Faculty Bibliography

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.

Microangiopathy is a major complication of SARS-CoV-2 infection and contributes to the acute and chronic complications of the disease¹. Endotheliopathy and dysregulated blood coagulation are prominent in COVID-19 and are considered to be major causes of microvascular obstruction^1,2. Here we demonstrate extensive endothelial cell (EC) death in the microvasculature of COVID-19 organs. Notably, EC death was not associated with fibrin formation or platelet deposition, but was linked to microvascular red blood cell (RBC) haemolysis. Importantly, this RBC microangiopathy was associated with ischaemia-reperfusion injury, and was prominent in the microvasculature of humans with myocardial infarction, gut ischaemia, stroke, and septic and cardiogenic shock. Mechanistically, ischaemia induced MLKL-dependent EC necroptosis and complement-dependent RBC haemolysis. Deposition of haemolysed RBC membranes at sites of EC death resulted in the development of a previously unrecognized haemostatic mechanism preventing microvascular bleeding. Exaggeration of this haemolytic response promoted RBC aggregation and microvascular obstruction. Genetic deletion of Mlkl from ECs decreased RBC haemolysis, microvascular obstruction and reduced ischaemic organ injury. Our studies demonstrate the existence of a RBC haemostatic mechanism induced by dying ECs, functioning independently of platelets and fibrin. Therapeutic targeting of this haemolytic process may reduce microvascular obstruction in COVID-19, and other major human diseases associated with organ ischaemia.

BACKGROUND: While prior studies have recommended immediate flap coverage within 72 hours of injury for soft tissue reconstruction for traumatic extremity injuries, recent evidence in the setting of advanced wound care techniques de-emphasizes the need for immediate coverage. Negative-pressure wound therapy (NPWT) has been an essential tool for extending the time to definitive soft tissue coverage. This study sought to elucidate the impact of preoperative NPWT use on the success of microsurgical reconstruction. METHODS: A literature search was conducted using the following databases from their inception up to February 2023: PubMed, OVID databases (Embase and Cochrane Library), Web of Science, and Scopus. Of 801 identified articles, 648 were assessed and 24 were included. Cases were divided based on whether NPWT was used preoperatively or not. Timing to definitive coverage, injury details, and basic demographics were recorded. Rates of flap failure, infection, bone nonunion, reoperation, and complications were compared between groups. RESULTS: A total of 1,027 patients and 1,047 flaps were included, of which 894 (85.39%) received preflap NPWT. The average time to definitive coverage for the NPWT and non-NPWT groups was 16 and 18 days, respectively. The NPWT group experienced lower postoperative complication rates than the non-NPWT group in all reported complications except for deep infections. Compared with the non-NPWT group, the NPWT group experienced lower rates of any flap failure (3.69 vs. 9.80%) and partial flap failure (2.24 vs. 6.54%). CONCLUSION/CONCLUSIONS: Preoperative NPWT was associated with reduced postoperative complications, most importantly flap failure rates. This merits further investigation into the decision-making process for traumatic extremity reconstruction. Future prospective studies adopting standardized protocols with longer follow-up are required to better understand the potentially beneficial role of preoperative NPWT use in soft tissue reconstruction.

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.

The objective of this prospective, longitudinal cohort study was to evaluate the pilot effects of a 24-month exercise and nutrition intervention, called the Lifestyle Intervention for Fibroid Elimination Program (LIFE), at NYU Langone Health's Center for Fibroid Care. Specifically, we evaluate the impact on quality of life (QOL), symptom severity (SS), and clinical lab markers in 22 fibroid patients. Patients who underwent a procedure within 3 months of the start of the LIFE Program and completed up to 12 months of the program were included in this study. Participants were excluded if currently pregnant, postmenopausal, or had dietary restrictions or physical constraints that prevented them from participating fully in the intervention. This intervention required participants to follow a prescribed nutrition and exercise regimen for up to 12 months and attend at least 2 office visits with a physician. Participants also completed two quality of life questionnaires and regular ultrasound imaging. The demographic breakdown of our study cohort was 63.6% Black and 18.2% Hispanic/LatinX. A clinically meaningful improvement in QOL and symptom severity was found within the first year of the LIFE program. The QOL sub-scale scores that showed the greatest improvement were concern and energy/mood. Vitamin D lab values also showed a clinically meaningful improvement. The LIFE Program was associated with a reduction in symptom burden and an improvement in quality of life up to 12 months after a procedural fibroid intervention, yielding insight into how a lifestyle intervention may be an effective adjunct in improving patient quality of life.

Chemotherapy-induced alopecia and radiation-induced alopecia, the thinning or loss of hair due to cytotoxic chemotherapy and radiation therapy, respectively, are distressing adverse effects of cancer treatment. Chemotherapy, targeted therapies, and radiation therapy used in pediatric oncology often lead to alopecia by damaging hair follicles, with varying degrees of severity depending on the specific treatment type, mechanism of action, and damage-response pathway involved. Pediatric chemotherapy-induced alopecia, radiation-induced alopecia, and permanent alopecia, defined as hair regrowth that remains incomplete 6 months or more after treatment, have significant negative impacts on mental health, self-esteem, and social interactions, highlighting the need for further research into supportive care strategies. There are currently no standard interventions for chemotherapy-induced alopecia or radiation-induced alopecia in children, with most recommendations limited to gentle hair care and camouflaging techniques during treatment. Scalp cooling has demonstrated safety and efficacy in reducing chemotherapy-induced alopecia in adults and is currently under investigation in children and adolescents. Topical and low-dose oral minoxidil have been studied in children for other hair loss disorders and may improve hair regrowth after chemotherapy or radiation. Increased awareness and continued research into management strategies for pediatric chemotherapy-induced alopecia and radiation-induced alopecia are necessary to help mitigate its significant negative impact on quality of life.

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.