bluuebunny/crossref_metadata_2025 huggingface dataset:
Designing a Website to Support a Multisite, International Clinical Trial
Authors: Pasek Tracy Ann , Napolitano Natalie , Cassidy Amy , Kalvas Laura Beth , Curley Martha A.Q.
Published: September 2024

Background

Safe and reliable implementation of complex study protocols in multisite clinical trials requires that all study personnel have 24/7 access to up-to-date study materials. Study websites can serve as an electronic manual of operations (eMOO) to support trial conduct.

Objective

We describe the development, organization, and maintenance of a study website and eMOO to facilitate quick and efficient communication during conduct of a complex, multisite, international clinical trial.

Methods

We worked closely with our information technology department to develop and maintain our study website, which includes a public home page, a section for parents and families, and three password-protected portals that serve as an eMOO for (a) study sites, (b) study site investigators, and (c) the operations team (e.g., clinical coordination center, data coordination center).

Results

The public home page is helpful for families contemplating study participation and for nonparticipating sites considering joining our trial. The patient and family education section supports family participation in the study. The study site portal contains all information needed for local study teams to safely manage a study patient. The investigator portal provides access to research-specific materials needed to lead the study at each site. The operations team portal supports overall study management. For other scientists considering use of a study website for their multisite research, we recommend close collaboration with information technology for development and maintenance, limited and clearly defined roles for version control, and use of unmodifiable file formats to prevent unapproved alterations of study materials.

Discussion

Although investment in development and maintenance has been significant, we have appreciated marked value to our operations team and study sites. Our study website development process is relevant to other scientists conducting multisite clinical research.
The Common Expression of INSM1 in HPV-related Oropharyngeal Squamous Cell Carcinomas Is Not Associated With True Neuroendocrine Transformation or Aggressive Behavior
Authors: Bhardwaj Swati , Veremis Brandon , Fernandino Rocco , Posner Marshall , Westra William H.
Published: September 2024

INSM1 has rapidly emerged as a robust marker for neuroendocrine (NE) differentiation, prompting the use of INSM1 as a standalone marker for NE differentiation in various sites. INSM1 staining could be an especially practical tool for evaluating HPV-associated oropharyngeal squamous cell carcinoma (HPV-OPSCCs) because high-grade NE transformation may be exceedingly difficult to recognize on morphologic grounds alone, even though it portends highly aggressive clinical behavior. The purpose of this study was to determine the incidence of INSM1 expression in HPV-OPSCC and study its role in determining NE transformation and clinical aggressiveness. Forty-six consecutive nonselected HPV-OPSCCs were stained with INSM1 and synaptophysin. In addition, 2 clinically matched cohorts of aggressive (n=28) versus nonaggressive (n=26) HPV-OPSCCs were retrospectively stained with the INSM1 and synaptophysin to determine the prognostic significance of INSM1 staining. In all, 42% of HPV-OPSCC showed positive INSM1 staining, but synaptophysin was not co-expressed in even a single case. In selected cases based on clinical behavior, INSM1 staining was observed more frequently in nonaggressive than aggressive tumors (50.0% vs. 21.4%, P=0.03). INSM1 expression is a common finding in HPV-OPSCC and is usually not linked with true NE transformation or aggressive behavior. Indeed, INSM1 expression is more commonly observed in nonaggressive cancers. Reliance on INSM1 staining alone in recognizing NE differentiation in HPV-OPSCC could be calamitous.
Effect of knee strengthening exercises and lifestyle modifications through mobile phone support in people suffering from knee osteoarthritis
Authors: Garg Nikhil , Gupta Nikhil , Khatri Kavin , Kanwal Abhinav , Hussain Zeeshan , Sachdeva Jimmy
Published: September 2024

Objective

The study aimed to evaluate the effectiveness of mobile phone-based support in improving exercise adherence and outcomes in knee OA.

Designs

A prospective comparative cohort study was conducted with a follow-up at 3, 6, and 12 weeks, involving 210 participants allocated into intervention and control groups. The intervention group received knee exercise flyers and mobile phone-based adherence support, while the control group received only standard instructions after physiotherapy. Outcome measures included Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, numeric rating scale pain scores, and quality of life assessments at baseline and follow-ups at 3, 6 and 12 weeks.

Results

The intervention group exhibited significant reductions in WOMAC scores, pain scores and improvement in quality of life over the 12-week follow-up compared to baseline. The intervention group exhibited significantly greater improvements in the outcomes as compared to control group.

Conclusion

A combined intervention of knee exercises leaflets and SMS/phone-call adherence support led to significant improvements in pain, functional outcomes and quality of life among individuals with knee OA. These findings underscore the potential of mobile phone-based interventions as effective adjuncts to traditional therapies for knee OA.
The emergence of letermovir and maribavir drug-resistant mutations: from clinical trials to real-world studies
Authors: Zhu Violet Z. , Horton Miles B. , Haeusler Gabrielle M. , Yong Michelle K.
Published: September 2024

Purpose of review

Cytomegalovirus (CMV) infection is associated with severe clinical disease and high morbidity in immunocompromised hosts. Letermovir and maribavir, are two recently developed antiviral drugs used in the prevention and treatment of resistant and refractory CMV. Following the publication of landmark randomized trials and increased use, both clinical trial data and real-world experience has reported the development of antiviral drug resistance. The aim of this review was to comprehensively review the published literature on letermovir and maribavir drug resistance and to describe the clinical scenarios in which they may emerge.

Recent findings

For letermovir, the most frequently detected resistance mutations occur in the UL56 gene (C325Y/W/F) and confer total resistance. Maribavir resistance mutations most often occur in the UL97 gene and resistance-associated variants (RAVs) T409M, H411Y, C480F have all been detected. The clinical context in which letermovir and maribavir resistance occurs include high viral loads at initiation, intensified immunosuppression, subtherapeutic drug exposure because of poor adherence, drug interactions, and inadequate central nervous system (CNS) penetration. Emergence of resistance mutations generally occurs within the first 3 months of initiation.

The detection of letermovir and maribavir resistance mutations highlights an ongoing clinical challenge in the management of CMV.
A Comparative Analysis of Patient-Reported Outcomes Following Free Tissue Transfer, Partial Foot Amputation, and Below-Knee Amputation in High-Risk Limb Salvage Patients
Authors: Lava Christian X. , Huffman Samuel S. , Li Karen R. , DiBello John R. , Ply Christopher M. , Rohrich Rachel N. , Steinberg John S. , Atves Jayson N. , Fan Kenneth L. , Youn Richard C. , Attinger Christopher E. , Evans Karen K.
Published: September 2024

Background

The surgical decision for limb-salvage with free tissue transfer (FTT), partial foot amputation (PFA), or below-knee amputation (BKA) for complex lower extremity (LE) wounds hinges on several factors, including patient choice and baseline function. However, patient-reported outcome measures (PROMs) on LE function, pain, and QoL for chronic LE wound interventions are limited. Thus, the study aim was to compare PROMs in patients who underwent FTT, PFA, or BKA for chronic LE wounds.

Methods

PROMs were collected via QR code for all adult chronic LE wound patients who presented to a tertiary wound center between June 2022 and June 2023. A cross-sectional analysis of patients who underwent FTT, PFA, or BKA was conducted. The 12-Item Short Survey (SF-12), PROM Information System Pain Intensity (PROMIS-3a), and Lower Extremity Functional Scale (LEFS) were completed at 1, 3, and 6 months and 1, 3, and 5 years postoperatively. Patient demographics, comorbidities, preoperative characteristics, and amputation details were collected.

Results

Of 200 survey sets, 71 (35.5%) underwent FTT, 51 (25.5%) underwent PFA, and 78 (39.0%) underwent BKA. Median postoperative time points of survey completion between FTT (6.2 months, IQR: 23.1), PFA (6.8 months, IQR: 15.5), and BKA (11.1 months, IQR: 21.3) patients were comparable (P = 0.8672). Most patients were male (n = 92, 76.0%) with an average age and body mass index (BMI) of 61.8 ± 12.6 years and 30.3 ± 7.0 kg/m2, respectively. Comorbidities for FTT, PFA, and BKA patients included diabetes mellitus (DM; 60.6% vs 84.2% vs 69.2%; P = 0.165), peripheral vascular disease (PVD; 48.5% vs 47.4% vs 42.3%; P = 0.790), and chronic kidney disease (CKD; 12.1% vs 42.1% vs 30.8%; P = 0.084). No significant differences were observed between FTT, PFA, and BKA patients in mean overall PROMIS-3a T-scores (49.6 ± 14.8 vs 54.2 ± 11.8 vs 49.6 ± 13.7; P = 0.098), LEFS scores (37.5 ± 18.0 vs 34.6 ± 18.3 vs 38.5 ± 19.4; P = 0.457), or SF-12 scores (29.6 ± 4.1 vs 29.5 ± 2.9 vs 29.0 ± 4.0; P = 0.298).

Conclusion

Patients receiving FTT, PFA, or BKA for chronic LE wounds achieve comparable levels of LE function, pain, and QoL postoperatively. Patient-centered functionally based surgical management for chronic LE wounds using interdisciplinary care, preoperative medical optimization, and proper patient selection optimizes postoperative PROMs.
Comparison of Normal Human Skin and Hypertrophic Scar Tissue Samples of Different Ages, Locations, and Stages of Maturity
Authors: Lv Tao , Zhang Peichao , Shi Huirong , Zhang Jiaojiao , Zhang Zhiying , Huo Ran
Published: September 2024

Background

Scars disrupt the normal structure and function of the skin. The primary goal of plastic surgery is to prevent and reduce scarring. Therefore, we aimed to establish a comparison scheme between normal skin (NS) tissues of different ages and locations; hypertrophic scars (HTS) of different ages, locations, and maturities; and NS and HTS tissues to provide evidence on scar severity for improving treatment evaluation.

Methods

Various methods including histology, immunohistochemistry, and immunofluorescence were employed to compare the general appearance, macrophage infiltration, fibroblast activity, degree of angiogenesis, and collagen fiber type and arrangement in human-sourced NS and HTS tissues of different ages, locations, and maturities in seven patients (three with NS and four with HTS) from the Department of Burn and Plastic Surgery of the Shandong Provincial Hospital from January 2019 to December 2020.

Results

The thicknesses of the epidermis and dermis of NS tissues varied with age and location. The epidermis of the upper arms, face, and upper eyelids of NS tissues sequentially thickened, whereas the dermis was sequentially thinner. Several glandular structures were identified in the upper eyelids but rarely in the face and upper arms. Histological changes in HTS tissue of different ages, locations, and maturity occur as scar formation time is prolonged, accompanied by increased CD86 levels and fibrosis. As the scar matured, connexin and VEGFR2 expression decreased, indicating reduced inflammation, fibroblast activity, and angiogenesis. The comparison between NS and HTS tissue also revealed significant differences; the positive expression of VEGFR2 and total collagen in HTS tissue was higher than that in NS tissue.

Conclusions

We discovered significant differences among NS, HTS, and NS and HTS tissues of different ages, locations, and maturities. Further, this study may provide a basis for clarifying the treatment effect of different methods for HTS compared with those for NS, efficiently individualizing patients' treatment plans and ultimately shortening the scar treatment process.
Skeletal and Soft Tissue Surgeries in the Long-term Management of Patients With Syndromic Craniosynostosis
Authors: Moshal Tayla , Roohani Idean , Jolibois Marah , Lasky Sasha , Stanton Eloise W. , Vallurupalli Medha , Wolfe Erin M. , Munabi Naikhoba C.O. , Hammoudeh Jeffrey A. , Urata Mark M.
Published: September 2024

Background

Soft tissue procedures are often crucial for normalizing the long-term facial appearance in patients with syndromic craniosynostosis, yet they are underrepresented in the literature and existing treatment algorithms. This study evaluated secondary soft tissue surgeries in relation to skeletal operations in patients with syndromic craniosynostosis.

Methods

A retrospective review evaluated patients with syndromic craniosynostosis treated at a tertiary children's hospital from 2003 to 2023. Craniofacial skeletal and soft tissue procedures were assessed for timing and frequency. Skeletal surgeries included redo fronto-orbital advancements, monobloc advancement/distraction ± facial bipartition, and LeFort III or III/I advancement/distraction. Soft tissue surgeries encompassed oculoplastic procedures, scalp reconstruction, fat grafting, and septorhinoplasty.

Results

Of 106 patients with syndromic craniosynostosis, 57 (57.8%) underwent ≥1 secondary skeletal operation, and 101 (95.3%) underwent ≥1 soft tissue procedures, averaging 3.7 ± 3.3 soft tissue procedures per patient. Patients who underwent secondary forehead advancement had significantly higher rates of subsequent lateral canthopexy (71.4% vs 25.6, P < 0.001), ptosis reconstruction (17.9% vs 7.7%, P = 0.025), and frontotemporal fat grafting (50.0% vs 15.4%, P < 0.001) than those who did not. Patients who underwent midface advancement surgery had significantly higher rates of subsequent lateral canthopexy (65.4% vs 11.1%, P < 0.001), medial canthopexy (7.7% vs 0.0%, P = 0.038), scalp reconstruction (36.5% vs 16.7%, P = 0.020), frontotemporal fat grafting (34.6% vs 14.8%, P = 0.018), malar fat grafting (11.5% vs 0.0%, P = 0.010), and septorhinoplasty (26.9% vs 1.9%, P < 0.001) than those who did not. Specifically, LeFort III or III/I advancement/distractions were significantly associated with higher rates of subsequent septorhinoplasties (33.3% vs 1.6%, P < 0.001). The mean follow-up was 10.2 ± 7.0 years.

Conclusions

This study revealed an intricate interplay between skeletal and soft tissue surgery in patients with syndromic craniosynostosis. Exploring techniques to reduce the need for further corrective surgery and anticipating necessary secondary interventions may improve patient counseling and outcomes.
Management of Pediatric Type III Tibial Shaft Fractures
Authors: MacIsaac Molly F. , Wright Joshua M. , Halsey Jordan N. , Fitzgerald Ryan E. , Snyder Christopher W. , Rottgers S. Alex
Published: September 2024

Background

Pediatric open tibial fractures represent a challenging subset of injuries with limited literature to guide management. For children, the epidemiology, management, and outcomes of tibial-shaft fractures have not been fully described.

Methods

A retrospective analysis of the Trauma Quality Improvement Program Data Bank from 2017–2020 was used to query demographics, injury patterns, and management strategies in pediatric open tibial fractures. Fractures were compared by age group (0–5, 6–12, 13–17 years) and type (I/II vs type III). A subgroup analysis was performed on patients with type III open fractures.

Results

A total of 3480 open tibial fractures were identified, 3049 were type I/II, and 431 were type III. Motor vehicle accidents (48%) were the most common mechanism of injury (P < 0.001). Subanalysis of 128 type IIIb/c tibial fractures revealed local flap reconstruction (25%) skin graft (25%), and free tissue transfer were the most common management strategies and soft-tissue coverage was achieved after 162 hours (interquartile range = 109–231). Negative pressure wound therapy was utilized in 63% of cases but used in isolation in only 23% of cases. Immediate fixation with intramedullary nailing was more frequently used in the 13–17 age group while plate fixation was more commonly used in younger age groups.

Conclusions

Soft-tissue management patterns following open tibial shaft fractures mirror those seen in adult cohorts. The median time to achieve soft-tissue coverage exceeds the traditional 72-hour target advocated by Godina. Age-based variation is seen in orthopedic management of these fractures based on growth maintenance concerns.
Efficacy of Nasal Septal Complex in the Endoscopic Reconstruction of Medial Orbital Wall
Authors: Zhang Shiyong , Xu Zhihua , Zhang Xiaoqing , Wang Xinhua , Ye Rui
Published: September 2024

The aim of this study is to investigate the efficacy of nasal septal complex reconstructing the medial orbital wall under some specific circumstances. The authors performed a study that included 10 patients who underwent isolated medial orbital wall fracture (blow-out fracture). All the reconstruction surgery of the patient included in this study fixed defect of medial orbital wall using autologous nasal septal complex (composed of nasal septal cartilage and perpendicular plate of ethmoid). The authors observed postoperative improvements of diplopia or ocular motility disorders of the affected orbit. The surgeries had gained satisfactory results, and without severe postoperative complications. After long-term follow-up, postoperative CT indicated the implant-covered defect of medial orbital wall, and there’s no incarceration of the medial rectus. Meanwhile, the authors found there is no crack in the implant, and the surgery using nasal septal complex achieved premorbid orbital form. Autologous nasal septal complex provides a better complement to endoscopic reconstruction of medial orbital wall; this strategy allows nasal septum to reconstruct isolated medial orbital wall defects of various degrees, such as nasal septum fracture and dysplasia of perpendicular plate of ethmoid.
Prolapse Treatment–Related Decisional Conflict After New Patient Visits
Authors: Shinnick Julia K. , Jackson Araba A. , Stanley Russel , Serna-Gallegos Tasha , Boyd Brittni , Joseph Ivrose , Das Deepanjana , Pancheshnikov Anna , Scarpaci Matthew M. , Sung Vivian W.
Published: September 2024

Importance

Patients with pelvic organ prolapse are often tasked with deciding between treatments. Decisional conflict is a measure of factors that go into effective decision making.

Objective

This study aimed to compare prolapse treatment–related decisional conflict reported by underrepresented patients (URPs) to non-URPs after new patient visits.

Study Design

A multicenter cohort study of new patients counseled regarding management of prolapse from July 2021 to December 2022 was performed. Participants completed the Decisional Conflict Scale (DCS), a validated measure of modifiable factors in decision making. Higher scores indicate feeling less comfortable with decisions. Race and ethnicity were viewed as social constructs. A URP was defined as self-identification with a non-White race or Hispanic ethnicity. Alpha was set at 0.05, power 80%, to detect an effect size of 0.4 between mean DCS scores.

Results

A total of 207 participants (103 URPs, 49.8%), with a mean age of 63.4 ± 11.9 years and mean body mass index of 29.7 ± 6.9 (calculated as weight in kilograms divided by height in meters squared), completed the study. Much of the URP group self-identified as Hispanic (50/103, 48.5%) and/or Black (39/103, 37.9%), and 30 of 103 (29.1%) had an interpreter at their visit. A greater proportion of non-URPs had a prior hysterectomy (16.1% difference; P = 0.017) and prolapse surgery (18/204, 10.5% difference; P = 0.020). A greater proportion of URPs had hypertension (23.6% difference; P = <0.001). There were no differences in the other pelvic floor disorders, prolapse stage, or treatments selected (all P > 0.05). The mean DCS scores were not different between groups (URP, 12.9 ± 12.3 vs non-URP, 11.6 ± 14.9; P = 0.31). Household income, education, and insurance were not associated with DCS scores (all P > 0.05).

Conclusions

Decisional Conflict Scale scores were not significantly different between groups. Possible differences between subgroups warrant further investigation.
Urinary Incontinence in Nulliparous Female Elite Athletes: A Mixed Methods Exploration
Authors: Gan Zoe S. , Bilger Andrea , Smith Ariana L.
Published: September 2024

Importance

Urinary incontinence (UI) occurs in 40–50% of nulliparous female elite athletes. However, causative factors, management, and perceptions of UI in this population are suboptimally understood.

Objectives

The objectives of this study were to (1) identify factors that precipitate UI in nulliparous female elite athletes and (2) explore management strategies for UI and its effect on sports performance and quality of life.

Study Design

This was a cross-sectional, mixed-methods study in Division 1, college-aged nulliparous female athletes. Surveys assessed demographics, sport characteristics, relevant medical history, bladder symptoms during exercise, and validated genitourinary symptom questionnaires (Lower Urinary Tract Dysfunction Network Symptom Index-29, Female Genitourinary Pain Index). Data were compared between symptomatic athletes (who had ever experienced urinary leakage during exercise) and asymptomatic athletes. Symptomatic athletes discussed their experiences with UI in focus groups.

Results

Symptomatic athletes (33/67, 49%) had more asthma (21% vs. 2.9%, P = 0.027) and constipation (15% vs. 0%, P = 0.025), were more sexually active (76% vs. 44%, P = 0.008), and had worse overall urinary symptoms and genitourinary pain than asymptomatic athletes. They described both stress and urgency incontinence precipitated by various factors, including running, jumping, sustained efforts, and stressful situations. Many described voiding frequently before and during exercise. Despite increasing normalization of UI in the female athlete population since the onset of adolescence and variable degrees of bother, interest in improving symptom management was common.

Conclusions

Urinary incontinence in nulliparous female elite athletes may be multifactorial given its association with medical, behavioral, exercise-specific, and environmental conditions, which may be explored longitudinally to inform prevention and treatment strategies.
Out-of-sync evolutionary patterns and mutual interplay of major and minor capsid proteins in norovirus GII.2
Authors: Xu Ruiquan , Xue Liang , Wang Jingmin , Chen Yiqing , Cao Yingwen , Gao Junshan , Gao Hui , Du Qingyao , Kou Xiaoxia , Yu Lin
Published: September 2024

An erratum of this article has been published full details can be found at 10.1099/jgv.0.002074.

Human noroviruses are the most common cause of viral gastroenteritis, resulting annually in 219 000 deaths and a societal cost of $60 billion, and no antivirals or vaccines are available. The minor capsid protein may play a significant role in the evolution of norovirus. GII.4 is the predominant genotype of norovirus, and its VP2 undergoes epochal co-evolution with the major capsid protein VP1. Since the sudden emergence of norovirus GII.2[P16] in 2016, it has consistently remained a significant epidemic strain in recent years. In the construction of phylogenetic trees, the phylogenetic trees of VP2 closely parallel those of VP1 due to the shared tree topology of both proteins. To investigate the interaction patterns between the major and minor capsid proteins of norovirus GII.2, we chose five representative strains of GII.2 norovirus and investigated their evolutionary patterns using a yeast two-hybrid experiment. Our study shows VP1–VP2 interaction in GII.2, with critical interaction sites at 167–178 and 184–186 in the highly variable region. In the intra-within GII.2, we observed no temporal co-evolution between VP1 and VP2 of GII.2. Notable distinctions were observed in the interaction intensity of VP2 among inter-genotype (P<0.05), highlighting the divergent evolutionary patterns of VP2 within different norovirus genotypes. In summary, the interactions between VP2 and VP1 of GII.2 norovirus exhibit out-of-sync evolutionary patterns. This study offered valuable insights for further understanding and completing the evolutionary mechanism of norovirus.
Exploiting pleiotropy to enhance variant discovery with functional false discovery rates
Authors: Bass Andrew J. , Wallace Chris
Published: September 2024

The cost of acquiring participants for genome-wide association studies (GWAS) can limit sample sizes and inhibit discovery of genetic variants. We introduce the surrogate functional false discovery rate (sfFDR) framework which integrates summary statistics of related traits to increase power. The sfFDR framework provides estimates of FDR quantities such as the functional local FDR andq-value, and uses these estimates to derive a functionalp-value for type I error rate control and a functional local Bayes’ factor for post-GWAS analyses (e.g., fine mapping and colocalization). Compared to a standard analysis, sfFDR substantially increased power (equivalent to a 60% increase in sample size) in a study of obesity-related traits from the UK Biobank, and discovered eight additional lead SNPs near genes linked to immune-related responses in a rare disease GWAS of eosinophilic granulomatosis with polyangiitis. Collectively, these results highlight the utility of exploiting related traits in both small and large studies.
Stroke recognition in medical emergency calls: A novel sensitivity definition as a basis for developing artificial intelligence decision support
Authors: Iversen Emil , Ihle-Hansen Hege , Halle Kari Krizak , Lundervold Alexander Selvikvåg , Myrmel Lars , Vestbø Anders Strand , Fromm Annette , Autenried Cristian , Brattebø Guttorm
Published: September 2024

Background

The sensitivity of emergency medical communication centers (EMCC) for stroke detection varies widely. However, few studies offer detailed insights into the entirety of prehospital pathways in patients with stroke. Therefore, this study aimed to lay the foundation for artificial intelligence (AI) decision support tools in EMCCs by exploring their ability to detect strokes in medical emergency calls, describe a novel method for stroke sensitivity calculation in the EMCC, and identify factors associated with stroke recognition during a call.

Methods

In total, 1,164 patients with stroke in the catchment area of Bergen EMCC in 2018 and 2019 were included, and a dataset from the EMCC was established manually and linked with data from the Norwegian Stroke Registry (NSR) for analysis. Descriptive statistics, Chi-square test for categorical variables, Mann–Whitney U test for continuous variables, and multivariate logistic regression (LR) were performed on data obtained from patients primarily assessed by EMCC (n=838).

Results

Using a novel method, we found a stroke detection sensitivity of 76.8% in our study, compared to the 63.4% when using the traditional sensitivity detection method. LR analysis showed a positive association between stroke suspicion and ischemic strokes (odds ratio [OR]=0.317 [0.209–0.481]; p<0,001, with ischemic stroke as the reference) and wake-up strokes (OR=1.716 [1.110–2.653]; p=0.015). Among the NSR symptoms, only aphasia/dysarthria was positively associated with stroke suspicion (OR=1.600 [1.087–2.353]; p=0.017), while leg paresis (OR=0.609 [0.390–0.953]; p=0.009) and vertigo (OR=0.376 [0.204–0.694]; p=0.002) were negatively associated.

Conclusions

This study introduced a novel and more accurate method for calculating EMCC stroke sensitivity, which is relevant for developing decision support tools, such as AI. Moreover, we identified factors of particular interest for future EMCC research that are relevant to developing AI decision-support tools.

Clinical trials

https://clinicaltrials.gov/study/NCT04648449
Single-cell multi-omics reveals tumor microenvironment factors underlying poor immunotherapy responses in ALK-positive lung cancer
Authors: Baek Seungbyn , Sung Euijeong , Kim Gamin , Hong Min Hee , Lee Chang Young , Shim Hyo Sup , Park Seong Yong , Kim Hye Ryun , Lee Insuk
Published: September 2024

Anaplastic lymphoma kinase (ALK) rearrangement is a major oncogenic driver in non-small cell lung cancer (NSCLC). While ALK tyrosine kinase inhibitors have shown promising therapeutic effects, overcoming resistance with immunotherapy becomes necessary when resistance develops. However, various clinical trials have revealed that their efficacies remain limited. To investigate the tumor microenvironment (TME) factors contributing to poor immune checkpoint blockade responses in ALK-positive patients, we performed single-cell RNA and ATAC sequencing on lung adenocarcinoma (LUAD) tumors with and without ALK rearrangements. Integrative analysis with additional public LUAD cohorts revealed distinct immune landscapes in ALK-positive tumors, marked by enriched innate immunity and depleted adaptive immunity. ALK-positive malignant cells exhibit higher stemness and aggressive phenotype. Tumor-associated macrophages (TAMs) in these tumors predominantly maintain pro-tumoral M2-like states, reinforcing immune suppression. B cells show reduced immune reactivity and impaired tertiary lymphoid structure formation, while CD8+T cells display bystander-like signatures and reduced tumor reactivity. Single-cell chromatin accessibility profiles combined with regulatory network analysis suggest that differences in transcription factor activities, rather than chromatin accessibility, may underlie T cell dysfunction. These findings provide insights into the immunosuppressive TME of ALK-positive LUAD, potentially explaining the failure of recent immunotherapy trials and highlighting targets for improving efficacy.
The Roboscope: Smart and Fast Microscopy for Generic Event-Driven Acquisition
Authors: Bonnet Julia , El-Habouz Youssef , Martin Célia , Guillout Maelle , Ruel Louis , Giroux Baptiste , Demeautis Claire , Mercat Benjamin , Bouchareb Otmane , Pécreaux Jacques , Tramier Marc
Published: September 2024

Automation of fluorescence microscopy is a challenge for capturing rare or transient events in biology and medicine. It relies on smart devices that integrate and interpret the observed data, and react to the targeted biological event. We report on the Roboscope, a novel autonomous microscope combining sequence interruption and deep learning integration, allowing generic event-driven acquisitions. This system distinguishes itself by its adaptability to various experiments, quick capture of dynamic events, and minimal data greediness – training with less than 100 images per class. The Roboscope’s capability is demonstrated in non-synchronized cells by capturing the metaphase, a 20-minute event happening once per day or less. Conversely, double thymidine-block synchronisation, despite occurring during DNA replication, may perturb mitotic-spindle mechanics. The Roboscope’s versatility and efficiency offer significant advancements to tackle the current challenges of cell biology, spreading out advanced microscopy methods to fundamental research as well as high content screening and precision medicine.
Decoding Biomolecular Condensate Dynamics: An Energy Landscape Approach
Authors: Biswas Subhadip , Potoyan Davit A
Published: September 2024

A significant fraction of eukaryotic proteins contain low-complexity sequence elements with unknown functions. Many of these sequences are prone to form biomolecular condensates with unique material and dynamic properties. Mutations in low-complexity regions often result in abnormal phase transitions into pathological solid-like states. Therefore, understanding how the low-complexity sequence patterns encode the material properties of condensates is crucial for uncovering the cellular functions and evolutionary forces behind the emergence of low-complexity regions in proteins. In this work, we employ an alphabet-free energy landscape framework of the stickers and spacers to dissect how the low complexity patterns of proteins encode the material properties of condensates. We find a broad phase diagram of material properties determined by distinct energy landscape features, showing that periodic repeat motifs promote elastic-dominated while random sequences are viscous-dominated properties. We find that a certain degree of sticker periodicity is necessary to maintain the fluidity of condensates, preventing them from forming glassy or solid-like states. Finally, we show that the energy landscape framework captures viscoelastic trends seen in the recent experiments on prion domains and makes predictions for systematic variation of protein condensate viscoelasticity via altering the periodicity and strength of sticker motifs.

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The formation and propagation of human Robertsonian chromosomes
Authors: Gomes de Lima Leonardo , Guarracino Andrea , Koren Sergey , Potapova Tamara , McKinney Sean , Rhie Arang , Solar Steven J , Seidel Chris , Fagen Brandon , Walenz Brian P , Bouffard Gerard G , Brooks Shelise Y , Peterson Michael , Hall Kate , Crawford Juyun , Young Alice C , Pickett Brandon D , Garrison Erik , Phillippy Adam M , Gerton Jennifer L.
Published: September 2024

Robertsonian chromosomes are a type of variant chromosome found commonly in nature. Present in one in 800 humans, these chromosomes can underlie infertility, trisomies, and increased cancer incidence. Recognized cytogenetically for more than a century, their origins have remained mysterious. Recent advances in genomics allowed us to assemble three human Robertsonian chromosomes completely. We identify a common breakpoint and epigenetic changes in centromeres that provide insight into the formation and propagation of common Robertsonian translocations. Further investigation of the assembled genomes of chimpanzee and bonobo highlights the structural features of the human genome that uniquely enable the specific crossover event that creates these chromosomes. Resolving the structure and epigenetic features of human Robertsonian chromosomes at a molecular level paves the way to understanding how chromosomal structural variation occurs more generally, and how chromosomes evolve.
Optical Control of Microtubule Accumulation and Dispersion by Tau-Derived Peptide-Fused Photo-Responsive Protein
Authors: Watari Soei , Inaba Hiroshi , Lv Qianru H , Ichikawa Muneyoshi , Iwasaki Takashi , Wang Bingxun , Tadakuma Hisashi , Kakugo Akira , Matsuura Kazunori
Published: September 2024

Microtubules, a major component of the cytoskeleton consisting of tubulin dimers, are involved in various cellular functions, including forming axons and dendrites of neurons and retaining cell shapes by forming various accumulated superstructures such as bundles and doublets. Moreover, microtubule-accumulated structures like swarming microtubule assemblies are attractive components for dynamic materials, such as active matter and molecular robots. Thus, dynamic control of microtubule superstructures is an important topic. However, implementing stimulus-dependent control of superstructures remains challenging. This challenge can be resolved by developing designer protein approaches. We have previously developed a Tau-derived peptide (TP), which binds to the inner or outer surface of microtubules depending on the timing of the incubation. In this report, we designed the TP-fused photo-switchable protein Dronpa (TP-Dronpa) that reversibly photoconverts between monomeric and tetrameric states to photocontrol microtubule assemblies. The formation of microtubule superstructures, including bundles and doublets, was induced by tetrameric TP-Dronpa, whereas monomeric TP-Dronpa ensured that microtubules remained dispersed. Tetrameric TP-Dronpa also induced motile aster-like structures and swarming movement of microtubules on a kinesin-coated substrate. The formation/dissociation of these microtubule superstructures can be controlled by light irradiation. This system can generate and photocontrol various microtubule superstructures and provides an approach to facilitate the assembly of dynamic materials for various applications.
Bulk and selective autophagy cooperate to remodel a fungal proteome in response to changing nutrient availability
Authors: Telusma Bertina , Farre Jean-Claude , Cui Danica S. , Subramani Suresh , Davis Joseph H.
Published: September 2024

Cells remodel their proteomes in response to changing environments by coordinating changes in protein synthesis and degradation. In yeast, such degradation involves both proteasomal and vacuolar activity, with a mixture of bulk and selective autophagy delivering many of the vacuolar substrates. Although these pathways are known to be generally important for such remodeling, their relative contributions have not been reported on a proteome-wide basis. To assess this, we developed a method to pulse-label the methylotrophic yeastKomagataella phaffii(i.e. Pichia pastoris) with isotopically labeled nutrients, which, when coupled to quantitative proteomics, allowed us to globally monitor protein degradation on a protein-by-protein basis following an environmental perturbation. Using genetic ablations, we found that a targeted combination of bulk and selective autophagy drove the vast majority of the observed proteome remodeling activity, with minimal non-autophagic contributions. Cytosolic proteins and protein complexes, including ribosomes, were degraded via Atg11-independent bulk autophagy, whereas proteins targeted to the peroxisome and mitochondria were primarily degraded in an Atg11-dependent manner. Notably, these degradative pathways were independently regulated by environmental cues. Taken together, our new approach greatly increases the range of known autophagic substrates and highlights the outsized impact of autophagy on proteome remodeling. Moreover, the resulting datasets, which we have packaged in an accessible online database, constitute a rich resource for identifying proteins and pathways involved in fungal proteome remodeling.
Intestinal Epithelial PTPN2 Limits Pathobiont Colonization by Immune-Directed Antimicrobial Responses
Authors: Chatterjee Pritha , Spalinger Marianne R. , Acevedo Charly , Gries Casey M. , Manz Salomon M. , Canale Vinicius , Santos Alina N. , Shawki Ali , Sayoc-Becerra Anica , Lei Hillmin , Crawford Meli’sa S. , Eckmann Lars , Borneman James , McCole Declan F.
Published: September 2024

Background and Aims

Loss of activity of the inflammatory bowel disease (IBD) susceptibility gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), is associated with altered microbiome composition in both human subjects and mice. Further, expansion of the bacterial pathobiont, adherent- invasiveE. coli(AIEC), is strongly linked to IBD pathogenesis. The mechanism by which intestinal epithelial cells (IEC) maintain equilibrium between commensal microbiota and immune cells to restrict invading pathobionts is poorly understood. Here, we investigated the role of IEC-specific PTPN2 in regulating AIEC colonization.

Methods

Tamoxifen-inducible, intestinal epithelial cell-specificPtpn2knockout mice (Ptpn2ΔIEC) and controlPtpn2fl/flmice were infected with either non-invasiveE. coliK12, or fluorescent-taggedmAIEC (mAIECred) for four consecutive days or administered PBS. Subsequently, bacterial colonization in mouse tissues was quantified. mRNA and protein expression were assayed in intestinal epithelial cells (IECs) or whole tissue lysates by PCR and Western blot. Tissue cytokine expression was determined by ELISA. Intestinal barrier function was determined byin vivoadministration of 4 kDa FITC-dextran (FD4) or 70kDa Rhodamine-B dextran (RD70) fluorescent probes. Confocal microscopy was used to determine the localization of tight-junction proteins.

Results

Ptpn2ΔIECmice exhibited increasedmAIECred- but not K12 - bacterial load in the distal colon compared to infectedPtpn2fl/flmice. The higher susceptibility tomAIECredinfection was associated with altered levels of antimicrobial peptide (AMPs). Ileal RNA expression of the alpha-defensin AMPs,Defa5andDefa6, as well as MMP7, was significantly lower inPtpn2ΔIECvs.Ptpn2fl/flmice, aftermAIECredbut not K12 infection. Further, we observed increased tight junction-regulated permeability determined by elevatedin vivoFD4 but not RD70 permeability inPtpn2ΔIEC-K12 mice compared to their respective controls. This effect was further exacerbated inPtpn2ΔIECmAIEC-infected mice. Further,Ptpn2ΔIECmice displayed lower IL-22, IL-6, IL-17A cytokine expression postmAIEC infection compared toPtpn2fl/flcontrols. Recombinant IL-22 reversed the FD4 permeability defect and reduced bacterial burden inPtpn2ΔIECmice postmAIEC challenge.

Conclusion:

Our findings highlight that intestinal epithelial PTPN2 is crucial for mucosal immunity and gut homeostasis by promoting anti-bacterial defense mechanisms involving coordinated epithelial-immune responses to restrict pathobiont colonization.
Impact of residual intimal flap displacement post-TEVAR on TBAD haemodynamics in compliant, patient-specific CFD simulations informed by MRI
Authors: Girardin Louis , Lind Niklas , von Tengg-Kobligk Hendrik , Balabani Stavroula , Díaz-Zuccarini Vanessa
Published: September 2024

We propose a novel formulation of a moving boundary method to account for the motion of the intimal flap (IF) in a TBAD post-thoracic endovascular aortic repair using patient-specific compliant computational fluid dynamics simulations. The simulations were informed by non-invasive 4DMRI sequences. Predicted flow waveforms, aortic wall and IF displacements were validated against in vivo 4DMRI and cine MRI data. The patient-specific simulation showed that at peak systole, the dynamic interplay between high IF displacement and high transmural pressures promoted true lumen compression and false lumen expansion, while luminal patterns were reversed at the deceleration phase. High vorticity and swirling flow patterns were observed throughout the cardiac cycle at the primary entry tear, the descending aorta and proximal to the visceral aortic branches, correlating with high relative residence time, which could indicate an increased localised risk of aortic growth proximal to the IF. A rigid IF simulation revealed significant discrepancies in haemodynamic metrics, highlighting the potential mispredictions when using a rigid wall assumption to assess disease progression. Simulations assuming a more compliant IF highlighted increased risks of visceral branches malperfusion and localised aortic wall degeneration. The study underscores the necessity of patient-specific-compliant IF simulations for accurate TBAD hemodynamic assessments. These insights can improve disease understanding and inform future treatment strategies.
Antibody response toPlasmodium vivaxin the context of Epstein-Barr virus (EBV) co-infection: A 14-year follow-up study in the Amazon rainforest
Authors: Guimarães Luiz F. F. , Rodrigues Bárbara A. , Dias Michelle H. F. , Barcelos Matheus G. , Nascimento Maria F. A. , Moreira-Nascimento Sâmick L. , Afonso Sofia L. , Abreu Barbara G. S. , Middeldorp Jaap. M. , Ntumngia Francis B. , Adams John H. , Fabbri Camila , Lopes Stefanie , Fernandes Cor J. F. , Kano Flora S. , Carvalho Luzia H.
Published: September 2024

Background

To develop an effective vaccine againstPlasmodium vivax, the most widely dispersed human malaria parasite, it is critical to understand how coinfections with other pathogens could impact malaria-specific immune response. A recent conceptual study proposed that Epstein-Barr virus (EBV), a highly prevalent human herpesvirus that establishes lifelong persistent infection, may influenceP. vivaxantibody responses. Here, it was investigated whether EBV could impact the longevity of humoral immune response toP. vivax.

Methodology/principal findings

A 14-year follow-up study was carried out among long-termP. vivax-exposed Amazonian individuals (272, median age 35 years), and included 9 cross-sectional surveys at periods of high and low malaria transmission. The experimental approach focused on monitoring antibodies to the major blood-stageP. vivaxvaccine candidate, the Duffy binding protein region II (DBPII-Sal1), including a novel engineered DBPII-based vaccine targeting conserved epitopes (DEKnull-2). In parallel, the status of EBV infection was determined over time by the detection of circulating EBV DNA (EBV-DNAemia) and EBV-specific antibodies to lytic (VCAp18) or latent (EBNA1) antigens. Regardless of the malaria transmission period, the results demonstrated that one or multiple episodes of EBV-DNAemia did not influence the longevity of DBPII immune responses to both strain-specific (Sal-1) or strain-transcending (DEKnull-2) antibodies. Also, the average time in which DBPII-responders lost their antibodies was unrelated to the EBV serostatus. Considering all malaria cases detected during the study, there was a predominance ofP. vivaxmono-infection (76%), with a positive association between malaria infection and detectable EBV-DNAemia.

Conclusions/significance

In an immunocompetentP. vivax-exposed adult population neither sporadic episodes of EBV-DNAemia nor antibody responses to lytic/latent EBV antigens influence the longevity of both strain-specific and strain-transcending DBPII immune responses. Further studies should investigate the role of acuteP. vivaxinfection in the activation of EBV replication cycle.
Prevalence and Factors Associated with Puerperal Sepsis among Postnatal Women at a Tertiary Referral Hospital in Western Uganda
Authors: Nabawanuka Brenda , Asiimwe Moses , Irumba Pauline , Aryampa Julian , George Wasswa , Muhoozi Michael , Acen Joy , Amumpaire Peterson , Katusabe Shamim , Tusabe Joan , Joshua Epuitai
Published: September 2024

Background

Puerperal sepsis remains one of the leading causes of maternal mortality and morbidity in Uganda.

Aim

This study assessed the prevalence and factors associated with puerperal sepsis among postpartum women at Fort portal Regional Referral Hospital located in western Uganda.

Methods

A cross-sectional design was employed in the study. We conducted a records review of the patient files of 180 postnatal mothers who were admitted at Fort Portal Regional Referral Hospital from 20 February, 2024 to 01 April, 2024. A data abstraction checklist was used to collect data from participant files based on strict inclusion and exclusion criteria. Data was entered in Microsoft Excel and exported to STATA17 for data analysis. Descriptive analysis and logistic regression analysis were performed to determine the prevalence of puerperal sepsis and determinants. Bivariate and multivariate logistic regression analysis was conducted for significant factors presented as Adjusted Odds Ratios (aOR) atp≤0.05.

Results

The median age of participants was 25.5 years (1QR=20-30) and the majority (77%) had primary education. The prevalence of postnatal sepsis was 24%. Duration of hospital stay [aOR=2.30; 95%CI (1.552-3.398);p=<0.001], history of antepartum hemorrhage [aOR=29.09; 95% CI (1.182-716.38);p=0.039] and Anemia [aOR=0.01; 95% CI (0.001-0.218);p=0.004] were identified as factors associated with puerperal sepsis among postnatal women upon multivariate logistic regression.

Conclusion

Puerperal sepsis was common in our setting. This study found that mode of delivery, duration of hospital stay, anemia, and Antepartum hemorrhage, were the determining factors contributing to puerperal sepsis, infection prevention measures during cesarean sections, and reducing the length of hospital stay would prove to be beneficial in the prevention of sepsis.