Faculty Bibliography

BACKGROUND AND AIMS/OBJECTIVE:Liver biopsy is the gold standard for assessing fibrosis in cirrhotic livers, yet cirrhosis is spatially heterogeneous and continuously remodels. This study evaluates a novel phenotypic digital pathology platform for continuous fibrosis severity quantification and sensitivity to sampling variability. APPROACH AND RESULTS/RESULTS:Five needle biopsies were collected from 20 HCV-cirrhotic livers during transplantation. Histological staging used the Laennec (4A-4C) and Beijing (progressive, regressive, indeterminate) systems. Collagen proportionate area (CPA) was measured via computerised morphometry. The FibroNest platform analysed high-resolution, single-fibre images to extract 336 parameters, generating a continuous fibrosis severity score (Ph-FCS) and tailored scores for Laennec (Ph-FCS(L)) and Beijing (Ph-FCS(B)) systems. A comparative MASLD cohort (n = 73, NASH-CRN stages) was also included. The range of the Ph-FCS was broader to cover the cirrhosis spectrum (6.44 units) than from F0 to F3 (5.39 units). Ph-FCS was less affected by biopsy variability (16.7% ± 1.3%) compared to CPA (47.3% ± 4.5%). Ph-FCS(L) and Ph-FCS(B) demonstrated moderate concordance with the Laennec and Beijing stages. Their ability to classify patients into Laennec and Beijing stages was limited (0.610 < AUROCS < 0.789). At best, Ph-FCS(L) and Ph-FCS(B) distinguished stages 4A from 4C and P from R with AUROCs of 0.747(95% CI: 0.611-0.879) and 0.798 (95% CI: 0.645-0.929). CONCLUSIONS:Phenotypic digital pathology biomarkers provide robust, continuous measures of fibrosis severity and activity. They enhance traditional staging systems by offering improved resolution and reduced sensitivity to biopsy variability, with potential value in cirrhosis sub-staging and clinical decision-making.

BACKGROUND/UNASSIGNED:This study investigates the association between intra-operative balance and 2-year outcomes within subgroups defined by demographics and pre-operative joint balance. Our hypothesis is that patient demographics and the pre-operative state of the joint will impact patient sensitivity to post-operative balance and laxity and subsequent impact on outcome. METHODS/UNASSIGNED:A retrospective analysis of prospectively captured data across 5 sites with 5 surgeons was performed. All cases completed pre-operative demographics surveys, 2-year post-operative Knee Injury and Osteoarthritis Outcome Score (KOOS) and had a robot assisted total knee arthroplasty with an integrated digital joint balancing tool. Differences in associations between intra-operative final joint balance and 2-year KOOS pain outcomes in demographic and pre-operative balance subgroups were characterized. Associations informed clinically relevant thresholds to optimize TKA treatment for subgroups. RESULTS/UNASSIGNED:A total of 276 patients completed 2-year KOOS scores. Subgroups were defined from Sex, Age, BMI and pre-operative extension laxity. Men prefer a tight tolerance medially in extension and mid-flexion while females prefer a tight lateral flexion gap. Patients <70 years show a strong preference for equal rectangular gaps in extension, mid-flexion, and flexion, while older patients do not show a preference. Patients with BMI ≤30 demonstrate a preference for rectangular gaps, while patients with higher BMI do not. Finally, patients with looser pre-operative extension laxity (>3 mm) preferred a TKA with increased extension laxity compared to patients with minimal preoperative laxity. CONCLUSION/UNASSIGNED:Intraoperative differences in knee balance can influence patient outcome scores among different demographic groups at two years postoperatively. This suggests further research is warranted to determine how ligament balance and laxity may be optimized based on individual patient factors.

BACKGROUND:High fasting plasma glucose (HFPG) plays an important role in the progression of breast cancer. This study aims to assess the global time trends of female breast cancer attributable to HFPG from 1990 to 2021 and projections to 2046. METHODS:This study obtained the number and age-standardised rate of deaths and disability-adjusted life years (DALYs) of female breast cancer burden attributable to HFPG by age, region, country, and socio-demographic index (SDI) from 1990 to 2021. Average Annual Percentage Change (AAPC) was analysed to assess time trends in female breast cancer burden attributable to HFPG. The age-period-cohort model was used to project the global burden by 2046. RESULTS:In 2021, 4.62% of female breast cancer deaths (30,000) and 4.04% of DALYs (820,000) globally were attributed to HFPG. Compared with 1990, the age-standardised mortality rate (ASMR) and age-standardised DALY rate (ASDR) increased, with AAPCs of 0.76 (95% CI: 0.71, 0.89) and 0.86 (95% CI: 0.84, 0.98), respectively. The burden of breast cancer attributable to HFPG was higher in the elderly and low SDI regions. Additionally, the burden of female breast cancer attributable to HFPG is projected to continue to increase through 2046. CONCLUSIONS:The burden of female breast cancer attributable to HFPG has increased over the past three decades and will continue to increase over the next 25 years. Therefore, it is important to control blood sugar to reduce the burden of breast cancer.

This work is an in-depth investigation of the in vitro and in vivo biocompatibility of processed and treated residual human hair samples with intact cuticle layers. The specimens included oxidized hair with minimal melanin (BLH) and hair with medium- (M-KAP) and low- (L-KAP) amounts of keratin associated proteins (KAPs), confirmed through gel electrophoresis, electron microscopy, trichrome histological staining, and tensile biomechanics, in comparison to the untreated regular hair (REG) control. All hair groups, high KAPs (H-KAPs: REG and BLH), M-KAP, and L-KAP, are non-cytotoxic in the adipose fibroblast's response to their extracts based on the ISO 10993-5 medical device biomaterial testing standard. In vivo mouse subcutaneous implantation (ISO 10993-6, local effects) at 2 weeks showed a foreign body response (FBR) with thin fibrous encapsulation at 28% relative skin dermis thickness; but the L-KAP implant mitigated a significant decrease in FBR area compared to H-KAPs and a lower number of immune cells of mostly macrophages and mast cells on the biomaterial's surface. In the bulk of the capsules, blood vessels and collagen extracellular matrix densities were similar among groups. These findings suggest that small globular KAPs diffuse out of the cortex to the host-biomaterial interface which induce a slightly-elevated FBR but limited to the implant's surface vicinity. For translatability, we evaluated the effectiveness of the residual hair with the most depleted KAPs (L-KAP) in a 10 mm-diameter, splinted, and full-thickness mouse skin excision wound. Treatment with the L-KAP mesh exhibited an 8% healing improvement per day compared to the untreated control: significantly reducing the projected complete healing time by 30%. On-going research focuses on purer keratin-based and macromolecularly organized residual hair biomaterials for drug-delivery as they are deemed the most biocompatible.

BACKGROUND:Plinabulin exerts immunomodulatory activity through guanine nucleotide exchange factor (GEF)-H1 release from depolymerizing tubulin in the cytoskeleton, leading to dendritic cell (DC) activation. Preclinical studies demonstrated that irradiation potentiates plinabulin-induced DC maturation and, when combined with immune checkpoint inhibitors (ICIs), triggers an abscopal antitumor response via increased tumor-infiltrating DCs and T cells. METHODS:A phase 1 translational study (NCT04902040) of plinabulin plus ICIs after radiation therapy (RT) initiation was conducted in ICI-relapsed/refractory cancers with primary (safety, tolerability, and objective tumor response rate) and secondary (disease control rate [DCR]) endpoints. FINDINGS/RESULTS:This triple regimen was safe and achieved a DCR of 54% (3/13 partial response [PR] and 4/13 stable disease [SD]) in mostly heavily pretreated patients. Responding tumors included non-small cell lung cancer (2/2 PR + SD), head-and-neck squamous cell carcinoma (2/3 PR + SD), and Hodgkin's lymphoma (2/2 PR in patients after 12 or 16 prior lines of therapy). PR + SD patients had significantly higher GEF-H1 immune-activation scores in peripheral blood and intratumorally at pretreatment/baseline and DC activation/T cell clonal expansion post-treatment compared with progressive disease patients. CONCLUSIONS:These preliminary results provide a rationale for testing RT/plinabulin/ICI combination in future post-ICI-failure confirmatory trials. FUNDING/BACKGROUND:This study was funded by BeyondSpring Pharmaceuticals, Inc.

Platelet transfusions are a cornerstone of hemorrhage management in patients with thrombocytopenia or platelet dysfunction, yet their indications and dosing are largely based on expert opinion and low-quality evidence. This review offers a timely and comprehensive analysis of platelet transfusion practices in the United States (U.S.), uniquely integrating clinical evidence, such as the pivotal PLADO trial, with emerging technological advancements. Using a holistic approach, this manuscript addresses not only conventional practices (such as dosing standards and storage methods), but also cutting-edge alternatives like cold-stored and freeze-dried platelets, pathogen reduction technologies, and synthetic platelet substitutes. By juxtaposing U.S. practices with international standards, it highlights inefficiencies in dosing and supply management, proposing actionable solutions like lower-dose transfusions and diversified platelet inventories. Furthermore, the manuscript's exploration of whole blood-derived platelets and the ethical debate surrounding paid donors adds a forward-looking perspective. By examining these innovations alongside strategies to optimize supply, this work aims to provide a comprehensive overview of how transfusion medicine is adapting to meet clinical and logistical demands.

BACKGROUND:Temporary epicardial pacing wires (TEPWs) are commonly used for postoperative arrhythmia management in cardiac surgery. Although generally safe, they can cause rare complications, including migration years after placement. CASE SUMMARY/METHODS:A 59-year-old man with a history of cardiac arrest and acute myocardial infarction requiring urgent coronary artery bypass grafting 2 years prior presented with new-onset dysphagia and odynophagia. Full workup and imaging revealed a migrated TEPW embedded in the right external carotid artery. The wire was successfully removed using advanced endovascular techniques, providing immediate symptom relief. DISCUSSION/CONCLUSIONS:This rare case of a retained TEPW highlights the importance of "thinking outside the box." Combinatorial analysis, which combines medical knowledge with comprehensive data from numerous simple observations, tests, and procedures, guided us to the optimal treatment for our patient. TAKE-HOME MESSAGE/CONCLUSIONS:Clinicians should maintain vigilance for delayed TEPW complications and consider alternatives that reduce long-term risks associated with retained wires.

BACKGROUND:Acute appendicitis is the most common abdominal surgical emergency worldwide. Researchers from various countries have evaluated the impact of the COVID-19 pandemic on its diagnosis and treatment, as well as a possible change in its management, such as outpatient treatment. The objective of this study was to describe the characteristics of acute appendicitis treated during the COVID-19 State of Emergency (SOE) and to assess whether it could be included in an ambulatory surgery program. METHODS:Retrospective observational study involving patients treated at public hospitals for appendix diseases (K35-K38). We collected sociodemographic and clinical data. The influence of the lockdown on each variable was evaluated with a multivariate analysis. RESULTS:201 patients were included. The SOE period group comprised 78 patients, and the pre-SOE period (control) included 123 patients who met the same inclusion criteria. The risk of complicated acute appendicitis increased by 1.015 times with age (p = 0.000). The longer surgery time was associated with a 7.265 times higher risk of postsurgical complications (p = 0.000). No differences were observed with respect to drain placement (p = 0.281), although the percentage was higher in 2020 (13.9% vs 19.7%). The length of hospital stay decreased significantly during the lockdown (p = 0.017). CONCLUSION/CONCLUSIONS:The lockdown did not influence the outcome of complicated acute appendicitis from the standpoint of morbidity and mortality, reducing the hospital stay, facilitating the path towards outpatient treatment.