Faculty Bibliography

BACKGROUND:The purpose of this study is to describe a Level 1 Trauma Center's orthopedic response to the COVID-19 pandemic, and to compare outcomes of acute fracture patients pre-COVID versus during the COVID-19 pandemic. METHODS:All inpatient fracture cases performed over a 5-month period were identified and retrospective chart review performed. Patients were divided into pre- and COVID-era groups based on when surgery was performed relative to March 16, 2020 (the date elective operations were ceased), and groups were statistically compared. Patients with a COVID test result were further sub-divided into COVID negative and positive groups, and statistically compared. Statistical analysis was performed using independent t-test for continuous variables and chi-square analysis for categorical variables. RESULTS:One hundred and nineteen patients were identified, 38% females with average age of 58 years. Average length of stay was 7 days with average time from injury to surgery of 3 days and average time from admission to surgery of 1.3 days. Overall in-hospital complication rate was 29.4%, and 30-day mortality and readmission rates were 2.5% and 5%, respectively. Sixty-nine patients comprised the pre-COVID group, and 50 in the COVID-era group. There was no significant difference with respect to length of stay, time from injury to surgery, time from admission to surgery, need for post-operative ICU stay, in-hospital complication rate, 30-day mortality rate and 30-day readmission rate. Thirty-four patients had COVID testing, with 24 negative and 10 positive. COVID-positive patients had longer time from injury to surgery (8.5 days vs. 2 days, p = 0.003) and longer time from admission to surgery (2.7 days vs. 1.2 days, p = 0.034). While more COVID-positive patients required ICU admission post-operatively (60% vs. 21%, p = 0.036), there was no difference in overall complication rate. CONCLUSIONS:Orthopedic care of acute fracture patients was not affected by a global pandemic. The response of our Level 1 Trauma Center's orthopedic department can guide other hospitals if and when new surges in COVID cases arise, in order to prevent compromising appropriate orthopedic care. LEVEL OF EVIDENCE/METHODS:Prognostic III.

BACKGROUND:Limited research has addressed the obesity-COVID-19 severity association in paediatric patients. OBJECTIVE:To determine whether obesity is an independent risk factor for COVID-19 severity in paediatric patients and whether age modifies this association. METHODS:SARS-CoV-2-positive patients at NYU Langone Health from 1 March 2020 to 3 January 2021 aged 0-21 years with available anthropometric measurements: weight, length/height and/or body mass index (BMI). Modified log-Poisson models were utilized for the analysis. Main outcomes were 1) hospitalization and 2) critical illness (intensive care unit [ICU] admission). RESULTS:One hundred and fifteen of four hundred and ninety-four (23.3%) patients had obesity. Obesity was an independent risk factor for critical illness (adjusted risk ratio [ARR] 2.02, 95% CI 1.17 to 3.48). This association was modified by age, with obesity related to a greater risk for critical illness in adolescents (13-21 years) [ARR 3.09, 95% CI 1.48 to 6.47], but not in children (0-12 years). Obesity was not an independent risk factor for hospitalization for any age. CONCLUSION/CONCLUSIONS:Obesity was an independent risk factor for critical illness in paediatric patients, and this association was modified by age, with obesity related to a greater risk for critical illness in adolescents, but not in children. These findings are crucial for patient risk stratification and care.

The field of cardio-oncology has emerged in response to the increased risk of cardiovascular disease (CVD) in patients with cancer. However, recent studies suggest a more complicated CVD-cancer relationship, wherein development of CVD, either prior to or following a cancer diagnosis, can also lead to increased risk of cancer and worse outcomes for patients. In this review, we describe the current evidence base, across epidemiological as well as preclinical studies, which supports the emerging concept of 'reverse-cardio oncology', or CVD-induced acceleration of cancer pathogenesis.

Hand injuries often result in significant functional impairments and are rarely completely restored. The spontaneous regeneration of injured appendages, which occurs in salamanders and newts, for example, has been reported in human fingertips after distal amputation, but this type of regeneration is rare in mammals and is incompletely understood. Here, we study fingertip regeneration by amputating murine digit tips, either distally to initiate regeneration, or proximally, causing fibrosis. Using an unbiased microarray analysis, we found that digit tip regeneration is significantly associated with hair follicle differentiation, Wnt, and sonic hedgehog (SHH) signaling pathways. Viral over-expression and genetic knockouts showed the functional significance of these pathways during regeneration. Using transgenic reporter mice, we demonstrated that, while both canonical Wnt and HH signaling were limited to epidermal tissues, downstream hedgehog signaling (through Gli) occurred in mesenchymal tissues. These findings reveal a mechanism for epidermal/mesenchyme interactions, governed by canonical hedgehog signaling, during digit regeneration. Further research into these pathways could lead to improved therapeutic outcomes after hand injuries in humans.

Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.

Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties. How these adaptations may affect tissue injury has not been previously examined in large animals and humans. Here, we show that blocking mechanotransduction signaling through the focal adhesion kinase pathway in large animals significantly accelerates wound healing and enhances regeneration of skin with secondary structures such as hair follicles. In human cells, we demonstrate that mechanical forces shift fibroblasts toward pro-fibrotic phenotypes driven by ERK-YAP activation, leading to myofibroblast differentiation and excessive collagen production. Disruption of mechanical signaling specifically abrogates these responses and instead promotes regenerative fibroblast clusters characterized by AKT-EGR1.

Purpose: Because of the COVID-19 pandemic, the Radiation Oncology Education Collaborative Study Group (ROECSG) hosted its annual international symposium using a virtual format in May 2020. This report details the experience of hosting a virtual meeting and presents attendee feedback on the platform. Approach/Methods: The ROECSG symposium was hosted virtually on May 15, 2020. A postsymposium survey was distributed electronically to assess attendee demographics, participation, and experience. Attendee preference and experience were queried using 3-point and 5-point Likert-type scales, respectively. Symplur LLC was used to generate analytics for the conference hashtag (#ROECSG). Results/Outcomes: The survey was distributed to all 286 registrants, with a response rate of 67% (191 responses). Seventeen nonattendee responses were omitted from this analysis, for a total of 174 included respondents. Eighty-two attendees (47%) were present for the entire symposium. A preference for a virtual symposium was expressed by 78 respondents (45%), whereas 44 (25%) had no preference and 52 (30%) preferred an in-person meeting. A total of 150 respondents (86%) rated the symposium as "extremely" well organized. Respondents who had not attended a prior in-person ROECSG symposium were more likely to prefer the virtual format (P =.03). Seventy-eight respondents (45%) reported a preference for the virtual platform for reviewing scholarly work, and 103 (59%) reported a preference for an in-person platform for networking. On the day of the symposium, #ROECSG had 408 tweets and 432,504 impressions. Discussion/Significance: The 2020 ROECSG symposium was well received and can serve as a framework for future virtual meetings. Although the virtual setting may facilitate sharing research, networking aspects are more limited. Effort is needed to develop hybrid virtual and in-person meetings that meet the needs of participants in both settings. Social media is a significant avenue for dissemination and discussion of information and may be valuable in the virtual setting. Keywords: Education, Virtual platform, Research scholarship
Copyright

OBJECTIVE: Over 15 million babies have been conceived by IVF, yet debate about its safety to offspring continues. We hypothesized that superovulation and in vitro fertilization (IVF) promote genomic changes, including altered telomere length (TL) and activation of the retrotransposon LINE-1 (L1), and tested this hypothesis in a mouse model. MATERIALS AND METHODS: Experimental laboratory study analyzing C57BL/6J mice produced blastocysts in vivo from natural mating cycles (N), in vivo following superovulation (S), or in vitro following superovulation (IVF). We also examined the effects of prolonged culture on TL and L1 in the IVF group. TL and L1 copy number were measured by Real Time PCR. Following log transformation, analysis of variance with Tukey post-test compared TL and L1 among the 3 groups. Students t test compared TL and L1 between embryos cultured for 120 vs. 96 hrs in the IVF group. Pvalue <0.05 was considered significant. Analyses were performed with SAS 9.4.
RESULT(S): In the IVF group, 10 replicates produced a fertilization rate of 90.52% (95% CI: 85.19-95.85), D4 blastocyst formation rate of 61.90% (95% CI: 52.62-71.19) and cumulative blastocyst rate (D4 plus D5) of 76.19% (CI: 68.04-84.34). TL in S (n=77; Mean: 1.50+/- 1.15; p 0.0007) and IVF (n=82; Mean: 1.72+/- 1.44; p <0.0001) exceeded that in N (n=16; Mean: 0.61+/- 0.27). L1 copy number in N (n=16; Mean: 0.80+/- 0.31) did not differ from S (n=77; Mean: 1.23+/- 0.75; p=0.1386) or IVF (n=82; Mean: 1.09+/- 1.16; p=0.6709). L1 copy number of embryos from S also did not differ significantly from IVF (n=82; Mean: 1.09+/- 1.16; p=0.0670). TL of blastocysts cultured 120h (n=14, Mean: 2.14 +/- 1.05) was significantly longer than that of embryos cultured for 96h (n=67, Mean: 1.63+/- 1.50, p=0.0414). L1 copy number of blastocysts cultured for 120h (n=15, Mean:1.71+/- 1.49) exceeded that of embryos cultured for 96h (n=67, Mean: 0.95+/- 1.03 p=0.0162).
CONCLUSION(S): Intriguingly ovarian hyperstimulation and IVF produced embryos with significantly longer telomeres compared to in vivo, natural cycle-produced embryos. The significance of this enriched telomere endowment for the health and longevity of offspring born from IVF merit future studies. The mechanism driving telomere lengthening in response to ovarian stimulation and IVF during early embryo development remains unclear, though may involve activation of L1. Recently we demonstrated a role for L1 in telomere elongation in preimplantation embryos, and Barbara McClintock's Nobel Prizing winning research previously identified activation of retrotransposons as a response to stress. Stress from IVF may elongate telomeres by activating L1. IMPACT STATEMENT: Millions of babies have been born following IVF, yet debate continues about its safety to offspring. We found genomic effects of IVF and ovarian stimulation in mice - telomere elongation and retrotransposon activation. Future studies should examine longevity and/or cancer risk in IVF offspring

PURPOSE/OBJECTIVE:Whether differences in stimulation parameters alter the number and proportion of MII oocytes retrieved. METHODS:Records of 2546 patients were examined, looking at age, day 2/3 follicle-stimulating hormone (FSH) and estradiol (E2) levels, total dose of gonadotropins administered (including FSH and human menopausal gonadotropin [hMG]), fraction of hMG administered, number of days of treatment with gonadotropins, and the dose of gonadotropins administered per day. We segregated the patients into 3 different classes depending on the trigger method used and 2 groups based on egg freeze vs. ICSI. Multiple regression methods were used to examine associations between stimulation parameters and the total number of eggs, number of immature oocytes (Poisson regression), and the fraction of retrieved oocytes that were immature (Logistic regression). RESULTS:After adjustments for different triggers and egg freeze versus ICSI, both the #immature oocytes and the immature fraction of oocytes were associated with the total gonadotropin dose (inversely) and the gonadotropin dose/day (positively). Other parameters were associated with the number of immature oocytes but were also associated with the number of oocytes retrieved. CONCLUSIONS:Stimulations using less total gonadotropin and more gonadotropin per day were associated with more immaturity. The type of trigger method used for final maturation was associated with immaturity but was believed to be predominantly due to trigger assignment to patients based on response. The association between use of ICSI and less immaturity was believed to be due to additional time for maturation in the ICSI group.

OBJECTIVE: To compare telomere length (TL) and telomerase gene expression in human euploid and aneuploid blastocysts generated from IVF treatment. MATERIALS AND METHODS: TL and telomerase gene expression were measured in cryopreserved aneuploid (N=115) and euploid (N=4) human blastocysts donated by 26 patients who consented research under approval of IRB study #16-00154. Blastocysts were classified according to number of aneuploid chromosomes (A1-one segmental error, A2-one whole chromosome error, A3-two chromosomal errors and A4- >= 3 chromosomal errors). Genomic DNA and messenger RNA were separated simultaneously from individual blastocysts after thawing in vitrification-warming media. Telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) mRNA levels were determined by RT-qPCR with GAPDH as internal control, and TL was measured by qPCR with 5s rDNA as internal control. Relative gene expression and TL were calculated by DELTADELTA^Ct method, and GraphPad Prism 8 software was used for statistical analysis.
RESULT(S): TL and telomerase gene expression were not normally distributed, so nonparametric tests were used to compare the medians among groups (Table 1). Median TL, TERTand TERC levels didn't differ by number of chromosome errors nor between aneuploid and euploid groups. Intriguingly, TL, TERT and TERC levels in aneuploid blastocysts tended to be greater compared to euploid blastocysts. TL in blastocysts correlated with telomerase TERT expression (R² =0.054, P = 0.011), but not TERC expression (R² =0.0002, P = 0.865).
CONCLUSION(S): To our knowledge, this is the largest study to measure telomere length and telomerase gene expression in human blastocysts. Our data indicated that telomeres are lengthened and telomerase is activated in aneuploid embryos at blastocyst stage. Moreover, telomere length and telomerase gene TERT in human blastocysts correlate regardless of ploidy status. Like cancer cells, TERT is highly expressed in aneuploid blastocysts. IMPACT STATEMENT: Robust TERT expression and telomere maintenance in aneuploid human blastocysts may explain why extended in vitro culture alone is insufficient to cull out aneuploidy embryos during IVF (Table Presented)