Citations

Background: It is crucial to evaluate liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). Digital pathology, an automated method for quantitative fibrosis measurement, provides valuable support to pathologists by providing refined continuous metrics and addressing inter-observer variability. Although non-invasive tests (NITs) have been validated as consistent with manual pathology, the relationship between digital pathology and NITs remains unexplored. Methods: This study included 99 biopsy-proven MASLD patients. Quantitative-fibrosis (Q-Fibrosis) used second-harmonic generation/two-photon excitation fluorescence microscopy (SHG/TPEF) to quantify fibrosis parameters (q-FPs). Correlations between eight NITs and q-FPs were analyzed. Results: Using manual pathology as standard, Q-Fibrosis exhibited excellent diagnostic performance in fibrosis stages assessment with area under the receiver operating characteristic curves (AUCs) ranging from 0.924 to 0.967. In addition, magnetic resonance elastography (MRE) achieved the highest diagnostic accuracy (AUC: 0.781–0.977) among the eight NITs. Furthermore, MRE-assessed liver stiffness measurement (MRE-LSM) showed the strongest correlation with q-FPs, particularly adjusted by string length, string width, and the number of short and thick strings within the portal region. Conclusions: Both MRE and digital pathology demonstrated excellent diagnostic accuracy. MRE-LSM was primarily determined by collagen extent, location and pattern, which provide a new perspective for understanding the relationship between the change in MRE and histological fibrosis reverse.

Abstract With the rapid advancements in large language model technology and the emergence of bioinformatics‐specific language models (BioLMs), there is a growing need for a comprehensive analysis of the current landscape, computational characteristics, and diverse applications. This survey aims to address this need by providing a thorough review of BioLMs, focusing on their evolution, classification, and distinguishing features, alongside a detailed examination of training methodologies, datasets, and evaluation frameworks. We explore the wide‐ranging applications of BioLMs in critical areas such as disease diagnosis, drug discovery, and vaccine development, highlighting their impact and transformative potential in bioinformatics. We identify key challenges and limitations inherent in BioLMs, including data privacy and security concerns, interpretability issues, biases in training data and model outputs, and domain adaptation complexities. Finally, we highlight emerging trends and future directions, offering valuable insights to guide researchers and clinicians toward advancing BioLMs for increasingly sophisticated biological and clinical applications.

OBJECTIVE Anterior cervical discectomy and fusion (ACDF) is an established treatment for cervical degenerative disc disease; however, the procedure can cause loss of cervical spine range of motion and potentially accelerate adjacent segment degeneration. Cervical disc arthroplasty (CDA) seeks to preserve native motion of the cervical spine, which can theoretically reduce the incidence of adjacent level degeneration. The literature regarding the relative efficacy of ACDF versus CDA remains inconsistent. In this study, the authors investigate the difference in outcomes between ACDF and CDA and identify factors contributing to the heterogeneity in the literature. METHODS The Ovid, Embase, Scopus, Cochrane, and ClinicalTrials.gov databases were systematically searched from inception to September 5, 2023, for randomized controlled trials (RCTs) comparing ACDF and CDA for degenerative disc disease. Studies were extracted by two authors and verified by a third. Random-effects meta-analysis was performed. The primary outcome was the difference in clinical outcomes between the two surgical groups. The secondary outcomes were the differences in radiological outcomes, surgical characteristics, complication rates, and hospital lengths of stay. The study was registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration no. CRD42023469204) and adhered to the PRISMA guidelines. RESULTS From 584 articles uploaded to the Covidence platform for screening, 35 studies derived from 25 RCTs were included in this systematic review and meta-analysis. A total of 4530 patients were treated with ACDF (2081) and CDA (2449). Forty-six percent of the patients (2063) were male, and the mean age of the study cohort was 45 ± 3 years. In terms of the primary outcome, CDA showed higher rates of neurological and overall success. Regarding the secondary outcomes, CDA demonstrated a significantly lower rate of adjacent level disease, higher rate of heterotopic ossification, and greater range of motion at the operated level. Additionally, CDA had lower rates of reoperation but significantly longer operative times than ACDF. The inclusion of myelopathic patients and variations in follow-up between the surgical groups contributed to the observed effect heterogeneity among studies. CONCLUSIONS In this study, CDA showed comparable or potentially greater success in overall and neurological outcomes, along with a lower incidence of adjacent level degeneration and reoperation rates but longer operative times.

ABSTRACT Levator ani syndrome (LAS) explains up to 7.4% of anorectal pain cases. Classic symptoms include rectal pain or pressure with sitting. We present 2 patients, ages 32 and 25 years, presenting initially with “diarrhea” and perianal hyperhidrosis. History revealed rectal discomfort, tenesmus, urgency, and sensation of incomplete evacuation. Puborectalis tenderness was present on digital rectal examination. Therapies were tailored to each patient, including pelvic floor physical therapy with biofeedback, bowel regulation, rectal diazepam, and ileostomy. These presentations offer insights into potential pathophysiological mechanisms in LAS and highlight the importance of considering LAS in non-pain presentations.

Importance Multiparametric magnetic resonance imaging (MRI), with or without prostate biopsy, has become the standard of care for diagnosing clinically significant prostate cancer. Resource capacity limits widespread adoption. Biparametric MRI, which omits the gadolinium contrast sequence, is a shorter and cheaper alternative offering time-saving capacity gains for health systems globally. Objective To assess whether biparametric MRI is noninferior to multiparametric MRI for diagnosis of clinically significant prostate cancer. Design, Setting, and Participants A prospective, multicenter, within-patient, noninferiority trial of biopsy-naive men from 22 centers (12 countries) with clinical suspicion of prostate cancer (elevated prostate-specific antigen [PSA] level and/or abnormal digital rectal examination findings) from April 2022 to September 2023, with the last follow-up conducted on December 3, 2024. Interventions Participants underwent multiparametric MRI, comprising T2-weighted, diffusion-weighted, and dynamic contrast–enhanced (DCE) sequences. Radiologists reported abbreviated biparametric MRI first (T2-weighted and diffusion-weighted), blinded to the DCE sequence. After unblinding, radiologists reported the full multiparametric MRI. Patients underwent a targeted biopsy with or without systematic biopsy if either biparametric MRI or multiparametric MRI was suggestive of clinically significant prostate cancer. Main outcomes and measures The primary outcome was the proportion of men with clinically significant prostate cancer. Secondary outcomes included the proportion of men with clinically insignificant cancer. The noninferiority margin was 5%. Results Of 555 men recruited, 490 were included for primary outcome analysis. Median age was 65 (IQR, 59-70) years and median PSA level was 5.6 (IQR, 4.4-8.0) ng/mL. The proportion of patients with abnormal digital rectal examination findings was 12.7%. Biparametric MRI was noninferior to multiparametric MRI, detecting clinically significant prostate cancer in 143 of 490 men (29.2%), compared with 145 of 490 men (29.6%) (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points; P = .50). Biparametric MRI detected clinically insignificant cancer in 45 of 490 men (9.2%), compared with 47 of 490 men (9.6%) with the use of multiparametric MRI (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points). Central quality control demonstrated that 99% of scans were of adequate diagnostic quality. Conclusion and relevance In men with suspected prostate cancer, provided image quality is adequate, an abbreviated biparametric MRI scan, with or without targeted biopsy, could become the new standard of care for prostate cancer diagnosis. With approximately 4 million prostate MRIs performed globally annually, adopting biparametric MRI could substantially increase scanner throughput and reduce costs worldwide. Trial registration ClinicalTrials.gov Identifier: NCT04571840

Abstract Background Post-traumatic headache (PTH) is a common acute and persistent symptom following mild traumatic brain injury (mTBI). Symptoms of cutaneous allodynia and presence of nociceptive sensitization might be associated with acute PTH and its persistence. The objectives of this study were to compare allodynia symptoms and cutaneous heat pain thresholds amongst males and females with acute PTH to healthy controls (HC) and determine if pain thresholds and allodynia symptoms are associated with PTH outcomes. Methods This prospective longitudinal study enrolled 139 adults with acute PTH attributed to mTBI as defined by the International Classification of Headache Disorders and 95 HC. All PTH participants completed a baseline research visit near PTH onset and a follow-up visit three to four months later. All PTH participants and a subset of HC completed the Allodynia Symptom Checklist (ASC-12) at each research visit. A different subset of the participants underwent quantitative sensory testing (QST) during baseline, 4-week, and 16-week research visits to quantify cutaneous heat pain thresholds at the forehead and forearms. Data from daily headache diaries were used to determine longitudinal PTH improvement versus non-improvement at three months. ASC-12 score and pain threshold comparisons were made between PTH and HC groups, PTH improved versus non-improved cohorts, and between PTH males and females. Results Participants with PTH had an average age of 42.6 years and 64.0% were female. HC had an average age of 40.0 years and 65.3% were female. At the first visit, PTH participant ASC-12 scores averaged 3.6 versus 0.1 amongst HC, p < 0.001. 44.8% of PTH participants had headache improvement at 3 months. ASC-12 scores were higher in the PTH non-improved versus improved group at baseline (4.0 versus 2.4, p = 0.038) and 3-month follow-up (3.4 versus 1.9, p = 0.012). ASC-12 scores were higher in females than males at baseline (4.7 versus 1.6, p < 0.001) and 3-months (3.9 versus 1.2, p < 0.001). Cutaneous heat pain thresholds at the forehead and forearm did not differ between any group. Conclusions PTH attributed to mTBI is associated with symptoms of cutaneous allodynia. Greater allodynia symptoms are present in females with PTH compared to males and may be associated with PTH non-improvement.

Abstract Background Direct measurement of low-density lipoprotein cholesterol (LDL-C) is widely used and recommended by professional society guidelines despite its potential limitations in patients with hypertriglyceridemia and low LDL-C. This study evaluated the performance of 3 direct LDL-C (LDL-CD) assays, 2 modern LDL-C calculation methods [LDL-C Martin (LDL-CM), LDL-C modified Sampson (LDL-CS)] and the conventional Friedewald (LDL-CF) method against the reference method, beta-quantification (LDL-CBQ). Methods A total of 181 remnant sera from patients with standard lipid panel orders or from patients with LDL-CBQ orders with triglycerides (TG) ≥ 400 mg/dL (4.5 mmol/L), or with TG ≥ 150 mg/dL (1.69 mmol/L) and LDL-C &lt; 70 mg/dL (1.8 mmol/L) were included. LDL-CD and lipid panel data were gathered from Abbott Alinity, Roche Cobas, and Siemens Atellica platforms. Results LDL-CD among the 3 platforms showed a median CV of 11.2%. In patients with TG &lt;400 mg/dL, LDL-CM and LDL-CS demonstrated less bias and less misclassification at the clinical decision LDL-C levels than LDL-CF or LDL-CD. In the 400 to 800 mg/dL (9.0 mmol/L) TG group, LDL-CS was superior to LDL-CD or LDL-CM in accuracy. When TG is ≥ 800 mg/dL, LDL-CD (Roche) showed substantial bias from LDL-CBQ while LDL-CS (Roche) showed smaller but significant bias. Conclusions In summary, LDL-CD or LDL-CF showed little advantage over the 2 modern LDL-C calculation methods. LDL-CS showed the best overall correlation with LDL-CBQ and therefore is recommended to replace LDL-CF and potentially LDL-CD when making clinical decisions in patients with low LDL-C and hypertriglyceridemia.

Objectives Cervical spine (c-spine) X-ray (XR) remains an important tool for pediatric trauma patients. XR is a low radiation alternative to multidetector CT (MDCT). Our primary aims were to analyze the sensitivity of a negative c-spine XR and to analyze what factors lead to additional imaging after a negative c-spine XR. Methods A retrospective cohort study was conducted at a level 1 pediatric trauma center from 2012 to 2021. We compared the group with negative c-spine XR and no additional imaging to the group with negative c-spine XR followed by additional c-spine MDCT and/or MRI. Results There were 2,081 negative XRs and 1,974 (95%) had their c-spines cleared without additional imaging. No patient required an operation for a clinically significant c-spine injury in this group, and we consider this no missed injuries. The remaining 108 patients had additional c-spine imaging after negative c-spine XR for c-spine clearance (24 MDCT, 76 MRI, 8 MDCT and MRI). Indications for additional c-spine imaging were pain (48.1%), Glasgow Coma Scale (GCS) score ≤14 (43.5%), and paresthesia (8.3%). Patients who received additional imaging were more likely to have a GCS score ≤12 (25.4% vs 4.1%), Injury Severity Score >15 (21.9% vs 8.1%), Level 1 Trauma activation (21% vs 5%), Abbreviated Injury Scale head score of 4 or 5 (29% vs 5%), be intubated (30% vs 2%), and have non-accidental trauma as their mechanism of injury (20% vs 1%) (p value<0.0001, for all). Five patients who received additional imaging were treated with a cervical collar, but no operative intervention. Conclusions In this cohort, screening XR had a sensitivity of 100% for clinically significant c-spine injuries. GCS was the most significant predictor of obtaining additional imaging. A negative XR combined with a normal physical examination in an evaluable pediatric patient is a safe way of clearing the c-spine. Level of evidence Study contains level III evidence.

Abstract Extracellular vesicles (EV) are phospholipid‐encapsulated nanoparticles secreted by cells into their surrounding environment. EVs can transfer a variety of biomolecules that mediate intercellular communication and play a key role in physiological and pathological processes. Therefore, EVs are emerging as new biomarkers for diseases, therapeutic targets, and drug delivery vehicles. The isolation and detection of EVs requires time‐consuming and labor‐intensive processes, first to extract EVs from biological and physiological fluids and then to detect EV‐associated molecules with high sensitivity. The methodologies and instruments commonly used for EV analysis are not widely accessible outside of dedicated research laboratories, creating practical barriers for the study of EV‐associated molecules in biology research and clinical applications. To bridge this gap, we developed a proof‐of‐concept digital microfluidic device that can automatedly extract EVs from 20 µL of culture and human plasma samples within 25 min and detect EV‐bound proteins (e.g PD‐L1) on‐chip using an electrochemical sensor. This work serves as a framework for the development of streamlined EV analysis in both research and diagnostics.

Background: Cholestatic liver diseases, including primary sclerosing cholangitis, are characterized by biliary fibroinflammation. TGFβ-activated cholangiocytes release signals that recruit immune cells and activate myofibroblasts, promoting inflammation and extracellular matrix (ECM) deposition. TGFβ also regulates stearoyl-CoA desaturase (SCD), an enzyme involved in lipid signaling. Yet, the role of SCD or its inhibitor, Aramchol, in biliary fibroinflammation had not been studied. Methods and Results: Mdr2 -/- with established biliary fibrosis and 3,5-diethoxycarboncyl-1,4-dihydrocollidine (DDC) diet-fed mice were treated with Aramchol meglumine (12.5 mg/kg/day). Hepatic fibrosis was assessed by qPCR, Picrosirius red staining, immunofluorescence, and hydroxyproline content. Human H69 or murine large cholangiocyte cell lines stimulated with TGFβ, as well as PSC-derived cholangiocytes (PSC-C), were treated with Aramchol or SCD siRNA. RNA-seq, fibroinflammatory marker expression, peroxisome proliferator-activated receptor (PPAR) activity, and targeted fatty acid profiling were performed. Aramchol treatment significantly reduced hepatic ECM gene expression, inflammatory cytokines ( Il6 , Tnfa ), collagen content, and myofibroblast activation (aSMA staining) in both mouse models. In TGFβ-stimulated H69 cells, Aramchol suppressed hepatic fibrosis pathways and enhanced PPAR signaling. Aramchol also reduced the expression of fibrotic markers, myofibroblast-activating mediators ( VEGFA and PDGFB ), and IL6, mirroring the effects of SCD knockdown. In PSC-C, Aramchol significantly downregulated SCD, VEGFA and IL6 . Conversely, PPARα and -γ activity and fatty acid agonist, linoleic acid levels were increased in cholangiocyte cell lines. Conclusions: Aramchol attenuates and prevents biliary fibrosis in mouse models of cholestatic liver disease by inhibiting TGFβ-induced fibroinflammatory mediators and activating PPARa/γ in cholangiocytes. These findings, combined with its favorable clinical safety profile, support the potential of Aramchol as a therapeutic candidate for PSC.