAVFs were approached using a suboccipital, lateral supracerebellar infratentorial approach (39.3%); extended retrosigmoid approach (ERS) (25%); or posterior subtemporal approach (19.6%). All ACF dAVFs used a subfrontal approach; 5.3% also included an anterior interhemispheric approach. Most TSS dAVFs were ligated via ERS (31.3%) or subtemporal (31.3%) approaches. All convexity/SSS dAVFs used an interhemispheric approach. All torcular dAVFs used the suboccipital, lateral supracerebellar infratentorial approach, with 10.5% undergoing simultaneous ERS craniotomy. Angiographic occlusion rates after microsurgery were 85.5%, 100%, 75.8%, 79.2%, and 73.7% for tentorial, ACF, TSS, convexity/SSS, and torcular dAVFs, respectively (P = .02); the permanent neurological complication rates were 1.8%, 2.6%, 9.1%, 0%, and 0% (P = .31). There were no statistically significant differences in development of complications (P = .08) or Modified Rankin Scale at the last follow-up (P = .11) by fistula location., Conclusion: Although endovascular embolization is the first-line treatment for most intracranial dAVFs, surgical ligation is an important alternative. ACF and tentorial fistulas particularly demonstrate high rates of postoperative obliteration., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

This study aimed to evaluate the dose-dependent brain temperature effects of transcranial photobiomodulation (t-PBM). Thirty adult subjects with major depressive disorder were randomized to three t-PBM sessions with different doses (low: 50 mW/cm 2 , medium: 300 mW/cm 2 , high: 850 mW/cm 2 ) and a sham treatment. The low and medium doses were administered in continuous wave mode, while the high dose was administered in pulsed wave mode. A 3T MRI scanner was used to perform proton magnetic resonance spectroscopy ( 1 H-MRS). A voxel with a volume of 30 × 30 × 15 mm 3 was placed on the left prefrontal region. Brain temperature (°C) was derived by analyzing 1 H-MRS spectrum chemical shift differences between the water (~ 4.7 ppm) and N-acetyl aspartate (NAA) (~ 2.01 ppm) peaks. After quality control of the data, the following group numbers were available for both pre- and post-temperature estimations: sham (n = 10), low (n = 11), medium (n = 10), and high (n = 8). We did not detect significant temperature differences for any t-PBM-active or sham groups post-irradiation (p-value range = 0.105 and 0.781). We also tested for potential differences in the pre-post variability of brain temperature in each group. As for t-PBM active groups, the lowest fluctuation (variance) was observed for the medium dose (σ 2  = 0.29), followed by the low dose (σ 2  = 0.47), and the highest fluctuation was for the high dose (σ 2  = 0.67). t-PBM sham condition showed the overall lowest fluctuation (σ 2  = 0.11). Our 1 H-MRS thermometry results showed no significant brain temperature elevations during t-PBM administration., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Background: Arteriovenous malformations (AVMs) are uncommon cerebral lesions that can cause significant neurological complications. Surgical resection is the gold standard for treatment, but endovascular embolization and stereotactic radiosurgery (SRS) are viable alternatives., Objective: To compare the outcomes of endovascular embolization versus SRS in the treatment of AVMs with Spetzler-Martin grades I-III., Methods: This study combined retrospective data from 10 academic institutions in North America and Europe. Patients aged 1 to 90 years who underwent endovascular embolization or SRS for AVMs with Spetzler-Martin grades I-III between January 2010 and December 2023 were included., Results: The study included 244 patients, including 84 who had endovascular embolization and 160 who had SRS. Before propensity score matching (PSM), complete obliteration at the last follow-up was achieved in 74.5% of the SRS group compared with 57.8% of the embolization group (OR=0.47; 95% CI 0.26 to 0.48; P=0.01). After propensity score matching, SRS still achieved significantly higher occlusion rates at last follow-up (78.9% vs 55.3%; OR=0.32; 95% CI 0.12 to 0.90; P=0.03).Hemorrhagic complications were higher in the embolization group than in the SRS group, although this difference did not reach statistical significance after PSM (13.2% vs 2.6%; OR=5.6; 95% CI 0.62 to 50.47; P=0.12). Similarly, re-treatment rate was higher in the embolization group (10.5% vs 5.3%; OR=2.11; 95% CI 0.36 to 12.31; P=0.40) compared with the SRS group., Conclusion: Our findings indicate that SRS has a significantly higher obliteration rate at last follow-up compared with endovascular embolization. Also, SRS has a higher tendency for fewer hemorrhagic complications and lower re-treatment rate. Further prospective studies are needed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The present study aims to investigate the feasibility of labeling ligaments using ultrasound-guided injections. On formalin-fixed cadavers, the anterolateral ligament was selected and targeted for demonstration. The development of portable ultrasound machines and the ability to connect them to tablets via Bluetooth or WLAN makes it an accessible tool to implement into the anatomical dissection courses in order to associate medical imaging (MRI and ultrasound), anatomical structures and their subsequent dissection., Methods: 8 formalin fixed human cadavers were used for the ultrasound-guided injections of 1 mL of blue latex into the anterolateral ligament. 8 cadavers were not injected with latex for comparative purposes. The injections were performed by an experienced ultra-sonographer. After approximately 10 months, five dissections were carried out by students during the dissection course and three specimens were dissected by anatomists., Results: The anterolateral ligament was successfully marked and demonstrated in 7 out of 8 cases. In 4 out of 5 cases, the dissection was primarily conducted by students, while in 3 out of 3 cases, it was performed by anatomists. The accuracy was 80 % and 100 %, respectively., Conclusion: The present study demonstrated that labeling obscure ligaments, such as the anterolateral ligament, using ultrasound guidance is feasible on formalin-fixed cadavers. It also showed that students can successfully perform the dissections as the structure is highlighted and that the time between injection and dissection (approximately 10 months) has little impact on the outcome. The use of ultrasound in dissection courses should be further encouraged., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Introduction: Accurate bracket positioning remains challenging. To avoid angulation errors, some recommend examining the panoramic radiograph during bonding. However, it can cause distortions. Cone-beam computed tomography (CBCT) provides a more precise panoramic reconstruction but with higher radiation doses. The main objective of this study is to compare the accuracy of axial positioning between direct bonding without radiography, with conventional panoramic radiograph, and with panoramic reconstruction from CBCT. The secondary objectives are to evaluate positioning accuracy of each tooth and to assess the influence of practitioner level of experience., Methods: Thirty practitioners, divided into two groups based on their experience performed direct bonding on a model thrice: without radiography, then with the conventional panoramic radiograph, then with the panoramic reconstruction from CBCT. Models were scanned, and angulation errors were measured using OrthoAnalyzer. Values were compared using the Friedman's test followed by the Bonferroni correction for multiple comparisons (P-value = 0.05)., Results: For the low level of experience group, angulation errors were significantly greater than the accepted limit without radiographic reference, and significantly lower with CBCT reconstruction. For the high level of experience group, angulation errors were significantly lower than the accepted limit for the three bonding methods. For every tooth, using the panoramic reconstruction from CBCT as a reference, was the most accurate method, regardless of the level of experience. More experienced practitioners made fewer errors for the three methods., Conclusions: Panoramic reconstruction from CBCT is the most accurate method to limit angulation errors during direct bonding. Conventional panoramic radiography remains a reliable tool if used with caution. Bonding without any radiographic reference should be avoided especially for less experienced practitioners., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: The presence of a mechanical aortic valve has been a contraindication to the use of an arch branch aortic endograft due to the risk of damaging the valve, resulting in acute aortic regurgitation, or a trapped endograft., Methods: We present a 67-year-old woman, with a background of Marfan's syndrome and a previous Bentall's procedure, who presented with a symptomatic enlarging aortic arch and descending thoracic aortic aneurysm, with a type 1A endoleak., Results: Using an inner branch arch endograft (Cook Medical, Bloomington, Indiana), the nose cone of the delivery system was passed laterally through the semi-circular aperture of the mechanical aortic valve to facilitate deployment just distal to the coronary buttons., Conclusions: With advancement of endovascular technology, techniques and experience, endovascular aortic arch repair in the presence of a mechanical aortic valve is feasible., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The respective roles of aligned collagen fiber morphology found in the extracellular matrix (ECM) of pancreatic cancer patients and cellular migration dynamics have been gaining attention because of their connection with increased aggressive phenotypes and poor prognosis. To better understand how collagen fiber morphology influences cell-matrix interactions associated with metastasis, we used Second Harmonic Generation (SHG) images from patient biopsies with Pancreatic ductal adenocarcinoma (PDAC) as models to fabricate collagen scaffolds to investigate processes associated with motility. Using the PDAC BxPC-3 metastatic cell line, we investigated single and collective cell dynamics on scaffolds of varying collagen alignment. Collective or clustered cells grown on the scaffolds with the highest collagen fiber alignment had increased E-cadherin expression and larger focal adhesion sites compared to single cells, consistent with metastatic behavior. Analysis of single cell motility revealed that the dynamics were characterized by random walk on all substrates. However, examining collective motility over different time points showed that the migration was super-diffusive and enhanced on highly aligned fibers, whereas it was hindered and sub-diffusive on un-patterned substrates. This was further supported by the more elongated morphology observed in collectively migrating cells on aligned collagen fibers. Overall, this approach allows the decoupling of single and collective cell behavior as a function of collagen alignment and shows the relative importance of collective cell behavior as well as fiber morphology in PDAC metastasis. We suggest these scaffolds can be used for further investigations of PDAC cell biology. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate, where aligned collagen has been associated with poor prognosis. Biomimetic models representing this architecture are needed to understand complex cellular interactions. The SHG image-based models based on stromal collagen from human biopsies afford the measurements of cell morphology, cadherin and focal adhesion expression as well as detailed motility dynamics. Using a metastatic cell line, we decoupled the roles of single cell and collective cell behavior as well as that arising from aligned collagen. Our data suggests that metastatic characteristics are enhanced by increased collagen alignment and that collective cell behavior is more relevant to metastatic processes. These scaffolds provide new insight in this disease and can be a platform for further experiments such as testing drug efficacy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Mitochondria are vital for cellular activities, influencing ATP production, Ca2 + signaling, and reactive oxygen species generation. It has been proposed that nuclear genome-derived circular RNAs (circRNAs) play a role in biological processes. For the first time, this study aims to comprehensively explore experimentally confirmed human mitochondrial genome-derived circRNAs (mt-circRNAs) via in-silico analysis. We utilized wide-ranging bioinformatics tools to anticipate their roles in molecular biology, involving miRNA sponging, protein antagonism, and peptide translation. Among five well-characterized mt-circRNAs, SCAR/mc-COX2 stands out as particularly significant with the potential to sponge around 41 different miRNAs, which target several genes mostly involved in endocytosis, MAP kinase, and PI3K-Akt pathways. Interestingly, circMNTND5 and mecciND1 specifically interact with miRNAs through their unique back-splice junction sequence. These exclusively targeted miRNAs (has-miR-5186, 6888-5p, 8081, 924, 672-5p) are predominantly associated with insulin secretion, proteoglycans in cancer, and MAPK signaling pathways. Moreover, all mt-circRNAs intricately affect the P53 pathway through miRNA sequestration. Remarkably, mc-COX2 and circMNTND5 appear to be involved in the RNA's biogenesis by antagonizing AGO1/2, EIF4A3, and DGCR8. All mt-circRNAs engaged with IGF2BP proteins crucial in redox signaling, and except mecciND1, they all potentially generate at least one protein resembling the immunoglobulin heavy chain protein. Given P53's function as a redox-sensitive transcription factor, and insulin's role as a crucial regulator of energy metabolism, their indirect interplay with mt-circRNAs could influence cellular outcomes. However, due to limited attention and infrequent data availability, it is advisable to conduct more thorough investigations to gain a deeper understanding of the functions of mt-circRNA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objectives: As the aging population increases, the incidence of chronic subdural hematomas (cSDHs) is expected to rise. Surgical evacuation, though effective, sees up to 30% recurrence. Middle meningeal artery (MMA) embolization, particularly with n-butyl cyanoacrylate (n-BCA) glue diluted in D5W for distal penetration, has shown promise in reducing recurrences. Limited reports have investigated the safety and technical feasibility of n-BCA as a primary liquid embolic agent using the D5W push technique in cSDH. This series is the largest in the literature investigating the outcomes of this technique in cSDH., Methods: A multicenter retrospective database analysis was conducted on consecutive patients who underwent MMA embolization using n-BCA embolisate. Data collected included patient demographics, procedural information, angiographic data, and periprocedural complications., Results: The study included 269 patients with a median age of 76 years. Nearly half of the patients had previous surgeries, and 93 underwent contralateral embolization for bilateral cSDH. Successful MMA embolization with effective distal penetration was achieved in all cases. The complication rate was 2.2%. Significant improvements were noted at a 60-day follow-up, with a median reduction in cSDH diameter of 40.6% (P < .001) and 53% of patients showing neurological improvement. No recurrent cSDH or need for retreatment was observed in patients who underwent follow-up., Conclusion: MMA embolization using n-BCA with the D5W push technique is safe and technically feasible. It can be used adjunctively or as an alternative to surgery in patients with cSDH, resulting in decreased recurrence, high technical success, improved distal penetration, and low complication rates., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Objective: The aim of this study was to investigate outcomes after endovascular aortic arch repair in patients with a mechanical aortic valve where the valve needs to be crossed., Methods: An international, multicentre, retrospective observational study was undertaken including all consecutive patients who underwent endovascular arch repair with mechanical aortic valve crossing., Results: From March 2020 to August 2023, 12 patients were included in the study (median age 55 years, interquartile range 45, 67 years; 58% male). Five patients (42%) had a genetically confirmed connective tissue disorder (CTD) and three more had a high clinical suspicion of CTD. Most patients had a bileaflet valve (11/12; 92%) and one patient had a monoleaflet one. All patients had previously undergone surgical ascending aortic repair. Technical success was 100% with successful completion of the procedure with no valve damage. Two deaths (17%) were observed in the first 30 days post-operatively with no signs of valve malfunction: one patient died of major stroke due to excessive wire and sheath manipulation in the arch; and another due to cardiac arrest of unknown cause, with no valve damage being detected in the autopsy. No intra-operative technical difficulties regarding valve cannulation were observed. During a median follow up of eight months, one patient died fifteen months after the procedure owing to non-aortic related causes, and four endoleaks were present on the latest computed tomography angiography, none type I or III., Conclusion: Endovascular aortic arch repair in a selected group of patients with a mechanical aortic valve, treated in experienced high volume aortic centres, seems technically feasible and reasonably safe. These preliminary results underline the complexity of the procedure and should be validated by larger cohort studies. With careful patient selection and adequate physician experience, the presence of a mechanical aortic valve could potentially no longer pose a major contraindication to endovascular arch repair in the future., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cancer is a complex disease driven by multiple genetic changes, including mutations in oncogenes, tumor suppressor genes, DNA repair genes, and genes involved in cancer metabolism. Synthetic lethality (SL) is a promising approach in cancer research and treatment, where the simultaneous dysfunction of specific genes or pathways causes cell death. By targeting vulnerabilities created by these dysfunctions, SL therapies selectively kill cancer cells while sparing normal cells. SL therapies, such as PARP inhibitors, WEE1 inhibitors, ATR and ATM inhibitors, and DNA-PK inhibitors, offer a distinct approach to cancer treatment compared to conventional targeted therapies. Instead of directly inhibiting specific molecules or pathways, SL therapies exploit genetic or molecular vulnerabilities in cancer cells to induce selective cell death, offering benefits such as targeted therapy, enhanced treatment efficacy, and minimized harm to healthy tissues. SL therapies can be personalized based on each patient's unique genetic profile and combined with other treatment modalities to potentially achieve synergistic effects. They also broaden the effectiveness of treatment across different cancer types, potentially overcoming drug resistance and improving patient outcomes. This review offers an overview of the current understanding of SL mechanisms, advancements, and challenges, as well as the preclinical and clinical development of SL. It also discusses new directions and opportunities for utilizing SL in targeted therapy for anticancer treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Alternaria species (Deuteromycetes, Ascomycota) as ubiquitous fungi and prolific producers of a variety of toxic compounds are a part of microbiomes of plants, humans, and animals, mainly causing disease, allergic reactions, and toxicosis. However, some species have also been reported as endophytic microorganisms with highly bioactive metabolites. Our previous results indicate that potentially endophytic Alternaria species from Cupressaceae produce bioactive metabolites that possibly contribute to plant holobiont's health. Here, a possible mechanism behind this bioactivity is elucidated. As some endophytic fungi are reported to produce cytotoxic taxane diterpenoids, eight potentially endophytic Alternaria isolates from our collection were analyzed for the presence of the key genes of the paclitaxel (Taxol) biosynthetic pathway, i.e., taxadin synthase (ts), 10-deacetylbaccatin III-10-O-acetyltransferase (dbat), and C-13-phenylpropanoid side-chain CoA acyltransferase (bapt). The presence of all genes, i.e., ts, dbat, and bapt, was detected by PCR in six isolates and dbat and bapt in two isolates. Chemical analyses of the fermentation broths by TLC and HPLC chromatography and IR spectroscopy indicated the synthesis of the final product, i.e., paclitaxel. So, we introduce the synthesis of taxane diterpenoids as a possible mechanism by which Alternaria occupies the plant niches and protects the plant holobiont in the presence of competing microorganisms., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ewing sarcoma (ES) is a rare malignancy that typically occurs within the skeletal system but can also develop extraskeletally. Extraskeletal ES typically presents paraspinally, in the limbs, and retroperitoneum. Rarely, it presents as a primary gastric ES. To our knowledge, there are only 13 reports of primary gastric ES, none of which originated in the cardia of the stomach. Increased identification of how extraskeletal ES, specifically primary gastric ES, presents and characterized is crucial for future treatment development and accurate prognosis. We present the case of a 36-year-old man with hematemesis, ultimately found to have primary gastric ES in the cardia., (© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Acquisition of specific cell shapes and morphologies is a central component of cell fate transitions. Although signaling circuits and gene regulatory networks that regulate pluripotent stem cell differentiation have been intensely studied, how these networks are integrated in space and time with morphological transitions and mechanical deformations to control state transitions remains a fundamental open question. Here, we focus on two distinct models of pluripotency, primed pluripotent stem cells and pre-implantation inner cell mass cells of human embryos to discover that cell fate transitions associate with rapid changes in nuclear shape and volume which collectively alter the nuclear mechanophenotype. Mechanistic studies in human induced pluripotent stem cells further reveal that these phenotypical changes and the associated active fluctuations of the nuclear envelope arise from growth factor signaling-controlled changes in chromatin mechanics and cytoskeletal confinement. These collective mechano-osmotic changes trigger global transcriptional repression and a condensation-prone environment that primes chromatin for a cell fate transition by attenuating repression of differentiation genes. However, while this mechano-osmotic chromatin priming has the potential to accelerate fate transitions and differentiation, sustained biochemical signals are required for robust induction of specific lineages. Our findings uncover a critical mechanochemical feedback mechanism that integrates nuclear mechanics, shape and volume with biochemical signaling and chromatin state to control cell fate transition dynamics., Competing Interests: Declaration of interests The authors declare no conflict of interest.

Background: There is a discrepancy in the surgical and endoscopic literature for managing duodenal perforations. Although often managed conservatively, surgical repair is the standard treatment for duodenal perforations. This contrasts with the gastroenterology literature, which now recommends endoscopic repair of duodenal perforations, which are more frequently iatrogenic from the growing field of advanced endoscopic procedures. This study aims to provide a scoping review to summarize the current literature content and quality on endoscopic repair of duodenal perforations., Methods: The protocol for performing this scoping review was outlined by the Joanna Briggs Institute. All studies that reported primary outcomes of patients who had undergone endoscopic repair of duodenal perforations before February 2022, regardless of perforation etiology or repair type were reviewed, with studies after 1999 meeting inclusion criteria. The study excluded articles that did not report clinical outcomes of endoscopic repair, articles that did not describe where in the gastrointestinal tract the endoscopic repair occurred, pediatric patients, and animal studies., Results: 7606 abstracts were screened, with 474 full articles reviewed and 152 studies met inclusion criteria. 560 patients had duodenal perforations repaired endoscopically, with a technical success rate of 90.4% and a survival rate of 86.7%. Most of these perforations (74.5%) were iatrogenic from endoscopic procedures or surgery. Only one randomized control trial (RCT) was found, and 53% of studies were case reports., Conclusion: These results suggest that endoscopic repair could emerge as a viable first-line treatment for duodenal perforation and highlight the need for more high-quality research in this topic., (© 2024. The Author(s).)

MXenes are a group of 2D transition metal carbonitrides, nitrides and carbides that have become widely recognized as useful materials since they were first discovered in 2011. MXenes, with their exceptional layered structures and splendid external chemistries, have excellent electrical, optical, and thermal properties, making them suitable for catalysis, biomedical uses, environmental remediation, energy storage, and EMI shielding. Over forty MXene compounds with surface terminations like hydroxyl, oxygen, or fluorine are hydrophilic and easily integrated into various applications. Advanced synthesis methods, including selective etching and etchant modifications, have broadened MXene surface chemistries for customized mechanical, thermal, and electrical applications. Integrating MXenes into polymer composites has demonstrated notable promise, enhancing the host polymers' electrical conductivity, thermal stability and mechanical strength. The MXene-polymer composites demonstrate remarkable prospective on behalf of advanced purposes, including flexible electronics, high-performance EMI shielding materials, and lightweight structural components. MXenes have the desirable characteristic of being able to create flexible and translucent films, as well as improve the properties of polymer matrices. This makes them very suitable for use in advanced technological applications. This review summarizes MXene research, methods, and insights, highlighting key discoveries and future directions. This also highlights the importance of ongoing research to fill in the gaps in current knowledge and improve the practical uses of MXenes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

The COVID-19 pandemic brought forth an urgent need for widespread genomic surveillance for rapid detection and monitoring of emerging SARS-CoV-2 variants. It necessitated design, development, and deployment of a nationwide infrastructure designed for sequestration, consolidation, and characterization of patient samples that disseminates de-identified information to public authorities in tight turnaround times. Here, we describe our development of such an infrastructure, which sequenced 594,832 high coverage SARS-CoV-2 genomes from isolates we collected in the United States (U.S.) from March 13th 2020 to July 3rd 2023. Our sequencing protocol ('Virseq') utilizes wet and dry lab procedures to generate mutation-resistant sequencing of the entire SARS-CoV-2 genome, capturing all major lineages. We also characterize 379 clinically relevant SARS-CoV-2 multi-strain co-infections and ensure robust detection of emerging lineages via simulation. The modular infrastructure, sequencing, and analysis capabilities we describe support the U.S. Centers for Disease Control and Prevention national surveillance program and serve as a model for rapid response to emerging pandemics at a national scale., (© 2024. The Author(s).)

We present a rare case of an intraparenchymal chordoma in the brain stem of a 69-year-old male with a history of multiple chordoma recurrences. Chordomas are uncommon tumors that originate from notochordal remnants, with intraparenchymal presentations in the brain stem being particularly rare. A 69-year-old male with a history of clival chordoma three years after primary endoscopic resection and adjuvant proton-beam radiotherapy and a recurrence one year postoperatively for which he underwent a second surgery, presented with severe headaches, weakness, diaphoresis, and difficulty ambulating. Head CT in the ER revealed a 2.7 x 3.5 cm hyperdense lesion in the pons, indicating acute hemorrhage. Magnetic resonance imaging (MRI) suggested a hemorrhagic radiation-induced cavernoma. A right retrosigmoid craniotomy was performed, and the lesion was resected without major complications. Final pathology reported an intraparenchymal hemorrhagic chordoma. To our knowledge, this is the first case of intra-axial chordoma, particularly in the brain stem. It highlights the importance of considering intraparenchymal chordoma on the differential when evaluating for recurrence versus other treatment-induced pathologies and changes. This may prompt the neurosurgeon to reconsider treatment options and weigh the risks of watchful waiting versus biopsy or even aggressive surgical management., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bashti et al.)

We are witnessing a steep increase in model development initiatives in genomics that employ high-end machine learning methodologies. Of particular interest are models that predict certain genomic characteristics based solely on DNA sequence. These models, however, treat the DNA as a mere collection of four, A, T, G and C, letters, dismissing the past advancements in science that can enable the use of more intricate information from nucleic acid sequences. Here, we provide a comprehensive database of quantum mechanical (QM) and geometric features for all the permutations of 7-meric DNA in their representative B, A and Z conformations. The database is generated by employing the applicable high-cost and time-consuming QM methodologies. This can thus make it seamless to associate a wealth of novel molecular features to any DNA sequence, by scanning it with a matching k-meric window and pulling the pre-computed values from our database for further use in modelling. We demonstrate the usefulness of our deposited features through their exclusive use in developing a model for A->C mutation rates., (© 2024. The Author(s).)

Wellbore stability analysis is a critical component of petroleum engineering, evaluating the risks of sanding, reservoir compaction, and casing failures. Laboratory rock mechanical measurements must be scaled up to reservoir scales to achieve accurate results. One challenge lies in upscaling dynamic measurements from petrophysical logs to pseudo-static elastic properties, which has significant implications for oil and gas operations. We present a novel approach that combines laboratory rock mechanical measurements with well-log data to develop a mechanical earth model (MEM) for an Iranian oilfield with over 350 wells. We conducted static elastic property measurements on 40 core samples from various layers and depths of carbonate and sandstone rocks, demonstrating the practical application of our approach. By integrating these measurements with dynamic log data and static-dynamic correlations, we established a framework for evaluating the mechanical properties of different layers. Our findings indicate that the safe mud weight window ranges from 41.5 to 118.59 pcf, while the stable mud weight window ranges from 41.5 to 156 pcf. We demonstrate the importance of conducting parallel rock mechanical studies on cores and logs to reduce uncertainties, costs, and risks during oil and gas operations. We also propose a novel methodology combining lithological characteristics, abnormally high pressure, and borehole instability mechanisms to evaluate the stability of borehole walls. This framework provides a fresh perspective on wellbore stability analysis and offers practical solutions for the industry. Essential novel techniques include developing a geomechanical model that integrates laboratory rock mechanical measurements with well-log data to evaluate mechanical properties and calculate safe and stable mud-weight windows. Our study advances wellbore stability analysis by providing a new method for addressing this long-standing challenge. It offers valuable insights for petroleum engineers working in the oil and gas industry., (© 2024. The Author(s).)

Polar van der Waals (vdW) crystals, composed of atomic layers held together by vdW forces, can host phonon polaritons-quasiparticles arising from the interaction between photons in free-space light and lattice vibrations in polar materials. These crystals offer advantages such as easy fabrication, low Ohmic loss, and optical confinement. Recently, hexagonal boron nitride (hBN), known for having hyperbolicity in the mid-infrared range, has been used to explore multiple modes with high optical confinement. This opens possibilities for practical polaritonic nanodevices with subdiffractional resolution. However, polariton waves still face exposure to the surrounding environment, leading to significant energy losses. In this work, we propose a simple approach to inducing a hyperbolic phonon polariton (HPhP) waveguide in hBN by incorporating a low dielectric medium, ZrS 2 . The low dielectric medium serves a dual purpose-it acts as a pathway for polariton propagation, while inducing high optical confinement. We establish the criteria for the HPhP waveguide in vdW heterostructures with various thicknesses of ZrS 2 through scattering-type scanning near-field optical microscopy (s-SNOM) and by conducting numerical electromagnetic simulations. Our work presents a feasible and straightforward method for developing practical nanophotonic devices with low optical loss and high confinement, with potential applications such as energy transfer, nano-optical integrated circuits, light trapping, etc.

Numerous technical advances in magnetic resonance imaging have opened up promising new approaches in dentomaxillofacial radiology in recent years. With its ability to simultaneously visualize soft and hard tissues, MRI has the potential to become an innovative method for accurate diagnosis and planning of dental implants. Dental MRI is already a valuable and useful complement to conventional X-ray imaging techniques and could further minimize the risks of surgery by optimizing existing treatment protocols. Considering current efforts in dentistry to reduce radiation exposure and take a further step toward personalized oral diagnostics that consider patient-specific factors, this article reviews the capabilities of dentomaxillofacial MR imaging in implant surgery. It highlights the various applications of MRI in dental implant surgery and evaluates both the benefits and the clinical challenges. Overall, considering the specific indications and limitations of MR sequences, dental MRI represents a further significant advance in individualized treatment planning in dentistry. It allows consideration of parameters not visualized by conventional imaging techniques and is particularly useful for evaluating surgically relevant parameters, especially those related to soft tissue., (Copyright 2024 Adib Al-Haj Husain, Bernd Stadlinger, Sebastian Winklhofer, Marco Piccirelli, Silvio Valdec. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

High-throughput imaging (HTI) generates complex imaging datasets from a large number of experimental perturbations. Commercial HTI software programs for image analysis workflows typically do not allow full customization and adoption of new image processing algorithms in the analysis modules. While open-source HTI analysis platforms provide individual modules in the workflow, like nuclei segmentation, spot detection, or cell tracking, they are often limited in integrating novel analysis modules or algorithms. Here, we introduce the High-Throughput Image Processing Software (HiTIPS) to expand the range and customization of existing HTI analysis capabilities. HiTIPS incorporates advanced image processing and machine learning algorithms for automated cell and nuclei segmentation, spot signal detection, nucleus tracking, nucleus registration, spot tracking, and quantification of spot signal intensity. Furthermore, HiTIPS features a graphical user interface that is open to integration of new analysis modules for existing analysis pipelines and to adding new analysis modules. To demonstrate the utility of HiTIPS, we present three examples of image analysis workflows for high-throughput DNA FISH, immunofluorescence (IF), and live-cell imaging of transcription in single cells. Altogether, we demonstrate that HiTIPS is a user-friendly, flexible, and open-source HTI software platform for a variety of cell biology applications., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply, 2024.)

Physical vapor deposition (PVD) coating is a versatile and well-liked method for depositing thin films of materials onto surfaces in a range of industries. Due to their numerous functional and aesthetic benefits, PVD coatings are beneficial in several applications, from electronics and optics to automotive and medical equipment. PVD coating technology dramatically improves the effectiveness and quality of medical implants. PVD-coated medical implants improve osseointegration, lower wear and friction, increase corrosion resistance, and have antibacterial properties, which lead to better patient outcomes, fewer complications, and overall higher quality of life for people who need implantable medical devices. The essential concepts of PVD coating and the numerous deposition techniques and materials used are covered at the study's outset. The specific uses of PVD-coated medical implants are then highlighted, including those for orthopedic and dental implants and cardiovascular and neurosurgical devices. The review also emphasizes the critical contribution of PVD coatings to reducing wear and friction, improving corrosion resistance, augmenting biocompatibility, enhancing osseointegration, and aesthetic appeal. The challenges and prospects of PVD coating technologies were further addressed in this article. This review is invaluable for academics, doctors, and businesspeople interested in the beneficial combination of PVD coating and medical implantology., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Purpose: The kissing stent (KS) method is low-risk compared with open surgery techniques. It is often used to treat aorto-iliac occlusive disease (AIOD). Deployment of the KS geometry has a high technical success rate. However, stent patency reduces in the first 5 years potentially due to deleterious flow behavior. Potentially harmful hemodynamics due to the KS were investigated in vitro., Methodology: A compliant phantom of the aorto-iliac bifurcation was manufactured. Two surrogate stent-grafts were deployed into the phantom in the KS configuration to investigate effects of the presence of the stents, including the compliance mismatch they cause, on the hemodynamics proximal and distal to the KS. The investigation used pulsatile flow through a flow circuit to simulate abdominal aortic flow. Particle image velocimetry (PIV) was used to quantify the hemodynamics., Results: PIV identified peak proximal and distal velocity in vitro was 0.71 and 1.40m·s -1 , respectively, which were within physiological ranges. Throughout systole, flow appeared normal and undisturbed. A lumen wall collapse in the sagittal plane formed during late systole and continued to early diastole proximal to the aorto-iliac bifurcation, distal to the inlet stent position. The wall collapse led to disturbed flow proximal to the stented region in early diastole producing potential recirculation zones and abnormal flow patterns., Conclusion: The normal systolic flow behavior indicates the KS configuration is unlikely to cause an inflammatory response of the arterial walls. The collapse has not been previously identified and may potentially cause long-term patency reduction. It requires further investigation., Clinical Impact: The role of this article is to provide further insight into the haemodynamic behavior through a stented aorto-iliac artery. The results of this investigation will improve the understanding of the effects that using the kissing stent method may have on a patient and help to identify high risk regions that may require more detailed monitoring. This paper also develops the in vitro modelling techniques that will enable further research that cannot be carried out within patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In modern burn care, the focus extends beyond mere patient survival to encompass long-term functional and cosmetic outcomes. Research suggests that the technique and manner of suturing during skin grafting play a significant role in scar formation. This study aimed to explore the effectiveness of wound edge approximation with skin grafting compared to the conventional approach, where the graft edge exclusively interacts with the wound edge, in reducing hypertrophic scar development. Seventy-four burn unit patients eligible for grafting were randomly allocated into two groups: those receiving grafts with overlapping edges (Group A) and those receiving grafts with edges tailored to the burn wound (Group B). Evaluation of graft sites occurred immediately post-surgery and at 1 and 6 months post-operatively using the standardized Vancouver Scar Scale (VSS) administered by trained surgeons. The findings of this study revealed that there was no statistically significant difference between the two examined groups regarding the average duration of hospitalization and the mean thickness of wounds (P>0.05). Similarly, the mean scores for pain, vascular index, and pigmentation index immediately post-surgery, at 1 month, and 6 months later, as well as the scar height index and flexibility immediately and at 1 month post-surgery, and the Vancouver Scar Scale index at the study's conclusion, showed no significant variation between the two groups (P>0.05). However, at the 6-month follow-up, the mean scar height score (P=0.004) in the overlapping group and the mean flexibility score (P=0.017) in the non-overlapping group were significantly lower compared to the respective alternative group. This indicates a notable improvement in scar height and wound flexibility in the overlapping group over the non-overlapping group after 6 months., (Published by Oxford University Press on behalf of the American Burn Association 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Subcutaneous (SC) injection of protein-based therapeutics is a convenient and clinically established drug delivery method. However, progress is needed to increase the bioavailability. Transport of low molecular weight ( M w therapeutics, such as monoclonal antibodies (mAbs), due to differences in molecular and formulation properties. In this study, an iodinated fluorescein analog rose bengal (RB) was used as a radiopaque and fluorescent label to track the distribution of bovine serum albumin (BSA) compared against unconjugated RB and sodium iodide (NaI) via CT and confocal microscopy following injection into ex vivo porcine SC tissue. Importantly, the high concentration BSA-RB exhibited viscosities more like that of viscous biologics than the small molecule contrast agents, suggesting that the labeled protein may serve as a more suitable formulation for the investigation of injection plumes. Three-dimensional (3D) renderings of the injection plumes showed that the BSA-RB distribution was markedly different from unconjugated RB and NaI, indicating the need for direct visualization of large protein therapeutics using conjugated tags rather than using small molecule tracers. Whereas this proof-of-concept study shows the novel use of RB as a label for tracking BSA distribution, our experimental approach may be applied to high M w therapeutics, such as monoclonal antibodies (mAbs), due to differences in molecular and formulation properties. In this study, an iodinated fluorescein analog rose bengal (RB) was used as a radiopaque and fluorescent label to track the distribution of bovine serum albumin (BSA) compared against unconjugated RB and sodium iodide (NaI) via CT and confocal microscopy following injection into ex vivo porcine SC tissue. Importantly, the high concentration BSA-RB exhibited viscosities more like that of viscous biologics than the small molecule contrast agents, suggesting that the labeled protein may serve as a more suitable formulation for the investigation of injection plumes. Three-dimensional (3D) renderings of the injection plumes showed that the BSA-RB distribution was markedly different from unconjugated RB and NaI, indicating the need for direct visualization of large protein therapeutics using conjugated tags rather than using small molecule tracers. Whereas this proof-of-concept study shows the novel use of RB as a label for tracking BSA distribution, our experimental approach may be applied to high M w biologics, including mAbs. These studies could provide crucial information about diffusion in SC tissue and the influence of injection parameters on distribution, transport, and downstream bioavailability.

Dural arteriovenous fistulas (dAVFs) are anomalous connections between arteries and veins within the dura mater, involving dural sinuses, bridging veins, or emissary veins. If untreated, these lesions can result in intracranial hemorrhage. The management of posterior fossa dAVFs is challenging due to the intricate venous anatomy near the brainstem and cranial nerves. This study leverages three-dimensional (3D) technology combined with dissections to understand the anatomy and microsurgical techniques for treating infratentorial dAVFs. Five embalmed heads and one dry skull were used to meticulously document the pertinent anatomy of the infratentorial compartment. Advanced 3D technology, including 3D sculpting and structured light scanning, was employed to construct high-resolution volumetric models (VMs). Two-dimensional (2D) images of dissections and VMs illustrate key anatomical landmarks of the posterior fossa. Infratentorial dAVFs primarily involve sinuses, which are divided into groups based on their location: basal, medullary, and petrosal. Most of the arterial supply originates from the external carotid artery, especially the ascending pharyngeal artery. This is followed by meningeal branches from the internal carotid artery (ICA) and vertebrobasilar system. The surgical approaches to treat infratentorial dAVFs include the retrosigmoid and far lateral approaches and their modifications. Our study describes the relevant vascular anatomy of the infratentorial compartment, focusing on the surgical treatment of infratentorial dAVFs. In conjunction with the included interactive models, this study improves our educational capabilities regarding the intricate vascular neuroanatomical features of this region. When applied to a clinical setting, precise anatomical knowledge and VMs tools enhance surgical outcomes, reduce complications, and ultimately improve patient care., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Payman et al.)

Purpose: Sickle-cell disease-associated moyamoya syndrome (SCD-MMS) carries a high risk for recurrent strokes and cerebrovascular morbidity in children. However, few data are available about complications that occur in children hospitalized with SCD-MMS. The purpose of this analysis was to determine the risk factors for in-hospital complications in pediatric SCD-MMS admissions, and thus aid physicians in optimizing future treatment plans., Methods: A national database of pediatric hospital admissions was examined across the years 2003-2019. ICD-9 and ICD-10 diagnosis codes were analyzed to identify discharges with a primary diagnosis of SCD-MMS and identify in-hospital complications, defined as complication-associated diagnostic codes logged during the same admission. Patient demographics, comorbidities, and hospital characteristics were examined using univariate and multivariate logistic regression analyses to determine associations with in-hospital complications., Results: In total, 274 admissions with a primary diagnosis of SCD-MMS were identified. During 64 (23.4%) admissions, transfusion therapy was given, and in 86 admissions (31.4%), surgical revascularization was performed. In 10 admissions (3.6%), a total of 11 in-hospital complications were identified. After multivariate regression, both comorbid chronic lung disease (adjusted OR 5.3 [1.1, 26.9], P = 0.04) and surgical revascularization (adjusted OR 10.2 [2.0, 52.4], P = 0.006) were associated with development of complications., Conclusions: In this nationwide database of pediatric SCD-MMS hospitalizations, comorbid chronic lung disease and surgical revascularization were associated with development of in-hospital complications. Patients with comorbid chronic lung disease or who are admitted for revascularization may warrant closer monitoring and greater medical optimization during the hospitalization., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The spatial arrangement of the genome within the nucleus is a pivotal aspect of cellular organization and function with implications for gene expression and regulation. While all genome organization features, such as loops, domains, and radial positioning, are nonrandom, they are characterized by a high degree of single-cell variability. Imaging approaches are ideally suited to visualize, measure, and study single-cell heterogeneity in genome organization. Here, we describe two methods for the detection of DNA and RNA of individual gene alleles by fluorescence in situ hybridization (FISH) in a high-throughput format. We have optimized combined DNA/RNA FISH approaches either using simultaneous or sequential detection of DNA and nascent RNA. These optimized DNA and RNA FISH protocols were implemented in a 384-well plate format alongside automated image and data analysis and enable accurate detection of individual gene alleles and their gene expression status across a large cell population. We successfully visualized MYC and EGFR DNA and nascent RNA with allele-level resolution in multiple cell types, and we determined the radial position of active and inactive MYC and EGFR alleles. These optimized DNA/RNA detection approaches are versatile and sensitive tools for mapping of chromatin features and gene activity at the single-allele level and at high throughput., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC., Methods: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 μg/kg, then escalated to 570 μg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22., Findings: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 μmol/L (95% CI -257 to -94) for maralixibat versus 11 μmol/L (-58 to 80) for placebo, also representing a significant difference of -187 μmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred., Interpretation: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC., Funding: Mirum Pharmaceuticals., Competing Interests: Declaration of interests AGM is a consultant and has a sponsored research agreement with Mirum Pharmaceuticals. JCE has received support to his institution from Mirum Pharmaceuticals. PC is a consultant for Ipsen-Albireo. FO is a speaker for Alexion Pharmaceuticals and Valentech Pharma. AAA is a consultant and adviser for Mirum Pharmaceuticals and Ipsen-Albireo. ES is the founder and chairperson of Cellaion; an investigator for Mirum Pharmaceuticals, Albireo, and Intercept; and an adviser for Mirum Pharmaceuticals and Albireo. UB is a consultant for and has received research funding from Mirum Pharmaceuticals, Ipsen-Albireo, Nestle, and Vivet Pharmaceuticals; and has served as a speaker for Mirum Pharmaceuticals and Ipsen-Alibreo. LD is a consultant and adviser for Mirum Pharmaceuticals, Albireo, Selecta, Vivet Pharmaceuticals, Tome, Spark, Genespire, and Alexion. NK is a consultant for Mirum Pharmaceuticals. C-HL has received a research grant from Mirum Pharmaceuticals. SG is an adviser for and has received research support to her institution from Mirum Pharmaceuticals. NM is an investigator for Mirum Pharmaceuticals. SPH is a hepatic safety adjudication committee member at Ipsen-Albireo and has received a research grant from Mirum Pharmaceuticals. TJ is a shareholder and has intellectual property rights in Mirum Pharmaceuticals, and is an employee of and shareholder in Galapagos. VFH is a consultant for and has received research support to her institution from Mirum Pharmaceuticals. RPG-P has received a research grant from Mirum Pharmaceuticals, and is an adviser, teacher, and educator for Mirum Pharmaceuticals and Albireo. UE is a steering committee member for Mirum Pharmaceuticals. JH has received a research grant from Mirum Pharmaceuticals. NO has received research support to her institution from Mirum Pharmaceuticals, Albireo, and Travere. RJT is a consultant, adviser, and speaker for and has received research support to his institution from Mirum Pharmaceuticals. TN, AL, LL, DBM, WG, and PV are employees of and shareholders in Mirum Pharmaceuticals. AMou, GP, AMos, RHS, DD, NLab, CA, FKC, W-DH, and NLav declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Cell type-specific enhancers are critically important for lineage specification. The mechanisms that determine cell-type specificity of enhancer activity, however, are not fully understood. Most current models for how enhancers function invoke physical proximity between enhancer elements and their target genes. Here, we use an imaging-based approach to examine the spatial relationship of cell type-specific enhancers and their target genes with single-cell resolution. Using high-throughput microscopy, we measure the spatial distance from target promoters to their cell type-specific active and inactive enhancers in individual pancreatic cells derived from distinct lineages. We find increased proximity of all promoter-enhancer pairs relative to non-enhancer pairs separated by similar genomic distances. Strikingly, spatial proximity between enhancers and target genes was unrelated to tissue-specific enhancer activity. Furthermore, promoter-enhancer proximity did not correlate with the expression status of target genes. Our results suggest that promoter-enhancer pairs exist in a distinctive chromatin environment but that genome folding is not a universal driver of cell-type specificity in enhancer function., Competing Interests: Conflicts of interests: The authors declare no financial conflict of interest.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that represents a significant challenge in cancer research and clinical management. In this study, we reanalyzed a published single-cell RNA sequencing (scRNA-seq) dataset from PDAC and adjacent tissues to investigate the heterogeneity of tumor and normal tissue, specifically focusing on the regulatory T cells (Tregs) and their interactions with other cells in the tumor microenvironment (TME). Treg cells were identified and clustered into natural Tregs (nTreg) and induced Tregs (iTreg) based on the expression of specific genes. It was found that the number of iTregs was higher in the tumor than in healthy tissues, while the number of n Tregs was higher in healthy tissues. Differential gene expression analysis was performed, and biological process analysis revealed that the Tregs in PDAC were mostly involved in protein targeting and translation pathways. In addition, ligand-receptor pairs between Tregs and other cell types were identified, and the critical communication pathways between Tregs and endothelial and ductal cells were revealed, which could potentially contribute to the immunosuppressive TME of PDAC. These findings provide insights into the role of Tregs in PDAC and their interactions with other cell types in the TME, highlighting potential targets for immunotherapy, such as the inhibitory immune checkpoint receptors CTLA4 and TIGIT, which are known to be expressed on Tregs and have been shown to play a role in suppressing anti-tumor immune responses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Toxoplasma gondii is the etiologic agent of toxoplasmosis, a highly prevalent parasitosis. Toxoplasma gondii ( T. gondii ) transits in the brain from acute (AT) to chronic toxoplasmosis (CT), under host immune control. In immunocompromised patients, reactivation of CT is potentially life-threatening. Behavioral and neurological complications have been associated with CT. Furthermore, an effective treatment targeting CT is still lacking. We previously reported the efficacy of imiquimod against CT. Here, we demonstrate the molecular effects of imiquimod or imiquimod followed by the clinically used combination of sulfadiazine and pyrimethamine (SDZ + PYR) on CT-associated behavior in a rat model. Imiquimod decreased the number of cysts in the brains of chronically infected rats due to an induced reactivation of bradyzoites into tachyzoites. Importantly, this decrease was more pronounced in rats treated with imiquimod followed by SDZ + PYR. Rats chronically infected with T. gondii exhibited an anxiety-like behavior. Notably, treatment with imiquimod reversed this behavior aberrancy, with even a more pronounced effect with imiquimod followed by SDZ/PYR. Similarly, rats chronically infected with T. gondii exhibited learning deficits, and imiquimod alone or followed by SDZ/PYR reversed this behavior. Our results enhance our knowledge of the implications of CT on behavioral aberrancies and highlight the potency of imiquimod followed by SDZ + PYR on these CT-associated complications., Competing Interests: The authors declare no conflicts of interest.

Researchers are now focusing on using the circular economy model to manufacture nanocellulose composites due to growing environmental issues related to waste management. The circular economy model offers a sustainable solution to the problem by optimizing resource efficiency and waste management by reducing waste, maintaining value over time, minimizing the use of primary resources, and creating closed loops for goods, components, and materials. With the use of the circular economy model, waste, such as industrial, agricultural, and textile waste, is used again to produce new products, which can solve waste management issues and improve resource efficiency. In order to encourage the use of circular economy ideas with a specific focus on nanocellulose composites, this review examines the concept of using circular economy, and explores ways to make nanocellulose composites from different types of waste, such as industrial, agricultural, and textile waste. Furthermore, this review investigates the application of nanocellulose composites across multiple industries. In addition, this review provides researchers useful insights of how circular economics can be applied to the development of nanocellulose composites, which have the goal of creating a flexible and environmentally friendly material that can address waste management issues and optimize resource efficiency., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Muhammad Adlan Azka reports financial support was provided by the Ministry of Higher Education, Malaysia. S. M. Ridzuan reports financial support was provided by Putra Malaysia University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To compare the three-dimensional (3D) effects of canine traction on the maxillary teeth when using two different traction methods, the continuous and the segmented arch wire techniques; then to test whether adding a transpalatal arch (TPA) would affect their response to traction., Design: Finite element analysis., Methods: A cone-beam computed tomography (CBCT) scan of a patient with bilateral palatally impacted canines was chosen, from which a 3D model was derived and imported into ABAQUS. Two arch wires were modelled, a continuous round one and a segmented rectangular one. Four models were obtained by adding a TPA to both techniques. A 100° imposed rotation was then applied at the intersection between the vertical loop and the horizontal segment of each wire. Initial displacement of the maxillary tooth in the labio-lingual and in the vertical directions was measured. The absolute maximum principal stress of the periodontal ligament (PDL) was also assessed., Results: Traction using a continuous arch wire led to different movement patterns of all teeth, some of them were tipped in a labial direction while others were lingually tipped. Traction using a segmented arch wire resulted in a retroclination of the posterior teeth and a proclination of the anterior teeth with a high level of stress on the premolars' PDL. Adding the TPA only affected the displacement of the first molars. The right side showed a maximum displacement of the first premolar, while the left side showed it on the lateral. The total displacement on the right side was higher than the left side., Conclusion: The segmented technique caused a uniform displacement of all teeth while the continuous one showed a non-uniform displacement. The angulation and position of the vertical loop affected the displacement of the maxillary teeth. The addition of a TPA acted only on the first molars., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Coronary obstruction (CO) is a rare but critical complication of transcatheter aortic valve implantation. It is associated with significant morbidity and mortality. This comprehensive review elucidates the evolving landscape of CO risk assessment and management strategies in the contemporary era of transcatheter aortic valve implantation. Drawing upon recent advances in computed tomography angiography, we delve into the nuanced evaluation of anatomic parameters crucial for predicting CO risk. Furthermore, this review explores the utility of interventional and surgical techniques, including chimney stenting and leaflet modification systems, in mitigating CO complications. In summary, this review serves as a practical guide for clinicians navigating the complexities of CO prevention and management in the evolving landscape of transcatheter aortic valve implantation, with the goal of optimizing patient outcomes and ensuring procedural success., Competing Interests: Disclosures Dr Ibrahim reports receiving advisory fees and being a proctor for Medtronic. The other authors report no conflicts.

Objective: Pseudoaneurysm formation post type A aortic dissection repair is rare. Revision surgical repair is challenging, with a risk of death from haemorrhage., Methods: We present a 56-year-old man who presented with a rapidly enlarging distal ascending aortic anastomotic pseudoaneurysm following a recent ascending and hemiarch replacement for acute type A aortic dissection., Results: A tight kink in the ascending aortic graft precluded an endovascular repair utilizing two antegrade branches, and so a novel custom-made 3 inner branched aortic endograft was designed, with an antegrade brachiocephalic inner branch and retrograde left common carotid and subclavian artery inner branches. The patient required an angioplasty to dilate the kinked/coarcted surgical graft, but made an uneventful recovery., Conclusion: An aortic arch inner branch design with an antegrade brachiocephalic branch but retrograde left common carotid and left subclavian branches was feasible and may prove particularly useful when there is limited space in the ascending aorta., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Objective: The placement of flow-diverting devices has become a common method of treating unruptured intracranial aneurysms of the internal carotid artery. The progressive improvement of aneurysm occlusion after treatment-with low complication and rupture rates-has led to a dilemma regarding the management of aneurysms in which occlusion has not occurred within 6-24 months. The authors aimed to identify clinical consensus regarding management of intracranial aneurysms displaying persistent filling 6-24 months after flow diversion and to ascertain questions that may drive future investigation., Methods: An international panel of 67 experts was invited to participate in a multistep Delphi consensus process on the treatment of intracranial aneurysms after failed flow diversion., Results: Of the 67 experts invited, 23 (34%) participated. Qualitative analysis of an initial survey with open-ended questions resulted in 51 statements regarding management of aneurysms showing persistent filling after flow diversion. The statements were grouped into 8 categories, and in the second round, respondents rated the degree of their agreement with each statement on a 5-point Likert scale. Flow diverters with surface modifiers did not influence administration of dual-antiplatelet therapy according to 83%. Consensus was also reached regarding the definition of treatment failure at specific time points, including at 6 months if there is aneurysm growth or persistent rapid flow through the entirety of the aneurysm (96%), at 12 months if there is aneurysm growth or symptom onset (78%), and at 24 months if there is persistent filling regardless of size and filling characteristics (74%). Although experts agreed that the degree of intimal hyperplasia or in-device stenosis could not be ascertained by noninvasive imaging alone (83%), only 65% chose digital subtraction angiography as the preferred modality. At 6 and 12 months, retreatment is preferred if there is persistent filling with aneurysm growth (96%, 96%), device malposition (48%, 87%), or a history of subarachnoid hemorrhage (65%, 70%), respectively, and at 24 months if there is persistent filling without reduction in aneurysm size (74%). Experts favored treatment with an additional flow diverter (87%) over aneurysm clipping, applying the same principles for follow-up (83%) and treatment failure (91%) as for the first flow diverter., Conclusions: The authors present the consensus practices of experts in the management of intracranial aneurysms without occlusion 6-24 months after treatment with a flow-diverting device.

Objective: Disparities in the epidemiology and growth rates of aneurysms between the sexes are known. However, little is known about sex-dependent outcomes after microsurgical clipping of unruptured intracranial aneurysms (UIAs). The aim of this study was to examine sex differences in characteristics and outcomes after microsurgical clipping of UIAs and to perform a propensity score-matched analysis using an international multicenter cohort., Methods: This retrospective cohort study involved the participation of 15 centers spanning four continents. It included adult patients who underwent clipping of UIAs between January 2016 and December 2020. Patients were stratified according to their sex and analyzed for differences in morbidities and aneurysm characteristics. Based on this stratification, female patients were matched to male patients in a 1:1 ratio with a caliper width of 0.1 using propensity score matching. Endpoints included postoperative complications, neurological performance, and aneurysm occlusion at discharge and 24 months after clip placement., Results: A total of 2245 patients with a mean age of 57.3 (range 20-87) years were included. Of these patients, 1675 (74.6%) were female. Female patients were significantly older (mean 57.6 vs 56.4 years, p = 0.03) but had fewer comorbidities. Aneurysms of the internal carotid artery (7.1% vs 4.2%), posterior communicating artery (6.9% vs 1.9%), and ophthalmic artery (6.0% vs 2.8%) were more commonly treated surgically in females, while clipping of aneurysms of the anterior communicating artery was more frequent in males (17.0% vs 25.3%; all p < 0.001). After propensity score matching, female patients were found to have had significantly fewer pulmonary complications (1.4% vs 4.2%, p = 0.01). However, general morbidity (24.5% vs 25.2%, p = 0.72) and mortality (0.5% vs 1.1%, p = 0.34), as well as neurological performance (p = 0.58), were comparable at discharge in both sexes. Lastly, rates of aneurysm occlusion at the time of discharge (95.5% vs 94.9%, p = 0.71) and 24 months after surgery (93.8% vs 96.1%, p = 0.22) did not significantly differ between male and female patients., Conclusions: Despite overall differences between male and female patients in demographics, comorbidities, and treated aneurysm location, sex did not relevantly affect surgical performance or perioperative complication rates.

Background: University spring break carries a two-pronged SARS-CoV-2 variant transmission risk. Circulating variants from universities can spread to spring break destinations, and variants from spring break destinations can spread to universities and surrounding communities. Therefore, it is critical to implement SARS-CoV-2 variant surveillance and testing strategies to limit community spread before and after spring break to mitigate virus transmission and facilitate universities safely returning to in-person teaching., Methods: We examined the SARS-CoV-2 positivity rate and changes in variant lineages before and after the university spring break for two consecutive years. 155 samples were sequenced across four time periods: pre- and post-spring break 2021 and pre- and post-spring break 2022; following whole genome sequencing, samples were assigned clades. The clades were then paired with positivity and testing data from over 50,000 samples., Results: In 2021, the number of variants in the observed population increased from four to nine over spring break, with variants of concern being responsible for most of the cases; Alpha percent composition increased from 22.2% to 56.4%. In 2022, the number of clades in the population increased only from two to three, all of which were Omicron or a sub-lineage of Omicron. However, phylogenetic analysis showed the emergence of distantly related sub-lineages. 2022 saw a greater increase in positivity than 2021, which coincided with a milder mitigation strategy. Analysis of social media data provided insight into student travel destinations and how those travel events may have impacted spread., Conclusions: We show the role that repetitive testing can play in transmission mitigation, reducing community spread, and maintaining in-person education. We identified that distantly related lineages were brought to the area after spring break travel regardless of the presence of a dominant variant of concern., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SW is currently employed by Illumina. BK, SP, JP, RD, LI, and AS are employed by Labcorp. The other authors declare no competing interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Napolitano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)