Faculty Bibliography

BACKGROUND:Anterior cruciate ligament (ACL) rupture frequently occurs alongside meniscal injury, together altering the intra-articular environment. While ACL injury triggers an inflammatory cascade within synovial fluid, meniscal injury may intensify these responses, contributing to joint degeneration. However, little is known about how combined ACL and meniscal injuries shape the synovial inflammatory milieu or whether these profiles influence long-term outcomes. PURPOSE/HYPOTHESIS/OBJECTIVE:The purpose was to characterize synovial fluid inflammatory phenotypes at the time of ACL reconstruction with concomitant meniscal injury and assess their association with patient-reported outcome measures (PROMs) and clinically meaningful improvement. It was hypothesized that (1) distinct inflammatory phenotypes would exist, (2) these phenotypes would correlate with symptom severity and recovery, and (3) individual biomarkers' effects on outcomes would vary by phenotype. STUDY DESIGN/METHODS:Cohort study; Level of evidence, 3. METHODS:-means clustering identified high- and low-inflammation phenotypes. PROMs were collected preoperatively on the day of surgery (baseline) and at long-term follow-up. Linear regression assessed biomarker associations with PROMs, with interaction models evaluating effect modification by inflammation phenotype. Minimal clinically important difference (MCID) achievement thresholds were calculated using a distribution-based approach (0.5 × baseline SD) and compared between clusters. RESULTS:< .05). CONCLUSION/CONCLUSIONS:Synovial fluid biomarker profiles at the time of ACL reconstruction with concomitant meniscal injury identified distinct inflammatory phenotypes associated with baseline symptom severity and differential patterns of clinical improvement. Although long-term PROMs were similar between groups, phenotype-dependent biomarker associations, particularly involving MCP-1, suggest that the biological context of recovery differs across inflammatory profiles.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are common conditions among patients with cirrhosis whose development is associated with increased morbidity and mortality. Recurrent episodes of AKI within this population can ultimately lead to CKD, while patients with underlying CKD are in turn more likely to experience AKI. Determining the etiology of kidney dysfunction in the setting of cirrhosis is often challenging given the considerable limitations of currently available diagnostic tools. Ongoing research into the role of novel serum and urine biomarkers may allow for more timely diagnosis and treatment of kidney injury among patients with cirrhosis. This review provides an overview of kidney dysfunction in cirrhosis with a focus on the role of these emerging biomarkers for diagnosis of AKI and CKD.

BACKGROUND/UNASSIGNED:We conducted a head-to-head study comparing outcomes among commonly used implant brands, Allergan, Mentor, and Sientra, used in breast reconstruction. METHODS/UNASSIGNED:A multicenter retrospective review of patients undergoing acellular dermal matrix-assisted implant-based breast reconstruction (IBR) with Allergan, Mentor, or Sientra implants between January 2014 and July 2022 was conducted. Primary outcomes included rates of return to the operating room for implant removal. Secondary outcomes included complications occurring within 30 days, between 31 and 60 days, and after 60 days. RESULTS/UNASSIGNED:. One hundred ninety-nine (17.2%) breasts underwent adjuvant radiation and 168 (14.5%) underwent neoadjuvant chemotherapy. Implants were most often inserted in the prepectoral plane (n = 584, 50.6%). After 60 days, there were no significant differences in overall complication rates between brands. One hundred sixty-one (13.9%) breasts underwent eventual reoperation, including unplanned explantation (n = 95, 8.2%), elective revision (n = 94, 8.1%), oncological indications (n = 20, 1.7%), and infection (n = 15, 1.3%). Indications for unplanned explantation included infection (n = 26, 2.3%), capsular contracture (n = 15, 1.3%), and nonhealing wounds (n = 14, 1.2%). There were no differences in other complications or reoperations between cohorts. Body mass index, diabetes mellitus, smoking history, chemotherapy, radiation, skin-sparing mastectomy, type of incision, and tissue expander use were independent predictors of postoperative complications. CONCLUSIONS/UNASSIGNED:Low rates of complications among Allergan, Mentor, and Sientra implants in IBR support their continued use. No single brand was superior to others regarding complication profile in our study. Patient characteristics and operative approach seem more predictive of postoperative outcomes than the implant brand alone.

BACKGROUND/UNASSIGNED:Alterations in microtubule dynamics have been shown to affect cardiomyocyte membrane stiffness and modulate ion channels, including the cardiac sodium channel. While conditions, such as heart failure and Duchenne muscular dystrophy, are associated with increased detyrosination of microtubules and reduced sodium current, a potential role for microtubule detyrosination in arrhythmogenic cardiomyopathy has not been explored. We here investigated the impact of microtubule detyrosination on membrane stiffness, cardiac sodium channel distribution, and function in mouse and human models of arrhythmogenic cardiomyopathy. METHODS/UNASSIGNED:-c.2013delC, and isogenic control human-induced pluripotent stem cell-derived-cardiomyocytes were incubated for 2 to 4 hours with compounds known to decrease microtubule detyrosination (parthenolide, 10 µmol/L; EpoY, 20 µmol/L) or vehicle (dimethyl sulfoxide). Immunocytochemistry, mechano-scanning ion conductance microscopy, patch-clamp analysis, and stochastic optical reconstruction microscopy were performed. RESULTS/UNASSIGNED:-c.2013delC human-induced pluripotent stem cell-derived-cardiomyocytes displayed increased microtubule detyrosination and reduced sodium current compared with isogenic control human-induced pluripotent stem cell-derived-cardiomyocytes, which were both prevented by parthenolide and EpoY. CONCLUSIONS/UNASSIGNED:Increased microtubule detyrosination secondary to loss of PKP2 impacts cardiomyocyte (dys)function beyond the desmosome, contributing to both electrical and mechanical alterations in the setting of arrhythmogenic cardiomyopathy. Our findings identify microtubule detyrosination as a novel therapeutic target in pathophysiological conditions, such as arrhythmogenic cardiomyopathy, aimed at improving both contractile and electrical function.

The upper extremity is a structure of incredible complexity able to perform unique tasks that span from the most delicate and intricate to highly strenuous and forceful. Fully functional and aesthetic replacement of the upper extremity after loss remains a medical and technological aspiration. Meaningful advancements continue to be made in all areas of upper extremity limb loss, specifically in traditional surgical reconstruction and prosthetics. This has generated a new field of treatment that is most accurately titled Bionic Reconstruction. Essentially, successful bionic reconstruction allows for the human body to effectively communicate and work in concert with the man-made technology.

OBJECTIVE/UNASSIGNED:To evaluate the safety of alopecia treatments during pregnancy, in-vitro fertilization (IVF), and polycystic ovary syndrome (PCOS) workup, with a focus on potential maternal and fetal risks. DATA SOURCES/UNASSIGNED:A comprehensive literature search was conducted across PubMed, Web of Science, and Scopus from November 2024 to December 2024. Search terms included medication names in combination with "pregnancy," "IVF," "in-vitro fertilization," and "PCOS." STUDY SELECTION/UNASSIGNED:Peer-reviewed studies addressing the use of therapies for androgenetic alopecia, alopecia areata, and scarring alopecias in the contexts of pregnancy, IVF, and PCOS were included. Articles evaluating maternal safety, fetal risks, and treatment timing were prioritized. Only English-language publications were reviewed. RESULTS/UNASSIGNED:Despite increasing therapeutic options for alopecia, significant knowledge gaps remain regarding their safety during pregnancy. Pregnant women are often excluded from clinical trials, leading to a reliance on older treatments with limited data on dosing or pharmacokinetics in the pregnant population. Unfortunately, there are few alopecia medications with robust safety data in pregnancy, and many medications are contraindicated during this period. Some medications may be used with caution, while others require additional investigation. During IVF, there are alopecia medications with potential benefit in women experiencing implantation failure or PCOS. For patients undergoing PCOS workup, some alopecia medications may impact hormonal labs or mask PCOS symptoms. CONCLUSION/UNASSIGNED:There is a critical need for more targeted research on alopecia treatments in pregnancy, IVF, and PCOS contexts. This review provides current evidence to guide clinicians and support informed, individualized treatment decisions during this vulnerable period.

PURPOSE/OBJECTIVE:The dependence of the long-time (tortuosity) limit of the extra-cellular diffusivity on the intra-cellular volume fraction is of fundamental importance for microstructure modeling. While such dependencies have been explored for the white matter, the tortuosity limit in gray matter is unknown due to complex cell composition and geometry. Here we rationalize and validate numerically the analytical relation between the extra-cellular diffusivity and intra-cellular fractions of cell bodies (somas) and neurites. METHODS:The tortuosity relation for extra-cellular diffusivity qualitatively follows from effective medium theory, coarse-grained by diffusion outside somas (spheres) and neurites (cylinders), respectively. This problem is equivalent to finding the overall conductivity in a medium of grains in a matrix, with methodology dating back to the 19th century. We extend the effective medium methodology to populations of impermeable spheres and randomly oriented cylinders with various volume fractions, yielding closed-form expressions corroborated by Monte Carlo simulations. RESULTS:We establish the power-law scaling of the extra-cellular diffusivity with the volume fractions of the extra-soma and extra-neurite spaces. We further evaluate the proposed framework using simulations in realistic tissue geometries, and by applying it to in vivo MRI data. CONCLUSION/CONCLUSIONS:Theory and simulations relate extra-cellular tortuosity to soma and neurite fractions, thereby offering a diffusion MRI protocol design optimized for in vivo assessment of soma size and soma/neurite fractions within clinical scan times. Such in vivo measurements can be used to study development, aging, and neurodegenerative disorders.

PURPOSE: Cardiovascular (CV) toxicity is prevalent in cancer survivors due to shared risk factors, direct CV injury from cancer therapy (CT), and development/exacerbation of CV risk factors during treatment. Succinct guidance on the minimum standard of CV care required of cancer care providers (CCPs) can improve outcomes for survivors. This clinical practice statement (CPS) is aimed at CCPs focused on identification, prevention, and management of CVD in individuals with cancer. METHODS: The International Cardio-Oncology Society and Multinational Association of Supportive Care in Cancer identified members with expertise across oncology, cardiology, and cancer survivorship. Key questions/areas of practice recommendations related to CV risk and CVD were identified across the cancer trajectory.Working groups performed targeted literature reviews and consensus was reached for all recommendations. RESULTS: 5 over-arching clinical practice recommendations for CCPs were identified: (1) perform a CV risk assessment prior to starting CT (2) identify and facilitate CV-related care during CT; (3) ensure measures are taken to mitigate the risk of cancer therapy related CV toxicity (CTR-CVT) prior to and during CT; (4) monitor CV status and risk factors during therapy and refer to the appropriate health care provider if CV risk factors are uncontrolled or new signs/symptoms develop; and (5) re-assess CV risk following completion of CT (periodically for those with advanced disease on life long treatment) and develop a CV surveillance plan. CONCLUSIONS: CCPs play a pivotal role in identifying and addressing CTR-CVT. This CPS provides specific, succinct, and actionable behaviours that can be readily implemented in cancer care globally.

BACKGROUND:AQST-109 is an investigational epinephrine prodrug sublingual film for anaphylaxis treatment, with well-characterized pharmacokinetics (PK) and pharmacodynamics (PD) in healthy adults. It is unclear how oral symptoms during allergic reactions may affect absorption and these parameters. OBJECTIVE:To compare AQST-109's PK and PD in adults with oral allergy syndrome (OAS) undergoing oral allergen challenge (OAC) to elicit symptoms METHODS: This was a phase 2, two-part, open-label, randomized, fixed-sequence, stratified, crossover study to evaluate the PK and PD of single (12mg) and repeat doses (12mg × 2) of AQST-109 in adults with screening-confirmed OAS administered with and without OAC, to single (0.3mg) and repeat doses (0.3mg × 2) of manual IM epinephrine injection (IM-EPI) given without OAC. Geometric means for PK and PD parameters were analyzed for PK, PD, and safety subsets. RESULTS:During screening OAC, 94.4% of n=36 subjects experienced moderate or severe oral symptoms. Pharmacodynamics were not impacted by OAC following single- and repeat-dose of AQST-109 vs without OAC. AQST-109 PK values were similar with or without OAC. Single and repeat-dosing PD parameters were higher with AQST-109 after OAC vs IM-EPI without OAC, and were non-significantly higher for AQST-109 with vs without OAC. Almost all participants experienced a related mild treatment-emergent adverse event, with four considered moderate in severity, and no new safety signals identified compared to prior studies. CONCLUSION/CONCLUSIONS:AQST-109 PK and PD are not diminished with oral symptoms and changes, supporting reliable absorption in allergic reactions with such contexts.