bluuebunny/crossref_metadata_2025 huggingface dataset:
Challenging the American College of Obstetricians and Gynecologists' Clinical Practice Update on Screening for Pre-existing Diabetes and Early Gestational Diabetes
Authors: Heyborne Kent D. , Barbour Linda A.
Published: October 2024

A recent American College of Obstetricians and Gynecologists Clinical Practice Update continues to recommend targeted (as opposed to universal) screening for pregestational diabetes, no longer recommends screening for early gestational diabetes mellitus (GDM), and provides updated guidelines for immediate postpartum testing for diabetes in patients with GDM. Here, we present data that the targeted screening paradigm, which has repeatedly been shown to fail in practice because of its complexity, no longer makes sense in the context of the high and rising prevalence of diabetes and diabetic risk factors, and we argue that the time has come for universal early pregnancy screening for pregestational diabetes. Furthermore, the recommendation against early screening for GDM is based on 2021 U.S. Preventive Services Task Force guidance, which in turn is based almost entirely on a single underpowered study that excluded individuals at highest risk and does not account for more recent research showing benefits of early diagnosis and treatment. Universal early pregnancy screening for pregestational diabetes may also help to identify patients at risk who will benefit from early GDM diagnosis and treatment and may provide rationale for prioritizing postpartum diabetes testing.
Use of Commercial Bacon to Extract Maggots from an Infested Chronic Wound
Authors: Fenati Gregory , Youssoffi Santana , Vejendla Shriya , Neeki Cameron C. , Nguyen Vinh T. , Dong Fanglong , Neeki Michael M.
Published: October 2024

Maggot therapy, also known as larval therapy or biosurgery, is the use of live, sterilized maggots to debride necrotic tissue. Alternatively, wound infestation by maggots, known as myiasis, can occur in patients with poor wound management, particularly in those living in poor socioeconomic conditions. In the case of myiasis, various maggot extraction solutions are used to encourage the live larvae to emerge from the wound on their own. Current recommendations include the use of hypochlorous acid, sodium hypochlorite solutions, isopropyl alcohol, betadine, and hydrogen peroxide for wound cleansing. This case report focuses on a unique utilization of commercial bacon strips for the extraction of maggots in an infested necrotic wound. The use of commercial bacon strips in selective patients as a noninvasive technique for the removal of maggots from necrotic wounds can be an additional tool for medical providers.
Restorative Treatments for Cervical Spinal Cord Injury, a Narrative Review
Authors: Kaleem Muhammad I. , Javeed Saad , Plog Benjamin A. , Gupta Vivek P. , Ray Wilson Z.
Published: October 2024

Study Design:

A narrative review.

Objective:

To summarize relevant data from representative studies investigating upper limb restorative therapies for cervical spinal cord injury.

Summary of Background Data:

Cervical spinal cord injury (SCI) is a debilitating condition resulting in tetraplegia, lifelong disability, and reduced quality of life. Given the dependence of all activities on hand function, patients with tetraplegia rank regaining hand function as one of their highest priorities. Recovery from cervical SCI is heterogeneous and often incomplete; currently, various novel therapies are under investigation to improve neurological function and eventually better quality of life in patients with tetraplegia.

Methods:

In this article, a narrative literature review was performed to identify treatment options targeting the restoration of function in patients with cervical SCI. Studies were included from available literature based on the availability of clinical data and whether they are applicable to restoration of arm and hand function in patients with cervical SCI.

Results:

We describe relevant studies including indications and outcomes with a focus on arm and hand function. Different treatment modalities described include nerve transfers, tendon transfers, spinal cord stimulation, functional electrical stimulation, non-invasive brain stimulation, brain-machine interfaces and neuroprosthetics, stem cell therapy, and immunotherapy. As the authors’ institution leads one of the largest clinical trials on nerve transfers for cervical SCI, we also describe how patients undergoing nerve transfers are managed and followed at our center.

Conclusions:

While complete recovery from cervical spinal cord injury may not be possible, novel therapies aimed at the restoration of upper limb motor function have made significant progress toward the realization of complete recovery.
Controversies in the Management of Type II Odontoid Fractures
Authors: Bhimani Abhiraj D. , Harrop James S. , Monnig Emery , Elkersh Yehia , Houten John K.
Published: October 2024

The management of type II odontoid fractures in the elderly is controversial, as these patients often have numerous medical comorbidities that increase the risks of surgery, but they may also fail to achieve fracture healing with nonsurgical management. Recent changes in technology and surgeon attitudes may influence the preferred approach to both surgical and nonsurgical treatments for many clinicians. While bony fracture healing remains the goal of management, a stable fibrous union is increasingly considered a satisfactory outcome. The optimal surgical approach remains debated, with some authors raising concerns about the risk of swallowing dysfunction being particularly problematic with odontoid screw placement in the elderly. The use of BMP-2 applied either anteriorly into the fracture site or posteriorly in the interlaminar space and placement of temporary posterior fixation to be removed upon demonstration of anterior bony healing are novel surgical techniques that are presently the subject of investigation. A clearer understanding of the currently available treatment options and the associated controversies may improve clinician decision-making and potentially better patient outcomes in the management of type II odontoid fractures for the growing geriatric population.
Three-Dimensional Fluoroscopic System to Assess Robotically Placed Pedicle Screws
Authors: Lebovic Jordan , Trudeau Maxwell , Charalambous Lefko T. , Venkat Nitya , Gallina Jason , Goldstein Jeffrey A.
Published: October 2024

Study Design:

Retrospective cohort study.

Objective:

The purpose of this study is to determine the utility of advanced imaging to confirm the placement of robotic pedicle screws.

Summary of Background Data:

With increasing robotic adoption, certain institutions and surgeons have developed protocols for obtaining 3D intraoperative imaging after robotic pedicle screw placement to ensure proper hardware placement. No studies have assessed the utility of these protocols relative to the potential risks of increased radiation exposure and operative time. The purpose of this study is to determine if we should be obtaining advanced imaging to confirm the placement of robotic pedicle screws.

Methods:

This is a single institution retrospective cohort study of patients from May 2022 to July 2023 who underwent lumbar spinal fusion by a high-volume orthopedic spine surgeon at a level 1 metropolitan hospital. All cases used combined robotics and navigation systems for pedicle screw placement and intraoperative 3D imaging for evaluation of screw position. Pedicle screw accuracy was assessed using the Gertzbein and Robbins system (GRS). Acceptable pedicle screw position was defined as GRS A or B.

Results:

Seventy patients with 354 robotically placed pedicle screws were assessed with intraoperative 3D fluoroscopy. All pedicle screws were placed in either a GRS type A or type B position. Three hundred fifty-one were placed in a GRS A classification (99.2%, 351/354), and 3 were placed in a GRS B classification (0.08% 3/354). No patients had screw-related complications. The average radiation dosage of 3D imaging was 289.7±164.6 mGy.

Conclusion:

The robotic system places pedicle screws accurately without 3D intraoperative imaging. Given the increased radiation and operative time associated with 3D imaging protocols 3D imaging scans should only be obtained in cases with heightened clinical concern.

Level of Evidence:

Level IV.
Using Virtual Reality in Mental Health Nursing to Improve Behavioral Health Equity
Authors: Howard Sheri , Meadows-Taylor Meghan
Published: October 2024

Nursing students often experience anxiety, stress, and fear during a clinical rotation in a mental health setting due to stressors and biases toward the setting as well as lack experience in caring for patients with mental health conditions. One in four people worldwide suffers from a mental disorder; therefore, it is critical that nurses feel confident interacting with these patients to provide equitable care. Undergraduate training is a critical period for changing students' attitudes toward this population. This study's goal was twofold. First, we offered students’ exposure to common behaviors and symptoms displayed by a patient with mental illness through an engaging and immersive virtual reality simulation experience before taking care of patients in a clinical setting. Second, we aimed to determine if a virtual reality simulation will change students' attitude and stigma, favorably, toward patients with mental health conditions. We used a mixed-method comparative analysis to collect information and identify themes on undergraduate students’ attitudes and stigma toward patients with mental health conditions. Our findings demonstrate that virtual reality simulations enhance awareness and sensitivity to the situations of others (empathy) while improving their communication skills. The use of virtual reality in a baccalaureate curriculum deepens the understanding of health equity in behavioral health for nursing students.
New Zealand Nurses' Ongoing Concerns of Using Digital Technologies During and After the COVID-19 Pandemic
Authors: Honey Michelle L.L. , Collins Emma
Published: October 2024

During the COVID-19 pandemic, there was a rapid global uptake by healthcare practitioners, including nurses, of digital health to support the healthcare needs of their communities. This increase in the use of technology has impacted nurses, although there is a lack of research that explores nurses' concerns internationally, and this is equally true for New Zealand. We report the qualitative results from two surveys with New Zealand nurses, one in 2020 (n = 220) and the second in 2022 (n = 191), about their concerns of using digital technologies. Similar themes were discovered between the two data sets. Challenges around access were a common theme to both surveys. This included access to systems, connectivity, devices, and the Internet. The 2020 survey also identified inequities as a theme, whereas the 2022 survey noted poor engagement from staff. Changes to the infrastructure of the New Zealand healthcare system have been introduced, and it is hopeful that the issues of access to data and digital technologies across the country will be rectified.
Perceptions of Cognitive Load and Workload in Nurse Handoffs
Authors: Galatzan Benjamin J. , Shan Liang , Johnson Elizabeth , Patrician Patricia A.
Published: October 2024

Medical errors, often resulting from miscommunication and cognitive lapses during handoffs, account for numerous preventable deaths and patient harm annually. This research examined nurses' perceived workload and cognitive load during handoffs on hospital units with varying patient acuity levels and patient-nurse ratios. Conducted at a southeastern US medical facility, the study analyzed 20 handoff dyads using the National Aeronautics and Space Administration Task Load Index to measure perceived workload and cognitive load. Linear regressions revealed significant associations between patient acuity levels, patient-nurse ratios, and National Aeronautics and Space Administration Task Load Index subscales, specifically mental demand (P = .007) and performance (P = .008). Fisher exact test and Wilcoxon rank sum test showed no significant associations between these factors and nurses' roles (P > .05). The findings highlight the need for targeted interventions to manage workload and cognitive load, emphasizing standardized handoff protocols and technological aids. The study underscores the variability in perceived workload and cognitive load among nurses across different units. Medical-surgical units showed higher cognitive load, indicating the need for improved workload management strategies. Despite limitations, including the single-center design and small sample size, the study provides valuable insights for enhancing handoff communications and reducing medical errors.
SOX-10 and Melan-A Immunostaining in Areas of Focal Acantholytic Dyskeratosis and Epidermolytic Hyperkeratosis Within Dysplastic Nevi Biopsies: An Observational Study
Authors: Erickson Kayley L. , Tripathi Raghav , Rohr Bethany R.
Published: October 2024

Background:

Focal acantholytic dyskeratosis (FAD) and epidermolytic hyperkeratosis (EHK) are common incidental epidermal histologic findings within dysplastic nevi biopsies. We evaluate whether areas of FAD and EHK within dysplastic nevi biopsies stain with immunostains used to characterize melanocytic neoplasms.

Methods:

In this case series, a natural language search of histopathology reports from our institution in the past year (2020–2021) identified dysplastic nevus biopsies with concurrent FAD and/or EHK. Tissue samples were examined for positive melanocytic immunostaining with SOX-10 and Melan-A in areas of FAD and EHK.

Results:

Out of 32 biopsies, 20 of 26 FAD specimens (76.9%) and 2 of 6 EHK specimens (33.3%) showed unexpected suprabasal layer staining with a melanocytic marker that did not correspond to definitively identified melanocytes on the H&E-stained sections. The immunohistochemical staining of FAD and EHK was observed in 2 forms: nonspecific background staining or “true” staining (ie, seemed nuclear on SOX-10 or cytoplasmic on Melan-A).

Conclusions:

This pilot examination provides evidence that areas of incidental FAD within dysplastic nevi biopsies demonstrate unexpected suprabasal layer staining with melanocytic markers. When dermatopathologists evaluate melanocytic neoplasms with melanocytic markers, it is possible the presence of incidental FAD could lead to over diagnosing pagetoid scatter within these lesions. This study is a proof of concept with mild to moderately dysplastic nevi that do not typically incur the use of melanocytic stains; however, the implication of this unexpected staining pattern would be important when using melanocytic markers on borderline melanocytic neoplasms that have incidental FAD. Close correlation with H&E is imperative to prevent misinterpretation in these cases.
Superficial Papular Neuroma: Two Cases of a Distinctive Dermal Neoplasm
Authors: Knittel Ronan , Paton David , Beer Trevor W.
Published: October 2024

Superficial papular neuroma is a rare cutaneous spindle cell lesion, with only 5 cases reported in 2 studies. We document 2 additional cases in a 45-year-old man and a 43-year-old woman (the first case identified in a woman). Clinically, superficial papular neuromas appear as a single, non-specific papule on the head, neck, or back. Histologically, these lesions are within the papillary and superficial reticular dermis, with nerve-like structures composed of bland spindle-shaped cells intersecting normal tissue with mild reactive acanthosis. The cells are SOX10 positive with neurofilament protein staining multiple axons within. The nerve-like structures in this study were occasionally surrounded by a thin rim of CD34 positivity, with no epithelial membrane antigen staining, similar to normal sensory neurons. Superficial papular neuroma are rare benign neoplasms with no reports of recurrence, even when incompletely excised.
Comparative Bulk RNA-Seq Analysis of Poly-l-Lactic Acid Versus Calcium Hydroxylapatite Reveals a Novel, Adipocyte-Mediated Regenerative Mechanism of Action Unique to PLLA
Authors: Waibel Jill , Ziegler Mary , Nguyen Thu Q. , Le Jennifer H. T. D. , Qureshi Aamir , Widgerow Alan , Meckfessel Matthew
Published: October 2024

BACKGROUND

Injectable biostimulators are widely used to improve facial aging signs. This study was performed to compare the genetic pathways affected by 2 different injectable biostimulators.

METHODS

Randomized 13-week study (n = 21) comparing gene expression after poly l-lactic acid (PLLA-SCA) and calcium hydroxylapatite (CaHA-R) injections (baseline [BL] and Day 28) as treatment of nasolabial fold wrinkles. Punch biopsy was performed at BL and day 90; RNA was isolated, gene expression was analyzed, and bulk RNA sequencing performed. Data from both pathways were studied using the Search Tool for Retrieval of Interacting Genes/Proteins and Reactome databases.

RESULTS

Analysis at Day 0 and Day 90 showed differing gene regulation for PLLA-SCA and CaHA-R (after accounting for minor differences at BL, p < .05 at Day 90 for 9–12 genes). PLLA-SCA uniquely correlates with genes involved in adipocyte regeneration, while CaHA-R did not affect these genes. Clinically, this could translate to healthy fat replacement with an enhanced effect beyond the improvement of the collagen structure and a longer-lasting effect with PLLA-SCA. Furthermore, the adipokines that appear to be upregulated are regenerative with a positive impact on skin health.

CONCLUSION

PLLA-SCA has a novel and unique signature, which supports a potential regenerative mechanism of action through its role in the modulation of adipocyte function.
Consensus Agreements on Regenerative Aesthetics: A Focus on Regenerative Biostimulation With Calcium Hydroxylapatite
Authors: Goldie Kate , Chernoff Greg , Corduff Niamh , Davies Owen , van Loghem Jani , Viscomi Bianca
Published: October 2024

BACKGROUND

A growing population of patients is seeking treatments that not only affect their overlying features but also restore a more biologically youthful structure and function to the underlying tissue. These strategies are part of what is known as regenerative aesthetics (RA). As an emergent field, clarity regarding the precise definitions and aims of RA and methods to measure the regenerative capacity of RA treatments are lacking.

METHODS

A panel of 6 multidisciplinary experts discussed the foundational aspects of RA. Consensus statements covered aspects of RA including terminology, goals of treatment, treatment strategies, and biological benchmarks indicating regeneration. Consensus on a statement was defined as ≥75% agreement.

Results

Panelists emphasized the importance of natural, youthful tissue architecture and function including cellular and extracellular components. Replacement of a single biological component was not considered sufficient for an aesthetic treatment to be described as regenerative. Rather, the relative amounts, ratios, types, and organization are important to determine regenerative potential. Calcium hydroxylapatite is an example of an aesthetic injectable with evidence of regenerative capacity, as demonstrated by its ability to improve collagen type I/III ratios as well as induce the production of elastin and proteoglycans, which ultimately improve measures of skin quality.
Estrous cycle regulates cephalic mechanical sensitivity and sensitization of the trigemino-cervical complex in a female rat model of chronic migraine
Authors: Barnet Maxime , Descheemaeker Amelie , Favier Lea , Moisset Xavier , Schopp Julien , Dallel Radhouane , Artola Alain , Monconduit Lenaic , Antri Myriam
Published: October 2024

The higher incidence of migraines in women compared with men has led to the inclusion of female animals in pain research models. However, the critical role of the hormonal cycle is frequently overlooked, despite its clear correlation with migraine occurrences. In this study, we show in a rat model of migraine induced by repeated dural infusions of an inflammatory soup (IS) that a second IS (IS2) injection performed in proestrus/estrus (PE, high estrogen) female rats evokes higher cephalic mechanical hypersensitivities than when performed in metestrus/diestrus (MD, low estrogen) or ovariectomized (OV) rats. This hypersensitivity induced by IS2 correlates with increased c-Fos expression in outer lamina II (IIo) neurons located in the periorbital projection area of the trigemino-cervical complex (TCC), in PE only. Four IS (IS4) repetition induced an enlargement of c-Fos expression in adjacent territories areas in PE, but not MD or OV animals. Unexpectedly, c-Fos expression in locus coeruleus neurons does not potentiate after IS2 or IS4 injections. To examine the impacts of the hormonal cycle on the physiology of lamina IIo TCC neurons, we performed whole-cell patch-clamp recordings. Second inflammatory soup depolarizes neurons in PE and MD but not in OV rats and enhances excitatory synaptic inputs in PE animals to a greater extent compared with MD and OV rats. These findings show that central TCC sensitization triggered by meningeal nociceptor activation and the resulting cephalic hypersensitivity are modulated by the estrous cycle. This highlights the crucial need to account for not just sex, but also the female estrous cycle in pain research.
Time to Ring in the Body Checking, Head Contact, and Suspected Injury Rates in Youth Ringette: A Video-Analysis Study in Youth Ringette and Female Ice Hockey
Authors: Heming Emily E. , Kolstad Ash T. , West Stephen W. , Williamson Rylen A. , Sobry Alexandra J. , Cairo Alexis L. , Dennett Brooke , Russell Kelly , Goulet Claude , Emery Carolyn A.
Published: October 2024

Objective:

To compare physical contacts (PCs), including head contacts (HCs), suspected concussion, and nonconcussion injury incidence rates between youth ringette and female ice hockey.

Design:

Cross-sectional.

Setting:

Alberta ice arenas.

Participants:

Players participating in 8 U16AA (ages 14-15 years) ringette and 8 U15AA (ages 13-14 years) female ice hockey games during the 2021 to 2022 season.

Assessment of Risk Factors:

Dartfish video-analysis software was used to analyze video recordings.

Main Outcome Measures:

Univariate Poisson regression analyses (adjusted for cluster by team-game, offset by game minutes) were used to estimate PCs (including HCs) and suspected injury (concussion and nonconcussion) and concussion-specific IRs and incidence rate ratios (IRRs) to compare sports. Proportions of all PCs that were body checks (level 4-5 trunk PC) and direct HCs (HC1) penalized were reported.

Results:

Ringette had a 2.6-fold higher rate of body checking compared with hockey (IRR = 2.63, 95% CI: 1.59-4.37). Ringette also had a 2-fold higher rate of HC1 compared with hockey (IRR = 2.08, 95% CI: 1.37-3.16). A 3.4-fold higher rate of suspected injury was found in ringette (IRR = 3.37, 95% CI: 1.40-8.15). There was no significant difference in suspected concussion IRs in ringette compared with hockey (IRR = 1.93, 95% CI: 0.43-8.74). Despite being prohibited in both sports, only a small proportion of body checks (Ringette = 18%; Hockey = 17%) and HC1 (Ringette = 6%; Hockey = 6%) were penalized.

Conclusions:

Higher rates of body checking, HC1, and suspected injuries were found in ringette compared with female ice hockey. Body checking and HC1 were rarely penalized, despite rules disallowing them in both sports. Future research should consider other youth age groups.
Role of Immunohistochemical Analysis of p16 and p53 in Vulvar Carcinoma
Authors: Choschzick Matthias , Gut Andre , Hoesli Ladina , Stergiou Cristina
Published: October 2024

Tumor human papillomavirus (HPV) status is an important prognostic factor in vulvar cancer as indicated in the latest WHO classification of female genital tract tumors. Immunohistochemical detection of p16 is well established as a surrogate biomarker for tumor HPV association, including squamous cell carcinomas of the vulva. HPV-independent vulvar carcinomas are heterogeneous with 2 subcategories according to the TP53 mutation status. Therefore, the simultaneous use of p53 and p16 immunohistochemistry is recommended for accurate subclassification of vulvar squamous cell carcinomas. However, the role of molecular analytical tools, in particular RNA ISH and TP53 sequencing, is not so clear. This study aimed to investigate the performance of p53 and p16 immunohistochemistry for the diagnosis of vulvar carcinomas in comparison to TP53 mutation analysis and HPV RNA ISH. We analyzed 48 vulvar carcinomas in a tissue microarray format. Sensitivity and specificity for both methods, p16 (100% and 96%) and p53 (95% and 90%) immunohistochemistry for detection of HPV association as well as for TP53 mutations was high. Combining p16 and p53 immunohistochemistry we correctly classified all carcinomas in our series according to current WHO criteria. The sensitivity of HPV RNA ISH for the detection of HPV association was lower compared to p16 immunohistochemistry. Rare HPV-associated cases with TP53 mutation and HPV-independent tumors with p16 overexpression are discussed. In summary, the combined use of p16 and p53 immunohistochemistry for subclassification of vulvar carcinomas is justified in daily practice. Molecular tests should be restricted to rare cases with ambiguous clinicopathologic or immunohistochemical features.
“Mini Brain” Appearance in Spinal Metastasis From Type A Thymoma Detected by 18F-FDG PET/CT
Authors: Dong Youwen
Published: October 2024

A 66-year-old man presented with persistent dull pain in the lower back for over 7 months. An expansile lytic lesion in the L4 vertebral body showed a characteristic “mini brain” appearance on MRI, which is highly suggestive of plasmacytoma. 18F-FDG PET/CT scan revealed increased FDG uptake in the L4 lesion, with an additional finding of a mass in the anterior mediastinum that showed mild FDG uptake. Lumbar surgery and complete resection of the anterior mediastinum tumor confirmed spinal metastatic type A thymoma, which was classified as p-T1aN0M1b, stage IVb. The patient’s condition improved postsurgery and chemotherapy, with long-term follow-up necessary due to recurrence risk.
Metastatic Mucinous Adenocarcinoma of Unknown Origin Showing 68Ga-DOTATATE Uptake
Authors: Filizoglu Nuh , Ozguven Salih , Dede Fuat , Turoglu Halil Turgut , Erdil Tanju Yusuf
Published: October 2024

Although the use of 18F-FDG PET/CT is well established in the evaluation of adenocarcinoma, the performance of 18F-FDG PET/CT in mucinous adenocarcinoma is not consistent. 68Ga-DOTATATE uptake can be observed in some non-neuroendocrine tumors as a result of tumor blood flow and somatostatin receptor expression at different levels. For this reason, 68Ga-DOTATATE PET/CT may have a prospective role in the evaluation of mucinous adenocarcinoma. However, there is no published case of mucinous adenocarcinoma with 68Ga-DOTATATE uptake. We present a unique case of metastatic mucinous adenocarcinoma of unknown origin on 68Ga-DOTATATE PET/CT.
Explainable machine-learning model to classify culprit calcified carotid plaque in embolic stroke of undetermined source
Authors: Sakai Yu , Kim Jiehyun , Phi Huy Q , Hu Andrew C , Balali Pargol , Guggenberger Konstanze V , Woo John H , Bos Daniel , Kasner Scott E , Cucchiara Brett L , Saba Luca , Huang Zhi , Haehn Daniel , Song Jae W
Published: October 2024

Background

Embolic stroke of undetermined source (ESUS) may be associated with carotid artery plaques with <50% stenosis. Plaque vulnerability is multifactorial, possibly related to intraplaque hemorrhage (IPH), lipid-rich-necrotic-core (LRNC), perivascular adipose tissue (PVAT), and calcification morphology. Machine-learning (ML) approaches in plaque classification are increasingly popular but often limited in clinical interpretability by black-box nature. We apply an explainable ML approach, using noncalcified plaque components and calcification features with SHapley Additive exPlanations (SHAP) framework to classify calcified carotid plaques as culprit/non-culprit.

Methods

In this retrospective cross-sectional study, patients with unilateral anterior circulation ESUS who underwent neck CT angiography and had calcific carotid plaque were analyzed. Calcification-level features were derived from manual segmentations. Plaque-level features were assessed by a neuroradiologist blinded to stroke-side and by semi-automated software. Calcifications/plaques were classified as culprit if ipsilateral to stroke-side. Eight baseline ML models were compared. Three CatBoost models were trained: Plaque-level, Calcification-level, and Combined. SHAP was incorporated to explain model decisions.

Results

70 patients yielded 116 calcific carotid plaques (60 ipsilateral to stroke; 270 calcifications (146 ipsilateral)). 17 plaque-level and 15 calcification-level features were extracted. Baseline CatBoost model outperformed other models. Combined model achieved test AUC 0.77 (95% CI: 0.59-0.92), accuracy 0.82 (95% CI: 0.71 - 0.91), mean cross-validation AUC 0.78. Plaque-level and calcification-level models performed lower (AUC 0.41 95% CI: 0.15-0.68, 0.60 95% CI 0.44-0.76). Combined model utilized five features: plaque thickness, IPH/LRNC volume ratio, PVAT volume, calcification minimum density, and total calcification volume over mean density ratio. Plaque thickness was most important feature based on SHAP values, with potential threshold at >2.6 mm.

Conclusions

ML model trained with noncalcified plaque and calcification features can classify culprit calcific carotid plaque with greater accuracy than models trained using only plaque-level or calcification-level features. Model using clinically interpretable features with SHAP framework provides explanations for its decisions and allows identification of potential thresholds for high-risk features.

Abstract Figure

Graphic Abstract

Overall design of our study.
Improving Accuracy of Somatic Mutation Profiling in Large Epidemiologic Studies: Addressing Cases without Matched Normal Samples
Authors: Arora Arshi , Luo Li , Kostrzewa Caroline E. , Reiner Allison , Seshan Venkatraman , Ernstoff Marc S. , Edmiston Sharon N. , Conway Kathleen , Gorlov Ivan , Busam Klaus , Orlow Irene , Hernando Eva , Thomas Nancy E. , Berwick Marianne , Begg Colin B. , Shen Ronglai ,   InterMEL
Published: October 2024

Ideally, detection of somatic mutations in a tumor is accomplished using a patient-matched sample of normal cells as the benchmark. In this way somatic mutations can be distinguished from rare germline mutations. In large retrospective studies, archival tissue collection can pose challenges in obtaining samples of normal DNA. In this article we propose a protocol that improves somatic mutation analysis in the absence of a matched normal sample. The method was motivated by the InterMEL study, a large-scale epidemiologic investigation involving multiomic, multi-institutional genomic profiling of 1000 primary melanoma samples. The key insight for accomplishing improved mutation calling is the fact that germline mutations should produce a variant allele frequency (VAF) of around 50%. While a similar VAF of 50% would also be expected for somatic mutations in pure tumor samples, typically the tumor purity is much less than 50%, resulting in a considerably lower VAF. Making use of a technique that can simultaneously estimate both tumor purity and VAF from tumor-only samples we have developed a method for better distinguishing somatic versus germline variants. Based on 137 melanomas from the InterMEL Study with matched normal tissue to provide a gold standard we show that the conventional pipeline using a panel of (unmatched) normal samples has a false positive rate of 15.6% and a false negative rate of 3.5%. Our new technique improves these error rates to 6.4% and 2.1%, respectively.
Genetic diversity and population structure of pedunculate oaks (Quercus robur) in Wytham Woods
Authors: Hung Tin Hang , Formaggia Elias , Morley Lucy , Kirby Keith , Salguero-Gómez Roberto , Sheldon Ben C. , MacKay John J.
Published: October 2024

Genetic diversity is fundamental for adaptation to changing environments. It is particularly important in forest trees because of their significant role in nature’s contribution to people. However, their genetic diversity has been significantly changed by human activities in the past centuries.

This paper investigates a focal site, the Wytham Woods, one of the most researched woodlands on Earth, and presents a population genetic study on pedunculate oaks (Quercus robur), a keystone species in the ecosystem. We characterised 210 trees with Genotyping by Sequencing (GbS) and quantified levels of genetic diversity across stands with different histories and management regimes.

We detected only a weak population structure within the 218,567 SNPs, such that most genetic variation occurred within but not among stands, which included semi-natural woodland areas and plantations aged between 200 to 50 years ago. We also observed little difference in observed and expected heterozygosity among stand types, but detected some inbreeding in the youngest plantation. We discovered 26,174 SNPs (11.98%) that were highly differentiated and under potential selection.

We suggest that the life history traits of oak contribute to its resistance against genetic erosion, which is also observed in beeches, spruces, and pines. Preference for oaks as a timber tree and the tendency to use local seed source might have resulted in the homogeneous population structure. However, tree-to-tree differences may harbour variation in putative adaptive loci. Our study contributes crucial baseline information on for conservation and management of human-modified woodlands, in addition to supporting long-term ecological studies on many other species, which depend on this keystone oak species.

Societal Impact Statement

Our study highlights the importance of monitoring and preserving genetic diversity in forest trees, particularly in keystone species like pedunculate oaks. Human activities, including land use changes and forestry practices, could influence their genetic diversity and potentially alter nature’s contribution to people. We demonstrate how understanding the genetic structure of oaks in stands ranging from semi-natural to plantations could (1) shed light on the natural history and the consequence of human activities in Wytham Woods, (2) support the many continuing, long-term ecological studies including adaptational potential in the oak population, and (3) be translated for other co-occurring species and other woodlands for effective genetic monitoring at large.
Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+T cells
Authors: Herbst Michael , Köksal Hakan , Brunn Silvan , Zanetti Dominik , Domocos Ioana , De Stefani Viola , Pereira Paulo , Nater Marc , Cecconi Virginia , van den Broek Maries
Published: October 2024

Using a mouse tumor model with inducible cancer-cell-intrinsic cGAS expression, we show that cancer-cell-derived cGAMP is essential and sufficient to trigger a sustained type I interferon response within the tumor microenvironment. This led to improved CD8+T cell-dependent tumor restriction. However, cGAMP limits the proliferation, survival, and function of STING-expressing but not of STING-deficient CD8+T cells.In vivo, STING deficiency in CD8+T cells enhanced tumor restriction. Consequently, cancer-cell-derived cGAMP both drives and limits the anti-tumor potential of CD8+T cells. Mechanistically, T cell-intrinsic STING is associated with pro-apoptotic and antiproliferative gene signatures. Our findings suggest that STING signaling acts as a checkpoint in CD8+T cells that balances tumor immunity.

Graphical abstract
GESIAP3.0: Sensor-based Image Analysis Program for Transmission VisualizationIn Vivo
Authors: Zhu Roger E. , Diao Xintong , Liu Xiaoyu , Ru Qin , Wu Zenan , Zhang Ziyuan , Looger Loren L. , Zhu Jiazhu
Published: October 2024

Synaptic transmission mediated by various neurotransmitters influences a wide range of behaviors. However, understanding how neuromodulatory transmitters encode diverse behaviors and affect their functions remains challenging. Here, we introduce GESIAP3.0, an advanced, third-generation image analysis program based on genetically encoded sensors. This tool enables precise quantitative analysis of transmission in both awake, freely moving animals and immobilized subjects. GESIAP3.0 incorporates movement correction algorithms that effectively eliminate image displacement in behaving animals while optimizing synaptic information extraction and simplifying computations on commodity computers. Quantitative analysis of cholinergic, dopaminergic, and serotonergic transmission, corrected for tissue movement, revealed synaptic properties consistent with measurements fromex vivowide-field andin vivotwo-photon imaging under stable conditions. This validates the applicability of GESIAP3.0 for analyzing synaptic properties of neuromodulatory transmission in behaving animals.
Epistasis and cryptic QTL identified using modified bulk segregant analysis of copper resistance in budding yeast
Authors: Buzby Cassandra , Plavskin Yevgeniy , Sartori Federica M.O. , Tong Qiange , Vail Janessa K. , Siegal Mark L.
Published: October 2024

The contributions of genetic interactions to natural trait variation are challenging to estimate experimentally, as current approaches for detecting epistasis are often underpowered. Powerful mapping approaches such as bulk segregant analysis, wherein individuals with extreme phenotypes are pooled for genotyping, obscure epistasis by averaging over genotype combinations. To accurately characterize and quantify epistasis underlying natural trait variation, we have engineered strains of the budding yeastSaccharomyces cerevisiaeto enable crosses where one parent’s chromosome is fixed while the rest of the chromosomes segregate. These crosses allow us to use bulk segregant analysis to identify quantitative trait loci (QTL) whose effects depend on alleles on the fixed parental chromosome, indicating a genetic interaction with that chromosome. Our method, which we term epic-QTL (forepistatic-with-chromosomeQTL) analysis, can thus identify interaction loci with high statistical power. Here we perform epic-QTL analysis of copper resistance with chromosome I or VIII fixed in a cross between divergent naturally derived strains. We find seven loci that interact significantly with chromosome VIII and none that interact with chromosome I, the smallest of the 16 budding yeast chromosomes. Each of the seven interactions alters the magnitude, rather than the direction, of an additive QTL effect. We also show that fixation of one source of variation — in this case chromosome VIII, which contains the large-effect QTL mapping toCUP1— increases power to detect the contributions of other loci to trait differences.

Author Summary

Most traits of interest that vary in populations are determined by multiple genetic factors, as well as by environmental variation and random chance. These influences may combine in complicated ways, for example when the effect of one genetic variant depends on genetic variants elsewhere in the genome. Such dependencies are difficult to identify and characterize because testing many possible combinations of influences reduces statistical power. We address this challenge by combining bulk segregant analysis, a robust method for detecting effects of individual genetic variants averaged across genetic backgrounds, with chromosome fixation in budding yeast. This approach allows us to detect gene-variant effects that depend on the fixed chromosome with statistical power comparable to that achieved when detecting background-independent effects. Applying the approach to copper sulfate resistance, we identify and characterize interaction effects and, by removing one source of variation (a single yeast chromosome), improve detection of background-independent effects as well.
Machine learning models reveal environmental and genetic factors associated with the plant circadian clock
Authors: Reynolds Connor , Colmer Joshua , Rees Hannah , Khajouei Ehsan , Rusholme-Pilcher Rachel , Kudoh Hiroshi , Dodd Antony N. , Hall Anthony
Published: October 2024

The circadian clock of plants contributes to their survival and fitness. However, understanding clock function at the transcriptome level and its response to the environment requires assaying across high resolution time-course experiments. Generating these datasets is labour-intensive, costly and, in most cases, performed under tightly controlled laboratory conditions. To overcome this barrier, we have developed ChronoGauge: an ensemble model which can reliably estimate the endogenous circadian time of plants using the expression of a handful of time-indicating genes within a single time-pointed transcriptomic sample. ChronoGauge can predict a plant’s circadian time with high accuracy across unseenArabidopsisbulk RNA-seq and microarray samples, and can be further applied across samples in non-model species, including field samples. Finally, we demonstrate how ChronoGauge can be applied to test hypotheses regarding the response of the circadian transcriptome to specific genotypes or environmental conditions.
To fly, or not to fly, that is the question: A deep learning model for peptide detectability prediction in mass spectrometry
Authors: Abdul-Khalek Naim , Picciani Mario , Wimmer Reinhard , Overgaard Michael Toft , Wilhelm Mathias , Echers Simon Gregersen
Published: October 2024

Identifying detectable peptides, known as flyers, is key in mass spectrometry-based proteomics. Peptide detectability is strongly related with the peptide sequence and its resulting physicochemical properties. Moreover, the high variability in MS data, particularly in peptide detectability and intensity across multiple analyses and samples, makes the development of a generic model for detectability prediction unfeasible. This underlines the need for tools that can be refined for specific experimental conditions. To address this need, we present Pfly, a deep learning model developed to predicts peptide detectability based solely on peptide sequence. Pfly distinguishes itself as a versatile and reliable state-of-the-art tool, offering high performance, accessibility, and easy customizability for end-users. This adaptability allows researchers to tailor the model to their specific experimental conditions, facilitating the creation of lab-specific models. This, in turn, can lead to more accurate results and expand the model’s applicability across various research fields. The model’s architecture is an encoder-decoder with an attention mechanism. This tool classifies peptides as either flyers or non-flyers, providing both binary probabilities and detailed categorical probabilities for four distinct classes defined in this study: non-flyer, weak flyer, intermediate flyer, and strong flyer. The model was initially trained on a synthetic peptide library and subsequently fine-tuned with a biological dataset to mitigate bias towards synthesizability, improving the predictive capacity and outperforming state-of-the-art predictors in a benchmark comparison. The study further investigates the influence of protein abundance and the search engine, illustrating the negative impact on peptide identification due to misclassification. Pfly has been integrated in the DLOmix framework and it is accessible on GitHub athttps://github.com/wilhelm-lab/dlomix.
Diffusion-based artificial genomes and their usefulness for local ancestry inference
Authors: Szatkownik Antoine , Planche Léo , Demeulle Maïwen , Chambe Titouan , Ávila-Arcos María C. , Huerta-Sanchez Emilia , Furtlehner Cyril , Charpiat Guillaume , Jay Flora , Yelmen Burak
Published: October 2024

The creation of synthetic data through generative modeling has emerged as a significant area of research in genomics, offering versatile applications from tailoring functional sequences with specific attributes to generating high-quality, privacy-preserving in silico genomes. Notwithstanding these advancements, a key challenge remains: while some methods exist to evaluate artificially generated genomic data, comprehensive tools to assess its usefulness are still limited. To tackle this issue and present a promising use case, we test artificial genomes within the framework of population genetics and local ancestry inference (LAI).

Building on previous work in deep generative modeling for genomics, we introduce a novel, frugal diffusion model and show that it produces high-quality genomic data. We then assess the performance of a downstream machine learning LAI model trained on composite datasets comprising both real and/or synthetic data. Our findings reveal that the LAI model achieves comparable performance when trained exclusively on real data versus high-quality synthetic data. Moreover, we highlight how data augmentation using high-quality artificial genomes significantly benefits the LAI model, particularly when real data is limited. Finally, we compare the conventional use of a single synthetic dataset to a robust ensemble approach, wherein multiple LAI models are trained on diverse synthetic datasets, and their predictions are aggregated.

Our study highlights the potential of frugal diffusion-based generative models and synthetic data integration in genomics. This approach could improve fair representation across populations by overcoming data accessibility challenges, while ensuring the reliability of genomic analyses conducted on artificial data.
NeuroTD: A Time-Frequency Based Multimodal Learning Approach to Analyze Time Delays in Neural Activities
Authors: Huang Xiang , Kalafut Noah Cohen , Alatkar Sayali , Li Athan Z. , Dong Qiping , Chang Qiang , Wang Daifeng
Published: October 2024

Studying temporal features of neural activities is crucial for understanding the functions of neurons as well as underlying neural circuits. To this end, recent researches employ emerging techniques including calcium imaging, Neuropixels, depth electrodes, and Patch-seq to generate multimodal time-series data that depict the activities of single neurons, groups of neurons, and behaviors. However, challenges persist, including the analysis of noisy, high-sampling-rate neuronal data, and the modeling of temporal dynamics across various modalities. To address these challenges, we developed NeuroTD, a novel deep learning approach to align multimodal time-series datasets and infer cross-modality temporal relationships such as time delays or shifts. Particularly, NeuroTD integrates Siamese neural networks with frequency domain transformations and complex value optimization for inference. We applied NeuroTD to three multimodal datasets to (1) analyze electrophysiological (ephys) time series measured by depth electrodes, identifying time delays among neurons across various positions, (2) investigate neural activity and behavioral time series data derived from Neuropixels and 3D motion captures, establishing causal relationships between neural activities and corresponding behavioral activities, and (3) explore gene expression and ephys data of single neurons from Patch-seq, identifying gene expression signatures highly correlated with time shifts in ephys responses. Finally, NeuroTD is open-source athttps://github.com/daifengwanglab/NeuroTDfor general use.