Faculty Bibliography

OBJECTIVE:Despite national guidelines, low-dose aspirin (LDA) for preeclampsia prevention is underutilized. Standardizing the screening process, increasing patient knowledge, and enhancing contact with the healthcare system may improve utilization rates. Our objective is to evaluate whether a multifaceted intervention increases the proportion of patients who initiate LDA at the recommended gestational age as compared to routine prenatal care. STUDY DESIGN/METHODS:This observational cohort study included patients entering prenatal care within a large urban medical center in the Bronx, NY. Patients initiating care through our Early Pregnancy Access Center (EPAC) and receiving the intervention, including standardized screening for preeclampsia risk factors, prescribing of aspirin with education during prenatal intake, and follow-up outreach, were compared to patients initiating routine prenatal care at other sites within the institution. The primary outcome was the proportion of eligible patients who initiated aspirin by 16 weeks gestation. Secondary outcomes included the proportion of patients who continued to utilize aspirin at 24 weeks gestation, development of hypertensive disorders of pregnancy (HDP), and pregnancy outcomes. RESULTS:366 patients (78.5%) in the EPAC cohort and 296 patients (81.1%) in the routine prenatal care cohort had qualifying risk factors for LDA. Patients in both groups were largely Black or Hispanic and had public insurance. EPAC patients were more likely to initiate aspirin by 16 weeks (70.7% vs. 38.6%, aOR 4.39, 95% CI 2.80-6.90) and more likely to continue to utilize aspirin at 24 weeks (74.7% vs. 43.8%, aOR 4.43, 95% CI 2.93-6.72). HDP were highly prevalent in both groups (37.8% in EPAC vs. 34.7% in routine prenatal care, p=0.45). CONCLUSION/CONCLUSIONS:A concerted and standardized effort to identify, educate, and support patients at risk for preeclampsia, is associated with higher LDA utilization in a high-risk population. Obstetric providers can consider similar approaches to reduce the "quality gap" in rates of LDA us.

Rotator cuff disease (RCD) is the leading cause of shoulder disability, characterized by progressive degeneration of tendon structure and function. Despite advances in surgical techniques that optimize repair biomechanics, biological healing remains a major challenge, leading to high rates of repair failure. Augmentation strategies, including biologic adjuvants, grafts, and bioinductive implants, aim to improve the healing environment and reduce re-tear rates. Although augmentation reliably reduces structural failure, its clinical benefits remain under investigation. Continued advancements in biologic therapies, graft technologies, and long-term clinical studies are needed to optimize outcomes and define best practices for augmentation in rotator cuff repair. This review summarizes the current understanding of RCD pathophysiology, natural history, treatment strategies, surgical repair techniques, healing mechanisms, and the role of augmentation.

PURPOSE/OBJECTIVE:Nonsteroidal anti-inflammatory drugs (NSAIDs) increase fluid retention and the risk of heart failure (HF). The NSAIDs are commonly used in total hip arthroplasty (THA) as part of a modern multimodal pain protocol, but the risk of selective cyclooxygenase-2 (COX-2)-preferential NSAIDs in THA for Type 2 diabetes mellitus (T2DM) patients, who have an increased risk for cardiac disease, is not well understood. This study aimed to compare rates of new-onset HF following THA in T2DM patients receiving perioperative meloxicam or celecoxib. METHODS:A retrospective review was conducted of 18,142 patients who underwent primary elective THA. Data included demographics, perioperative aspirin, meloxicam and celecoxib use, T2DM diagnosis, and development of new-onset postoperative HF. Cohorts were separated based on the presence of a T2DM diagnosis and use of meloxicam or celecoxib. Propensity-matching controlled for age, American Society of Anesthesiologists score, and perioperative aspirin use. Rates of HF within T2DM patients who utilized peri-THA meloxicam versus celecoxib were compared. RESULTS:Of patients who utilized meloxicam or celecoxib, T2DM patients experience new-onset postoperative HF at higher rates than non-diabetics (6.1 [T2DM] versus 2.8% [non-T2DM], P < 0.001). Within the T2DM patients, the patients who utilized celecoxib developed HF at higher rates than T2DM patients who utilized meloxicam (4.0 [meloxicam] versus 7.1% [celecoxib], P = 0.013). CONCLUSIONS:Patients who have T2DM experience a higher incidence of new-onset postoperative HF compared to non-diabetics following perioperative selective NSAID use for THA. Additionally, T2DM patients developed HF at a greater rate when treated with perioperative celecoxib versus meloxicam. Given that both agents were associated with HF events in this high-risk population, caution is warranted when prescribing selective NSAIDs in T2DM patients undergoing THA. Risk-benefit considerations and individualized perioperative pain management strategies should be carefully considered.

PURPOSE/OBJECTIVE:Knee dislocations (KDs) can be limb-threatening injuries that may require a temporising knee-spanning external fixator (KSEF) for stabilisation. Precise indications for this commonly utilised invasive immobilisation technique remain controversial and poorly defined. The purpose of this study was to establish consensus-driven indications for temporising KSEF use in the initial management of KDs. METHODS:A working group of fellowship-trained orthopaedic surgeons generated clinical scenarios reflecting commonly debated indications for temporising KSEF application. Utilising a modified Delphi technique, 23 surgeons from the International Knee Dislocation Study Group completed two anonymous online survey rounds. Consensus was defined a priori as ≥70% agreement or disagreement. RESULTS:Response rates were 100% for Round 1 and 96% for Round 2. Four scenarios achieved unanimous consensus: (1) KD without post-reduction instability (100% disagreement), (2) inability to maintain tibiofemoral reduction in the sagittal/coronal plane with non-invasive knee immobilisation (NIKI) after initial reduction (i.e., redislocation/subluxation) (100% agreement), (3) tibial plateau fracture-dislocation with post-reduction subluxation (100% agreement), and (4) in bilateral closed KDs where one limb is indicated and the other is NOT, span ONLY the indicated limb (100% agreement). Two scenarios achieved strong positive consensus (90%-99.9% agreement): (1) morbid obesity (BMI ≥ 40) without NIKI of sufficient size (91.3% agreement), and (2) extensor mechanism injury with post-reduction subluxation (91.3% agreement). Four and one additional scenarios achieved positive and negative consensus, respectively. CONCLUSIONS:This modified Delphi study established consensus-driven indications for temporising KSEF application in the initial management of KDs, which advocate for more selective use than what is demonstrated in the literature. LEVEL OF EVIDENCE/METHODS:Level V.

The heat shock protein 70 (Hsp70) family consists of ATP-driven molecular chaperones essential for maintaining protein homeostasis (proteostasis) across all cell types, however, modulation of chaperone activity by small molecules remains challenging. In bacteria, a major Hsp70 called DnaK represents a putative antibacterial target, as it plays essential roles in growth, antibiotic resistance, and stress response. While Hsp70 inhibitors are in development as potential cancer and neurodegenerative disease treatments in humans, we lack generalizable methods to target Hsp70s across species. Here, we address how peptidomimetic scaffolds designed to inhibit proteases, exemplified by the drug telaprevir, interact with two different bacterial DnaKs to disrupt chaperone function. We perform extensive structure-function studies of telaprevir analogs against DnaK to inform the design of synthetic unnatural peptide sequences with a range of inhibitory potencies. X-ray crystallography analysis of telaprevir and several synthetic peptidomimetics reveal interactions with DnaK's substrate binding domain via ligand side chain recognition reminiscent of that observed in protease active sites, but in two orientations. These co-complexes inspire the synthesis of shorter peptidomimetics capable of allosterically inhibiting DnaK's ATPase activity. Overall, this work demonstrates that chemical scaffolds devised for protease inhibition may be modified to disrupt Hsp70 chaperone activities.

Primary graft dysfunction (PGD) is a proinflammatory syndrome occurring within the first days following lung transplantation. It is initiated by ischemia-reperfusion injury and perpetuated by donor and recipient immunologic factors, resulting in alveolar damage and progressive hypoxemic respiratory failure.¹ PGD is a known risk factor for both early allograft failure and chronic lung allograft dysfunction (CLAD).² Incidence of severe PGD remains high at 10-25%, though is variable; risk factors for PGD include center experience, underlying recipient disease type, size matching, donor lung storage conditions, operative time, and post-operative management.² Strategies to prevent PGD or mitigate the long -term consequences after it develops, are sorely needed. However, lack of specificity of the current PGD definition may hamper further progress in the field, especially as it pertains to the development of robust and relevant clinical trials. We propose that future modifications of the PGD definition incorporate more objective surrogates of allograft injury and subsequent diffuse alveolar damage, which may improve our ability to accurately study disease pathogenesis and improve outcomes.

OBJECTIVE:Phthalates are recognized endocrine disruptors and emerging neurotoxicants. Prenatal exposure to di-2-ethylhexyl phthalate (DEHP) has been linked to adverse neurodevelopmental and neuropsychiatric outcomes, and maternal oxidative stress may play a mechanistic role in prenatal DEHP's neurotoxicity. MATERIALS AND METHODS/METHODS:Participants were drawn from the New York University Children's Health and Environment Study. Prenatal DEHP exposure and maternal lipid peroxidation were assessed using repeated creatinine-adjusted maternal urinary measurements across pregnancy, collected from January 2016-April 2020. Neonatal brain-derived neurotrophic factor (BDNF) was measured in cord serum (N = 337), and internalizing and externalizing problems were assessed at an average age of 2 years using the Child Behavior Checklist for Ages 1.5-5 (CBCL 1½-5) (N = 824). DEHP metabolites (mEHHP; mEOHP; mECPP) were averaged across pregnancy, and cumulative lipid peroxidation biomarkers (8-iso-PGF2α; 15-PGF2α; 8,15-PGF2α; MDA) were estimated using area-under-the-curve values from linear mixed-effects spline models. Partial least squares path modeling evaluated direct and indirect associations using latent constructs for DEHP exposure, lipid peroxidation, CBCL 1½-5, and socioeconomic status; other covariates were modeled as single variables. Sex differences were assessed using bootstrapping and sex-stratified models, adjusting for maternal and child age, parity, pre-pregnancy body mass index, cotinine exposure, and socioeconomic status. RESULTS:Prenatal DEHP exposure was positively associated with maternal lipid peroxidation in all models (β's = 0.11-0.27). Sex-stratified analyses showed that prenatal DEHP exposure was positively associated with CBCL 1½-5 in male children only (β = 0.11), but not with BDNF in either sex. Maternal lipid peroxidation was not associated with BDNF or CBCL 1½-5 in either sex. CONCLUSION/CONCLUSIONS:Prenatal DEHP exposure is associated with maternal oxidative stress and total behavioral problems in male children only, but maternal oxidative stress does not mediate these relationships. Alternative upstream mechanisms may underlie both maternal oxidative stress and neurobehavioral outcomes. Future studies should investigate endocrine, metabolic, and epigenetic pathways to clarify DEHP neurotoxicity.

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) rarely occurs in pediatric and young adult populations, where little is known about its clinicopathologic and molecular features. We characterized 16 cases of PTCL, NOS diagnosed in patients ≤21 years old. Seven (44%) cases demonstrated SMARCB1/INI1 loss by immunohistochemistry and SMARCB1/INI1 alterations by next-generation sequencing, including biallelic SMARCB1/INI1 deletion (n=4), stop codon variant with 1-copy deletion (n=1) or copy-neutral loss-of-heterozygosity (CN-LOH; n=1), and frameshift variant (n=1). One case demonstrated biallelic SMARCE1 alterations (a nonsense variant and CN-LOH), which, to our knowledge, has not been previously described in a hematopoietic neoplasm. The SWI/SNF-intact group harbored pathogenic TET2, PTEN, EZH2, or TP53 variants. CDKN2A deletions were present in 3/7 SWI/SNF-deficient and 0/4 SWI/SNF-intact cases. 22q11.2 alterations were present on karyotype of 2/3 SMARCB1/INI1-deficient cases. SWI/SNF-deficiency was associated with intermediate-to-large cell cytomorphology, frequent mitotic (88%; p=0.041) and apoptotic (88%) activity, Reed-Sternberg-like cells (63%), necrosis (50%), and fibrosis (50%). All cases expressed CD45 and CD43 at initial diagnosis. SWI/SNF-deficient cases predominantly demonstrated a CD4+/CD8-, TCRab, and PTCL-GATA3 phenotype, whereas SWI/SNF-intact cases predominantly demonstrated a CD8+/CD4-, TCRgd, and PTCL-TBX21 phenotype. A PTCL-TBX21 phenotype was more common in SWI/SNF-intact than SWI/SNF-deficient cases (p=0.041). Cytotoxic markers were expressed in 71% of SWI/SNF-deficient and 88% of SWI/SNF-intact cases. Decreased or absent CD3 expression characterized 88% of SWI/SNF-deficient and 13% of SWI/SNF-intact cases (p=0.01). 63% of SWI/SNF-deficient cases demonstrated decreased/absent expression of ≥3 pan-T-cell antigens, compared to 13% of SWI/SNF-intact cases. Treatment was heterogeneous. Primary treatment failure or relapse occurred in 4/8 SWI/SNF-deficient and 4/7 SWI/SNF-intact cases. The median OS and EFS were 48.7 and 47.5 months for the SWI/SNF-deficient, and 16.4 and 8.9 months for the SWI/SNF-intact groups, respectively (p=NS). Death due to disease or therapy-related complications occurred in 4/8 (50%) cases in the SWI/SNF-deficient group and 6/7 (86%) of cases in the SWI/SNF-intact group. Our findings expand the knowledge of the clinicopathologic and molecular features of pediatric PTCL and highlight SWI/SNF-deficient T-cell lymphoma as a biologically distinct type of PTCL that is associated with characteristic clinicopathologic features.