bluuebunny/crossref_metadata_2025 huggingface dataset:
trace: a code for time-reversible astrophysical close encounters
Authors: Lu Tiger , Hernandez David M , Rein Hanno
Published: August 2024

We present trace, an almost time-reversible hybrid integrator for the planetary N-body problem. Like hybrid symplectic integrators, trace can resolve close encounters between particles while retaining many of the accuracy and speed advantages of a fixed time-step symplectic method such the Wisdom–Holman map. trace switches methods time-reversibly during close encounters following the prescription of Hernandez & Dehnen. In this paper we describe the derivation and implementation of trace and study its performance for a variety of astrophysical systems. In all our test cases, trace is at least as accurate and fast as the hybrid symplectic integrator mercurius. In many cases, trace’s performance is vastly superior to that of mercurius. In test cases with planet–planet close encounters, trace is as accurate as mecurius with a 12× speed-up. If close encounters with the central star are considered, trace achieves good error performance while mercurius fails to give qualitatively correct results. In ensemble tests of violent scattering systems, trace matches the high-accuracy IAS15 while providing a 15× speed-up. In large N systems simulating lunar accretion, trace qualitatively gives the same results as ias15 but at a 41× speed-up. We also discuss some cases such as von Zeipel–Lidov–Kozai cycles where hybrid integrators perform poorly and provide some guidance on which integrator to use for which system. trace is freely available within the rebound package.
A CRISPR-dCas13 RNA-editing tool to study alternative splicing
Authors: Núñez-Álvarez Yaiza , Espie-Caullet Tristan , Buhagiar Géraldine , Rubio-Zulaika Ane , Alonso-Marañón Josune , Luna-Pérez Elvira , Blazquez Lorea , Luco Reini F
Published: August 2024

Alternative splicing allows multiple transcripts to be generated from the same gene to diversify the protein repertoire and gain new functions despite a limited coding genome. It can impact a wide spectrum of biological processes, including disease. However, its significance has long been underestimated due to limitations in dissecting the precise role of each splicing isoform in a physiological context. Furthermore, identifying key regulatory elements to correct deleterious splicing isoforms has proven equally challenging, increasing the difficulty of tackling the role of alternative splicing in cell biology. In this work, we take advantage of dCasRx, a catalytically inactive RNA targeting CRISPR-dCas13 ortholog, to efficiently switch alternative splicing patterns of endogenous transcripts without affecting overall gene expression levels cost-effectively. Additionally, we demonstrate a new application for the dCasRx splice-editing system to identify key regulatory RNA elements of specific splicing events. With this approach, we are expanding the RNA toolkit to better understand the regulatory mechanisms underlying alternative splicing and its physiological impact in various biological processes, including pathological conditions.
Metabolic RNA labeling in non-engineered cells following spontaneous uptake of fluorescent nucleoside phosphate analogues
Authors: Pfeiffer Pauline , Nilsson Jesper R , Gallud Audrey , Baladi Tom , Le Hoang-Ngoan , Bood Mattias , Lemurell Malin , Dahlén Anders , Grøtli Morten , Esbjörner Elin K , Wilhelmsson L Marcus
Published: August 2024

RNA and its building blocks play central roles in biology and have become increasingly important as therapeutic agents and targets. Hence, probing and understanding their dynamics in cells is important. Fluorescence microscopy offers live-cell spatiotemporal monitoring but requires labels. We present two fluorescent adenine analogue nucleoside phosphates which show spontaneous uptake and accumulation in cultured human cells, likely via nucleoside transporters, and show their potential utilization as cellular RNA labels. Upon uptake, one nucleotide analogue, 2CNqAXP, localizes to the cytosol and the nucleus. We show that it could then be incorporated into de novo synthesized cellular RNA, i.e. it was possible to achieve metabolic fluorescence RNA labeling without using genetic engineering to enhance incorporation, uptake-promoting strategies, or post-labeling through bio-orthogonal chemistries. By contrast, another nucleotide analogue, pAXP, only accumulated outside of the nucleus and was rapidly excreted. Consequently, this analogue did not incorporate into RNA. This difference in subcellular accumulation and retention results from a minor change in nucleobase chemical structure. This demonstrates the importance of careful design of nucleoside-based drugs, e.g. antivirals to direct their subcellular localization, and shows the potential of fine-tuning fluorescent base analogue structures to enhance the understanding of the function of such drugs.
How Do Digital Advertising Auctions Impact Product Prices?
Authors: Bergemann Dirk , Bonatti Alessandro , Wu Nicholas
Published: August 2024

We present a model of digital advertising with three key features: (1) advertisers can reach consumers on and off a platform, (2) additional data enhances the value of advertiser–consumer matches, and (3) the allocation of advertisements follows an auction-like mechanism. We contrast data-augmented auctions, which leverage the platform’s data advantage to improve match quality, with managed-campaign mechanisms that automate match formation and price-setting. The platform-optimal mechanism is a managed campaign that conditions the on-platform prices for sponsored products on the off-platform prices set by all advertisers. This mechanism yields the efficient on-platform allocation but inefficiently high off-platform product prices. It attains the vertical integration profit for the platform and the advertisers, and it increases off-platform product prices while decreasing consumer surplus, relative to data-augmented auctions.
Racialising Refugees: The Global Colour Line in US Resettlement
Authors: Coen Alise
Published: August 2024

Following the 2021 Taliban takeover of Afghanistan and the 2022 Russian invasion of Ukraine, there were notable differences in access to resettlement and other pathways of humanitarian migration. Drawing on an analysis of statements by US policymakers, this article considers the global context and implications of the disparate language and approaches used in responses to Afghan and Ukrainian displacement. It shows how racialised and gendered narratives contributed to and were constituted within a broader international hierarchy and global colour line. The positioning of Ukrainians as possessing higher civilisational attributes deserving of solidarity and support, and their portrayal through prisms of strong agency, sovereignty, and kindred Western values, echoed across transnational constructions of collective white identity. In contrast, Afghan resettlement was rendered conditional on extensive security vetting and proof of loyal service to US and NATO missions in Afghanistan. Portrayals of Afghans as less assimilable, as potential terrorist infiltrators, as incapable of self-governance and unable to generate their own progress perpetuated features of the global colour line. Attending to the different logics used to construct refugee and parolee groups and policies broadens our understanding on how multilayered processes of Orientalism and racialisation shape resettlement and disparities in access to protection.
The actigraphic evaluation of daytime sleep in central disorders of hypersomnolence: comparison with polysomnography
Authors: Biscarini Francesco , Vandi Stefano , Riccio Caterina , Raggini Linda , Neccia Giulia , Plazzi Giuseppe , Pizza Fabio
Published: August 2024

Study Objectives

The role of actigraphy in central disorders of hypersomnolence (CDH) is expanding but evidence of reliability with polysomnography (PSG) is scarce and provided only during nighttime. We explored the agreement between actigraphy and continuous 24-hour PSG at CDH diagnosis.

Methods

Forty-four consecutive drug-naïve patients (28 narcolepsy and 16 idiopathic hypersomnia [IH]) underwent actigraphy during 24 hours of free-running PSG, during multiple sleep latency test (MSLT) and 13 of them also during maintenance of wakefulness test (MWT). Daytime and nighttime sleep features and MSLT and MWT mean sleep latencies (mSL) were estimated with the actigraphic algorithms by Cole-Kripke (CK), Sadeh (Sad), and University of California San Diego (UCSD). Agreement to corresponding PSG measures was assessed with Bland–Altman plots.

Results

Nighttime-total sleep time (TST) in narcolepsy was significantly underestimated with CK (bias 27.8 minutes, 95% CI 13.7 to 41.9) and Sad (bias 56.7 minutes, 95% CI 38.8/74.5). Daytime-TST was overestimated in IH and narcolepsy with all algorithms (CK: bias −42.2, 95% CI −67/−17.4; Sad: bias −30.2 minutes, 95% CI −52.7/−7.7; UCSD bias −86.9 minutes, 95% CI −118.2/−55.6). 24-hour-TST was overestimated by CK and UCSD in IH (CK: bias −58.5 minutes, 95% CI −105.5/−11.5; UCSD: bias −118.8 minutes, 95% CI −172.5/−65), and by UCSD in narcolepsy (bias −68.8 minutes, 95% CI −109.3/−38.2). In the entire cohort, actigraphy overestimated MSLT mSL but not MWT mSL.

Conclusions

Conventional actigraphic algorithms overestimate 24-hour TST in IH and underestimate nighttime TST in narcolepsy. These discrepancies call for the cautious application of actigraphy in the diagnostic process of CDH and the development of new quantitative signal analysis approaches.
A new theropod dinosaur from the Callovian Balabansai Formation of Kyrgyzstan
Authors: Rauhut Oliver W M , Bakirov Aizek A , Wings Oliver , Fernandes Alexandra E , Hübner Tom R
Published: August 2024

Recent fieldwork in the late Middle Jurassic Balabansai Formation of Kyrgyzstan has yielded a partial skeleton of a large theropod dinosaur. The material includes a few bones of the skull (postorbital, quadratojugal), dorsal and sacral vertebrae, fragments of the pectoral girdle and forelimbs, and an almost complete pelvic girdle and hindlimbs, and is here made the type of a new theropod taxon, Alpkarakush kyrgyzicus gen. et sp. nov. Alpkarakush can be diagnosed by an extremely developed orbital brow on the postorbital, a pneumatic opening leading into cavities in the neural arch from the centroprezygodiapophyseal fossa in the posterior dorsal vertebrae, an almost enclosed ventral sulcus in manual phalanx II-1, a narrow and deep intercondylar groove on the anterior side of the distal femur, and an epicondylar crest on the distal femur that is offset from the distal end. A second, fragmentary, and smaller specimen from the same site represents the same taxon. Based on long bone histology, the type of Alpkarakush represents a late subadult individual, whereas the smaller specimen is a juvenile, possibly indicating gregarious behaviour. Phylogenetic analysis places Alpkarakush in the Metriacanthosauridae, underlining the diversity and wide distribution of this clade in the Jurassic of Asia.
Detection and Characterization of Potato Virus Y (PVY) Strains and Mixed Infections in San Luis Valley, Colorado
Authors: Rushton Jennifer , Larsen Brandon , Houser Andrew , Pitt W. Jacob , Charkowski Amy O. , Chikh-Ali M. , Nalam Vamsi J.
Published: August 2024

Potato virus Y (PVY) is a major economic threat to potato production worldwide. Understanding the prevalent PVY strains and their dynamics is crucial for effective management. This study investigated PVY trends and diversity in the San Luis Valley (SLV), CO, U.S.A. We leveraged the Colorado Seed Potato Certification Program data (2017 to 2022), revealing a persistent problem with PVY incidence in certified seed lots that fluctuated between 2.6% (2017) and 6.5% (2022). PVYN-Wi was the dominant strain, with others such as PVYO also detected. A complementary field study (2021 to 2022) investigated PVY prevalence and diversity in 600 samples collected from 30 fields. PVYN-Wi was identified as the main strain, followed by PVYO and PVYNTN. Notably, the incidences of dual and triple infections, along with inconclusive samples, increased in both postharvest and field study samples. High-throughput sequencing (HTS) of the inconclusive samples identified from the field study samples determined PVYN-Wi as the predominant strain and identified polymorphisms that may hinder accurate identification by traditional strain typing methods. Beyond PVY, potato virus S (PVS) was the only other major potato-infecting virus detected. HTS revealed diverse nonplant-infecting viruses as well. This study provides valuable insights into the evolving PVY landscape and the complex potato virome in SLV. It highlights the importance of continued surveillance and improved diagnostics to mitigate the impact of viruses on potato production.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Heterogeneous Outcome Selection and Incomplete Prespecification of Outcomes in Systematic Reviews: A Case Study on Pressure Injury
Authors: Zhang Jun , Zhang Mingyue , Xu Caihua , Tian Jinhui , Yang Donghua , Wang Bo
Published: August 2024

OBJECTIVE

To understand how reviewers select and prespecify outcomes for systematic reviews (SRs), the authors report on the outcomes used in SRs of pressure injury (PI) intervention and treatment and evaluate their completeness of prespecification.

DATA SOURCES

The authors searched four electronic databases for SRs involving PI prevention and/or treatments.

STUDY SELECTION

Inclusion criteria were SRs and meta-analyses evaluating interventions for preventing or treating PI. Studies without systematic search or risk-of-bias assessment, conference proceedings, and articles not in Chinese or English were excluded.

DATA EXTRACTION

Two reviewers extracted and categorized the outcomes in domains, assessing outcome prespecification using a five-element framework. Data items included study characteristics, target population, type of interventions, and outcome variables.

DATA SYNTHESIS

This review included 95 SRs that reported a total of 432 instances of 24 different outcome domains. An average of four outcome domains were reported per SR. The most frequently reported domains were PI healing, PI occurrence, and PI status. Of the 62 SRs that prespecified primary outcomes, 40 (64.52%) reported more than one primary outcome. Only 24 of the 432 instances (5.56%) were completely specified. Among the 24 outcome domains, 12 (50.00%) were listed as primary outcomes at least once. Primary outcomes were more completely specified than nonprimary outcomes.

CONCLUSIONS

Systematic reviews of PI prevention and/or treatment report diverse, incompletely prespecified outcomes, highlighting the need for a core outcome set to standardize key clinical outcomes.
Observation of the Therapeutic Effect of Hydrogel Combined with Alginate Dressings for a Patient with Grade 4 Acute Radiation Dermatitis: A Case Report
Authors: Cao Yongli , Zhu Changhui , Zhu Hongyu , Chen Xiumei , Luo Huiyu
Published: August 2024

In this case report, the authors summarize their experience of using hydrogel combined with alginate dressings in the wound care of a patient with grade 4 acute radiation dermatitis. With the combination of hydrogel and alginate dressings, the authors achieved autolytic debridement of the wound and created a moist healing environment to facilitate wound closure. Hydrogel helps the dressing adhere better to the wound bed, ensuring that it does not easily detach during the wound healing process. It also eliminates the need for traditional adhesive tapes for fixation, thus avoiding damage to the fragile skin in the radiation field.

The wound gradually decreased in size from an area of 10 × 12 cm, and exudate decreased continuously. The wound completely healed in 20 days with a total of 17 dressing changes. As the wound gradually healed, the patient’s psychological burden decreased and comfort level increased. The patient expressed satisfaction and hope for the gradual healing of the wound.

Thus, the treatment of severe acute radiation dermatitis with hydrogel combined with alginate dressings yields remarkable results, aligning the noninvasive, low-adhesive, absorbent, conformable, and comfortable attributes of optimized wound care. This experience provides a practical foundation for wound management in acute radiation dermatitis and supports clinical application and promotion of the approach.
Project Extension for Community Healthcare Outcomes Intervention Evaluations: A Scoping Review of Research Methods
Authors: Maizel Jennifer , Filipp Stephanie L. , Zori Gaia , Yadav Sandhya , Avaiya Kishan , Figg Lauren , Hechavarria Melanie , Roque Xanadu , Anez-Zabala Claudia , Lal Rayhan , Addala Ananta , Haller Michael J. , Maahs David M. , Walker Ashby F.
Published: August 2024

Introduction:

Since its inception in 2003, the Project Extension for Community Healthcare Outcomes (ECHO) tele-education model has reached and improved outcomes for patients, providers, and health centers through interventions in >180 countries. Utilization of this model has recently increased due to the COVID-19 pandemic and a higher demand for remote education. However, limited research has examined the methodologies used to evaluate Project ECHO interventions.

Methods:

We conducted a scoping review to determine the extent and types of research methods used to evaluate outcomes and implementation success of Project ECHO interventions and to identify gaps and opportunities for future investigation. Using Arksey and O'Malley's scoping review framework and the PRISMA-ScR checklist, we reviewed study designs, temporality, analysis methods, data sources, and levels and types of data in 121 articles evaluating Project ECHO interventions.

Results:

Most interventions addressed substance use disorders (24.8%, n = 30), infectious diseases (24%, n = 29), psychiatric and behavioral health conditions (21.5%, n = 26), and chronic diseases (19%, n = 23). The most frequently reported evaluation methods included cohort studies (86.8%, n = 105), longitudinal designs (74.4%, n = 90), mixed methods analysis (52.1%, n = 63), surveys (61.2%, n = 74), process evaluation measures (98.3%, n = 119), and provider-level outcome measures (84.3%, n = 102). Few evaluations used experimental designs (1.7%, n = 2), randomization (5.8%, n = 7), or comparison groups (14%, n = 17), indicating limited rigor.

Discussion:

This scoping review demonstrates the need for more rigorous evaluation methods to test the effectiveness of the Project ECHO model at improving outcomes and standardized reporting guidelines to enhance the dissemination of evaluation data from future Project ECHO interventions.
From Snack Time to the Operating Room: A Case Report of Septic Arthritis in a Child After a Toothpick Injury
Authors: Gutierrez-Tobar Ivan Felipe , Marquez Herrera Kelly , Rueda Alfonso Blanca Nathalia , Riaño Ocampo Maria Paula , Sierra Parada Claudia Rocío
Published: August 2024

Eikenella corrodens and Streptococcus sanguinis are indigenous to the oral cavity and infrequently associated with osteoarticular infections. We detail a case of septic arthritis in a 13-year-old boy who suffered a puncture wound with a toothpick after eating. This case highlights the ability of these microorganisms to instigate osteoarticular infections through penetrating trauma and not only through the hematogenous route.
Efficacy evaluation and survival analysis of the combination of oxaliplatin plus Teysuno (SOX) with immune checkpoint inhibitors in the conversion therapy of locally advanced gastric cancer
Authors: Liu Shuai , Zhang Kai , Zhang Xiaoqing , Luan Wei
Published: August 2024

Background

The efficacy of combining immune checkpoint inhibitors (ICIs) with chemotherapy in neoadjuvant therapy for locally advanced gastric cancer has been explored. However, limited research exists on its effectiveness in conversion therapy, and its superiority over standalone chemotherapy remains to be elucidated. This study aims to investigate the efficacy and survival outcomes of patients treated with ICIs in combination with conversion therapy for locally advanced gastric cancer.

Methods

Retrospective data from patients with locally advanced gastric cancer treated with either oxaliplatin + S-1(SOX) alone or in combination with ICIs in conversion therapy were collected. Clinical and pathological characteristics, disease-free survival, and efficacy assessments in nonoperable patients were compared between the 2 treatment groups. Efficacy was further evaluated through dynamic changes in serum markers, and patients’ quality of life was assessed using the QLQ-STO22 (Gastric Cancer–Specific Quality of Life Questionnaire) quality-of-life measurement scale.

Results

A total of 140 patients underwent conversion therapy: 80 in the SOX alone group and 60 in the SOX combined with the ICIs group. There were no significant differences in baseline characteristics between the 2 groups. Compared with the SOX alone group, the SOX combined with ICIs group exhibited a higher conversion rate (83.3% vs 75%, P = 0.23), R0 resection rate (90.0% vs 83.3%, P = 0.31), pathological complete response (pCR) rate (18% vs 5%, P = 0.02), median disease-free survival (21.4 vs 16.9 months, P = 0.007), the objective response rate in nonoperable patients (60% vs 40%, P = 0.301), and median progression-free survival time (7.9 vs 5.7 months, P = 0.009). The QLQ-STO22 quality-of-life assessment revealed statistically significant improvements in pain, swallowing difficulties, and dietary restrictions in the combination therapy group compared with those in the monotherapy group. The enhanced efficacy of immune combination with SOX is evident, as demonstrated by the significantly prolonged surgical duration in operated patients (206.6 ± 26.6 min vs 197.8 ± 19.8 min, P = 0.35) and intraoperative blood loss (158.9 ± 21.2 mL vs 148.9 ± 25.1 mL, P = 0.59). No significant differences were observed in postoperative complications.

Conclusions

Compared with the SOX conversion therapy regimen, SOX combined with ICIs demonstrated higher conversion rates, R0 resection rates, pathological response rates, and disease-free survival without increasing surgical difficulty or complications. Nonoperable patients also experienced longer progression-free survival and objective response rates.
Nanomaterials for refining tumor microenvironment and enhancing therapy in head and neck squamous cell carcinoma: a review
Authors: Zheng Kaifeng , Song Ruibiao , Li Ruifeng , Liu Mengli , Ba Yunpeng , Jiang Wei , Fan Kelong
Published: August 2024

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal solid tumor with a high mortality rate. Conventional cancer treatments, including surgery, radiotherapy, and chemotherapy, primarily target cancer cell eradication. However, uncontrolled proliferation and metabolic activities of these cells result in abnormalities in nutrient levels, hypoxia, and immunosuppression within the tumor microenvironment (TME). These factors constrain the efficacy of traditional treatments by promoting drug resistance, recurrence, and metastasis. Nanomaterials (NMs), such as nanozymes, can exhibit enzymatic activity similar to that of natural enzymes and offer a promising avenue for the direct modification of the TME through catalytic oxidation-reduction processes. Moreover, they can serve as sensitizers or drug delivery carriers, enhancing the efficacy of traditional treatment methods. Recently, NMs have garnered significant attention from oncologists. This review begins with an overview of the composition and unique characteristics of the TME. Subsequently, we comprehensively explored the application of NMs in the treatment of HNSCC. Finally, we discuss the potential prospects and challenges associated with using NMs in biomedical research.
Exploring the connection between BRCA2 and thyroid cancer
Authors: Liu Xinjie , Wang Xueqin
Published: August 2024

Background

This study investigated the multifaceted role of BRCA2 (breast cancer 2) in various cancer types, with a specific focus on thyroid carcinoma (THCA).

Methods

Data sets were obtained from the University of California Santa Cruz database to analyze BRCA2 expression, genetic alterations, and clinical implications. Sample filtering criteria were applied, and immunohistochemistry from the Human Protein Atlas was used to validate protein expression. Correlation analyses were used to explore associations between immune-related genes, and immunological signatures were assessed using various tools. Genetic alterations in BRCA2 were analyzed using cBioPortal, and prognostic analysis involved evaluating gene expression differences at different clinical stages of THCA.

Results

In patients with THCA, differences in BRCA2 expression were observed at both the mRNA and protein levels when comparing tumor and normal tissues. Correlation studies revealed associations between BRCA2 and immune-related genes, emphasizing its potential role in modulating the tumor microenvironment. Immunological signature analyses indicated distinct frequencies of tumor-infiltrating immune cell subsets in BRCA2 high versus low tumors. Moreover, genetic alterations in BRCA2, particularly the A2738S mutation in exon 18, have been identified in patients with THCA. The prognostic analysis demonstrated a significant correlation between altered BRCA2 levels and improved overall survival in patients with THCA. Additionally, BRCA2 expression was associated with prognostic factors such as stage and N.

Conclusions

This study provides a holistic exploration of BRCA2 in cancer and highlights its diverse roles in expression, immune modulation, genetic alterations, and clinical prognosis. These findings underscore the potential significance of BRCA2 as a diagnostic and prognostic marker and offer valuable insights for future research and potential clinical applications in cancer management.
Cell-mediated Immunity to Guide Primary Prophylaxis for CMV Infection in Organ Transplant Recipients: A Multicenter Single-arm Prospective Study
Authors: Solera Javier T. , Ferreira Victor H. , Cervera Carlos , Hosseini-Moghaddam Seyed M. , Gill John , Shalhoub Sarah , Zaltzman Jeff , Kumar Deepali , Humar Atul
Published: August 2024

Background.

There are few interventional studies using CMV cell-mediated immunity (CMI) to guide antiviral prophylaxis. We assessed the Quantiferon-CMV (QTF-CMV) assay to guide CMV prophylaxis duration in high-risk organ transplant recipients.

Methods.

A single-arm, multicenter, prospective interventional study including high-risk kidney, pancreas, liver, and heart transplant recipients who were either donor CMV-seropositive, recipient-seronegative (D+/R–) or recipient-seropositive with antithymocyte globulin (R+/ATG) induction. CMI testing was performed using the QTF-CMV assay at months 3, 4, 5, and 6 posttransplant. Prophylaxis was discontinued for a positive CMI but continued for a negative result up to a maximum of 6 mo. The primary endpoint was CMV viremia ≥1000 IU/mL up to 1 y posttransplant.

Results.

One hundred eight patients were included, comprising kidney (n = 89), kidney-pancreas (n = 7), liver (n = 10), and heart (n = 2) transplants. Eighty-nine patients (82.4%) completed the study protocol (n = 39 D+/R– and n = 50 R+/ATG). In the D+/R– group, only 1 of 39 patients (2.6%) had a positive QTF-CMV result. In the R+/ATG group, 33 of 50 patients (66%) had a positive QTF-CMV result before 6 mo, allowing for early discontinuation of prophylaxis (28 at month 3, 4 at month 4, and 1 at month 5). During the follow-up, CMV viremia ≥1000 IU/mL occurred in only 4 of 33 patients (12.1%) who discontinued prophylaxis early compared with 6 of 17 patients (35.3%) with negative QTF-CMV results and continued prophylaxis (hazard ratio 0.31; 95% confidence interval, 0.09-1.09; P = 0.07). No R+ patient developed CMV disease.

Conclusions.

QTF-CMV-guided prophylaxis appears useful in R+ patients who may benefit from a tailored duration of prophylaxis. This strategy does not appear to be useful in D+/R– patients.
Mycotic aneurysms: uncommon pathogens and treatment conundrums
Authors: Ravindra Akshatha , Naguthevar Santhanam , Kumar Deepak , Rajagopal Rengarajan , Khera Pushpinder Singh , Tak Vibhor , Ramankutty Neetha Thayil , Meena Durga Shankar , Midha Naresh , Bohra Gopal Krishana , Garg Mahendra Kumar
Published: August 2024

Introduction. Mycotic aneurysms, characterized by vessel wall dilation resulting from infections including bacteria, fungi, and viruses, are a rare but severe consequence of systemic infections. The term ‘mycotic’ was coined by William Osler to describe the first instance of a fungal-induced infected aneurysm. These aneurysms, accounting for 0.6% of aneurysms in Western countries, carry a higher risk of rupture compared to uninfected aneurysms. While the femoral artery, aorta, and intracranial arteries are commonly affected, pathogens causing mycotic aneurysms vary across regions. Diagnostic challenges arise from nonspecific symptoms such as fever, and discomfort. To prevent the substantial morbidity and mortality associated with mycotic aneurysms, timely identification and treatment are paramount. We present a case series highlighting mycotic aneurysms caused by some rare pathogens – Salmonella Paratyphi A, Streptococcus pneumoniae, and Pseudomonas aeruginosa.

Methods. This case series involves three patients diagnosed with mycotic aneurysms due to unusual pathogens. We describe each patient’s clinical presentation, medical history, physical examination findings, laboratory results, imaging studies, and the diagnostic process leading to the identification of the causative pathogens.

Results. The first patient is a 70-year-old gentleman who presented with a ruptured infra-renal abdominal aortic pseudoaneurysm caused by Salmonella Paratyphi A. The second patient is a 66-year-old gentleman with a Streptococcus pneumoniae-associated descending thoracic aortic pseudoaneurysm. The third patient is a 70-year-old gentleman with a ruptured descending thoracic aortic aneurysm with an occult aorto-oesophageal fistula due to Pseudomonas aeruginosa infection. The description highlights unique clinical features, laboratory findings, imaging results, and the management approaches undertaken in each patient.

Conclusion. Mycotic aneurysms, pose diagnostic challenges due to their nonspecific symptoms. Early identification and intervention are essential to mitigate the severe complications associated with these aneurysms. The presented cases underscore the need for a comprehensive approach to diagnosis and management, ensuring optimal outcomes for patients affected by mycotic aneurysms.
A Single Center Observational Study on 25-hydroxyvitamin D levels in Meniscus Injury Patients
Authors: Hu Shuaishuai , Zhang Duzheng , Cong Ruijun
Published: August 2024

There is limited research on the association between 25-hydroxyvitamin D levels and meniscus injury. This study investigated serum 25-hydroxyvitamin D (25-OHD) in meniscus injury patients and its association with other bioinorganic chemistry of micronutrients, and immune cells numbers from January 2023 to December 2023. A total of 198 participants were recruited between the age of 18 and 89 years. Participants with renal or liver failure, or any other chronic conditions, who were taking medications that might affect the metabolism of vitamin D, were not included in the study. In this study, we categorized serum 25(OH)D concentrations as follows: ≤30ngm/dl was categorized as insufficient, and >30ngm/dl was deemed sufficient. Among the 198 participants, 82% (n=162) were serum 25(OH)D deficient, while only 18% (n=36) participants were serum 25(OH)D sufficient. No significant difference observed in vitamin D deficiency among difference age, BMI, sex, blood pressure, inflammatory cell numbers, and other vitamins compared to the vitamin D sufficient group. Moreover, the serum 25(OH)D concentrations were negatively related to the severity of meniscus injury based on MRI examination. In conclusion, severe vitamin D deficiency is more common in patients with meniscus injury and may play a significant role in their prognosis.
Noninvasive electrocardiographic imaging assessment of intraventricular synchrony for conduction system pacing device: a novel algorythm to assess intraventricular synchrony
Authors: Eltsov Ivan , Del Monte Alvise , Pannone Luigi , Overeinder Ingrid , Della Rocca Domenico , Scacciavillani Roberto , Verbrugge Frederik H , Zeng Qingguo , Bala Gezim , Paparella Andrea Maria , Talevi Giacomo , Stroker Erwin , Sieira Juan , Gharaviri Ali , Sarkozy Andrea , Chierchia Gian-Battista , La Meir Mark , de Asmundis Carlo , Almorad Alexandre
Published: August 2024

Structured Abstract

Background

Left Bundle branch area pacing has become the procedure of choice for various indications including atrioventricular block and considered to be a physiologic modality of pacing compared to RV apex pacing.

Objectives

The purpose of this study was to assess ventricular activation and synchrony in patients with LBBAP device using ECG imaging (ECGI).

Methods

25 consecutive patients underwent an LBBAP device implantation have been included in the study. ECG and ECGI analysis have been performed the day after implantation. Native and paced QRS, LVAT, RVAT and V1AD were calculated using ECG. TVACT, LVACT, LVACTi, RVACT, RVACTi and IVDS were calculated based on ECGI. All patients have been followed up for 12 months.

Results

All patients were divided in 2 groups (wide and narrow QRS) based on intrinsic ECG and then based on paced ECG QRS.

For initially narrow QRS group, activation time and synchrony during pacing was comparable to native. In wide QRS group these parameters were significantly improved.

At paced rhythm analysis, classic ECG LBBAP parameters (paced QRS and LVAT) were not sufficient to properly evaluate the ventricular activation for paced rhythm. Discordance between ECG and ECGI analysys was identified in 25 patients. Two additional 12 lead ECG parameters predicting the ECGI measurements were found - V1AD and dRVAT. Follow up showed stable values of ejection fraction, paced QRS and pacing parameters.

Conclusions

ECG imaging can bring a significant value into assessing the efficacy of new pacing modalities and provide more data for precise determination of implantation outcomes, including detailed activation assessment and comparison to intrinsic conduction. Key ECGI values confirming proper ventricular activation have been defined and correlated with 12 lead ECG parameters to predict ventricle activation from ECG only.
Using Meta-Transformers for Multimodal Clinical Decision Support and Evidence-Based Medicine
Authors: Mohammed Sabah , Fiaidhi Jinan , Martinez Abel Serracin
Published: August 2024

The advancements in computer vision and natural language processing are keys to thriving modern healthcare systems and its applications. Nonetheless, they have been researched and used as separate technical entities without integrating their predictive knowledge discovery when they are combined. Such integration will benefit every clinical/medical problem as they are inherently multimodal - they involve several distinct forms of data, such as images and text. However, the recent advancements in machine learning have brought these fields closer using the notion of meta-transformers. At the core of this synergy is building models that can process and relate information from multiple modalities where the raw input data from various modalities are mapped into a shared token space, allowing an encoder to extract high-level semantic features of the input data. Nerveless, the task of automatically identifying arguments in a clinical/medical text and finding their multimodal relationships remains challenging as it does not rely only on relevancy measures (e.g. how close that text to other modalities like an image) but also on the evidence supporting that relevancy. Relevancy based on evidence is a normal practice in medicine as every practice is an evidence-based. In this article we are experimenting with meta-transformers that can benefit evidence based predictions. In this article, we are experimenting with variety of fine tuned medical meta-transformers like PubmedCLIP, CLIPMD, BiomedCLIP-PubMedBERT and BioCLIP to see which one provide evidence-based relevant multimodal information. Our experimentation uses the TTi-Eval open-source platform to accommodate multimodal data embeddings. This platform simplifies the integration and evaluation of different meta-transformers models but also to variety of datasets for testing and fine tuning. Additionally, we are conducting experiments to test how relevant any multimodal prediction to the published medical literature especially those that are published by PubMed. Our experimentations revealed that the BiomedCLIP-PubMedBERT model provide more reliable evidence-based relevance compared to other models based on randomized samples from the ROCO V2 dataset or other multimodal datasets like MedCat. In this next stage of this research we are extending the use of the winning evidence-based multimodal learning model by adding components that enable medical practitioner to use this model to predict answers to clinical questions based on sound medical questioning protocol like PICO and based on standardized medical terminologies like UMLS.
A Scalable Framework for Benchmarking Embedding Models for Semantic Medical Tasks
Authors: Soffer Shelly , Glicksberg Benjamin S , Kovatch Patricia , Efros Orly , Freeman Robert , Charney Alexander W , Nadkarni Girish N , Klang Eyal
Published: August 2024

Text embeddings convert textual information into numerical representations, enabling machines to perform semantic tasks like information retrieval. Despite its potential, the application of text embeddings in healthcare is underexplored in part due to a lack of benchmarking studies using biomedical data. This study provides a flexible framework for benchmarking embedding models to identify those most effective for healthcare-related semantic tasks. We selected thirty embedding models from the multilingual text embedding benchmarks (MTEB) Hugging Face resource, of various parameter sizes and architectures. Models were tested with real-world semantic retrieval medical tasks on (1) PubMed abstracts, (2) synthetic Electronic Health Records (EHRs) generated by the Llama-3-70b model, (3) real-world patient data from the Mount Sinai Health System, and the (4) MIMIC IV database. Tasks were split into ‘Short Tasks’, involving brief text pair interactions such as triage notes and chief complaints, and ‘Long Tasks’, which required processing extended documentation such as progress notes and history & physical notes. We assessed models by correlating their performance with data integrity levels, ranging from 0% (fully mismatched pairs) to 100% (perfectly matched pairs), using Spearman correlation. Additionally, we examined correlations between the average Spearman scores across tasks and two MTEB leaderboard benchmarks: the overall recorded average and the average Semantic Textual Similarity (STS) score. We evaluated 30 embedding models across seven clinical tasks (each involving 2,000 text pairs), across five levels of data integrity, totaling 2.1 million comparisons. Some models performed consistently well, while models based on Mistral-7b excelled in long-context tasks. ‘NV-Embed-v1,’ despite being top performer in short tasks, did not perform as well in long tasks. Our average task performance score (ATPS) correlated better with the MTEB STS score (0.73) than with MTEB average score (0.67). The suggested framework is flexible, scalable and resistant to the risk of models’ overfitting on published benchmarks. Adopting this method can improve embedding technologies in healthcare.
Overcoming off-target optical stimulation-evoked cortical activity in the mouse brainin vivo
Authors: Weiler Simon , Velez-Fort Mateo , Margrie Troy W.
Published: August 2024

Genetic engineering of exogenous opsins sensitive to a wide range of light wavelengths allows the interrogation of brain circuits to an unprecedented temporal and spatial precision. In particular, red-shifted opsins offer access deeper within the brain tissue. It is however crucial to consider the potential unintended back-activation of endogenous opsins due to laser light striking the back of the retina. Here, we found that in complete darkness and with no expression of exogenous opsins, optical fiber laser stimulation at wavelengths of 637 nm (red), 594 nm (orange), or 473 nm (blue) from within the ipsilateral mouse visual cortex resulted in a strong neuronal response in its contralateral counterpart. This neuronal activation occurred even at low laser intensities (1 mW at the fiber tip, ~31.8 mW/mm2) and was most pronounced using red wavelengths. We therefore took advantage of retinal light adaptation using external illumination with a relatively dim ambient light source (20 lux) which was found to completely abolish orange and blue laser-evoked neuronal activation from within the brain, even at high laser intensities (15 mW, ~477.3 mW/mm2). To prevent red laser-evoked retinal activation, however, only much lower intensities (2.5 mW, ~79.6 mW/mm2) combined with external illumination (20 lux) could be used. These findings demonstrate the critical need for careful selection of light wavelengths and intensities for laser stimulation during optogenetic experiments in the mouse brainin vivo. Additionally, light adaptation of the retina through ambient light exposure offers an effective solution to minimize unintended retinal activation.
Integrated multi-model analysis of intestinal inflammation exposes key molecular features of preclinical and clinical IBD
Authors: González-Acera Miguel , Patankar Jay V. , Erkert Lena , Cineus Roodline , Gámez-Belmonte Reyes , Leupold Tamara , Bubeck Marvin , Bao Li-Li , Dinkel Martin , Wang Ru , Limberger Heidi , Stolzer Iris , Gerlach Katharina , Mascia Fabrizio , Koop Kristina , Plattner Christina , Sturm Gregor , Weigmann Benno , Günther Claudia , Wirtz Stefan , Hildner Kai , Kühl Anja A. , Siegmund Britta , Atreya Raja ,   The IBDome Consortium, Hegazy Ahmed N. , Trajanoski Zlatko , Neurath Markus F. , Becker Christoph
Published: August 2024

Background

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the intestine with a complex and multifaceted pathogenesis. While various animal models exist to study specific disease mechanisms relevant to human IBD, a comprehensive comparative framework linking these to IBD pathophysiology is lacking.

Objective

In our study, we aimed at providing a framework that delineates common and unique features encountered in 13 widely used mouse models comparing them with human IBD to identify translatable pathways in model-cohort pairs. Another aim of our study was to provide an explorable resource for looking up gene and pathway level changes in mouse models assisting in hypothesis testing and minimizing animal burden abiding by the 3R principals.

Design

We employed comparative transcriptomic analyses with curated anda prioristatistical correlative methods between mouse models versus established as well as own patient datasets at both bulk and single cell levels.

Results

We identify IBD-related pathways, ontologies, and cellular processes that are translatable between mouse models and patient cohorts. Moreover, we identify, known and novel IBD-associated subcellular mechanisms and how they are recapitulated in specific mouse models.

Conclusion

Our findings provide a valuable resource for selecting the most appropriate experimental paradigm to model unique features of IBD pathomechanisms, allowing analysis at the tissue, cellular, and subcellular levels.

What is already known on this topic

Preclinical modelling of IBD is key to the discovery of pathomechanisms and the evaluation of therapeutic approaches. However, individual models do not recapitulate the complexity of the disease and comprehensive studies comparing modelling paradigms with human IBD are lacking.

What this study adds

Our study provides a comparative analysis of thirteen commonly used intestinal inflammation models, identifying core-conserved pathways between mouse models and IBD patient cohorts. In addition, our study shows how specific pathways involved in IBD are recapitulated in specific mouse models and introduces a web tool to analyse the models.

How this study might affect research, practice or policy

By identifying conserved and discrepant pathways between specific mouse models and IBD patient cohorts, our analysis platform provides an invaluable resource for translational IBD research.
Autoencoders with shared and specific embeddings for multi-omics data integration
Authors: Wang Chao , O’Connell Michael J.
Published: August 2024

Motivation

In cancer research, different levels of high-dimensional data are often collected for the same subjects. Effective integration of these data by considering the shared and specific information from each data source can help us better understand different types of cancer.

Results

In this study we propose a novel autoencoder (AE) structure with explicitly defined orthogonal loss between the shared and specific embeddings to integrate different data sources. We compare our model with previously proposed AE structures based on simulated data and real cancer data from The Cancer Genome Atlas. Using simulations with different proportions of differentially expressed genes, we compare the performance of AE methods for subsequent classification tasks. We also compare the model performance with a commonly used dimension reduction method, joint and individual variance explained. In terms of reconstruction loss, our proposed AE models with orthogonal constraints have a slightly better reconstruction loss. All AE models achieve higher classification accuracy than the original features, demonstrating the usefulness of the embeddings extracted by the model. Particularly, we show that the proposed models have consistently high classification accuracy on both training and testing sets. In comparison, the recently proposed MOCSS model that imposes an orthogonality penalty in the post-processing step has lower classification accuracy that is on par with JIVE.

Availability and Implementatio

The relevant datasets and models developed in this study are available in the following GitHub repository:https://github.com/wangc90/AE_Data_Integration.
Single-cell and spatial transcriptomics of vulvar lichen sclerosus reveal multi-compartmental alterations in gene expression and signaling cross-talk
Authors: Sun Peng , Kraus Christina N. , Zhao Wei , Xu Jiahui , Suh Susie , Nguyen Quy , Jia Yunlong , Nair Arjun , Oakes Melanie , Tinoco Roberto , Shiu Jessica , Sun Bryan , Elsensohn Ashley , Atwood Scott X. , Nie Qing , Dai Xing
Published: August 2024

Vulvar diseases are a critical yet often neglected area of women’s health, profoundly affecting patients’ quality of life and frequently resulting in long-term physical and psychological challenges. Lichen sclerosus (LS) is a chronic inflammatory skin disorder that predominantly affects the vulva, leading to severe itching, pain, scarring, and an increased risk of malignancy. Despite its profound impact on affected individuals, the molecular pathogenesis of vulvar LS (VLS) is not well understood, hindering the development of FDA-approved therapies. Here, we utilize single-cell and spatial transcriptomics to analyze lesional and non-lesional skin from VLS patients, as well as healthy control vulvar skin. Our findings demonstrate histologic, cellular, and molecular heterogeneities within VLS, yet highlight unifying molecular changes across keratinocytes, fibroblasts, immune cells, and melanocytes in lesional skin. They reveal cellular stress and damage in fibroblasts and keratinocytes, enhanced T cell activation and cytotoxicity, aberrant cell-cell signaling, and increased activation of the IFN, JAK/STAT, and p53 pathways in specific cell types. Using both monolayer and organotypic culture models, we also demonstrate that knockdown of select genes, which are downregulated in VLS lesional keratinocytes, partially recapitulates VLS-like stress-associated changes. Collectively, these data provide novel insights into the pathogenesis of VLS, identifying potential biomarkers and therapeutic targets for future research.