Faculty Bibliography

Articular cartilage injury, as a hallmark of arthritic diseases, is difficult to repair and causes joint pain, stiffness, and loss of mobility. Over the years, the most significant problems for the drug-based treatment of arthritis have been related to drug administration and delivery. In recent years, much research has been devoted to developing new strategies for repairing or regenerating the damaged osteoarticular tissue. The RNA interference (RNAi) has been suggested to have the potential for implementation in targeted therapy in which the faulty gene can be edited by delivering its complementary Short Interfering RNA (siRNA) at the post-transcriptional stage. The successful editing of a specific gene by the delivered siRNA might slow or halt osteoarthritic diseases without side effects caused by chemical inhibitors. However, cartilage siRNA delivery remains a challenging objective because cartilage is an avascular and very dense tissue with very low permeability. Furthermore, RNA is prone to degradation by serum nucleases (such as RNase H and RNase A) due to an extra hydroxyl group in its phosphodiester backbone. Therefore, successful delivery is the first and most crucial requirement for efficient RNAi therapy. Nanomaterials have emerged as highly advantage tools for these studies, as they can be engineered to protect siRNA from degrading, address barriers in siRNA delivery to joints, and target specific cells. This review will discuss recent breakthroughs of different siRNA delivery technologies for cartilage diseases.

Treacher Collins syndrome (TCS: OMIM 154500) is an autosomal dominant craniofacial disorder belonging to the heterogeneous group of mandibulofacial dysostoses.

Past studies in autism spectrum disorder (ASD) indicate atypical peripheral physiological arousal. However, the conditions under which these atypicalities arise and their link with behavioral emotional expressions and core ASD symptoms remain uncertain. Given the importance of physiological arousal in affective, learning, and cognitive processes, the current study examined changes in skin conductance level (ΔSCL) in 41 toddlers with ASD (mean age: 22.7 months, SD: 2.9) and 32 age-matched toddlers with typical development (TD) (mean age: 21.6 months, SD: 3.6) in response to probes designed to induce anger, joy, and fear emotions. The magnitude of ΔSCL was comparable during anger (P = 0.206, d = 0.30) and joy (P = 0.996, d = 0.01) conditions, but significantly lower during the fear condition (P = 0.001, d = 0.83) in toddlers with ASD compared to TD peers. In the combined samples, ΔSCL positively correlated with intensity of behavioral emotional expressivity during the anger (r[71] = 0.36, P = 0.002) and fear (r[68] = 0.32, P = 0.007) conditions, but not in the joy (r[69] = -0.15, P = 0.226) condition. Finally, ΔSCL did not associate with autism symptom severity in any emotion-eliciting condition in the ASD group. Toddlers with ASD displayed attenuated ΔSCL to situations aimed at eliciting fear, which may forecast the emergence of highly prevalent internalizing and externalizing problems in this population. The study putatively identifies ΔSCL as a dimension not associated with severity of autism but with behavioral responses in negatively emotionally challenging events and provides support for the feasibility, validity, and incipient utility of examining ΔSCL in response to emotional challenges in very young children. LAY SUMMARY: Physiological arousal was measured in toddlers with autism exposed to frustrating, pleasant, and threatening tasks. Compared to typically developing peers, toddlers with autism showed comparable arousal responses to frustrating and pleasant events, but lower responses to threatening events. Importantly, physiological arousal and behavioral expressions were aligned during frustrating and threatening events, inviting exploration of physiological arousal to measure responses to emotional challenges. Furthermore, this study advances the understanding of precursors to emotional and behavioral problems common in older children with autism. Autism Res 2020, 13: 1476-1488. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

A 71-year-old male with history of clear cell renal cell carcinoma (RCC) 6-years status post nephrectomy presented for gross hematuria. Cystoscopy revealed a bulge of the right ureteral orifice, and transurethral resection confirmed RCC metastasis to the ureteral stump. Ureterectomy with bladder cuff excision was performed, and the patient is currently undergoing aggressive imaging surveillance. This is the 57th case of metastasis of RCC to the ureteric stump, and this case occurred beyond baseline surveillance recommendation of five years. Potential mechanisms of metastasis of RCC are reviewed, and RCC surveillance is discussed.

Objective/UNASSIGNED:To assess the presence and content of policies toward posthumous assisted reproduction (PAR) using oocytes and embryos among Society for Assisted Reproductive Technology (SART) member clinics in the United States. Design/UNASSIGNED:Cross-sectional questionnaire-based study. Setting/UNASSIGNED:Not applicable. Patients/UNASSIGNED:A total of 62 SART member clinics. Interventions/UNASSIGNED:Questionnaire including multiple choice and open-ended questions. Main Outcome Measures/UNASSIGNED:Descriptive statistics regarding presence and content of policies regarding PAR using oocytes and embryos, consent document content regarding oocyte and embryo disposition, and eligibility of minors and those with terminal illness for fertility preservation. Results/UNASSIGNED:Of the 332 clinics contacted, 62 responded (response rate 18.7%). Respondents were distributed across the United States, and average volume of in vitro fertilization (IVF) cycles per year ranged from <250 to >1,500, but 71.2% (n = 42) reported a volume of <500. Nearly one-half (42.4%, n = 25) of clinics surveyed reported participating in any cases of posthumous reproduction during the past 5 years, and 6.8% (n = 4) reported participation in >5 cases. Participation in cases of posthumous reproduction was not significantly associated with practice type or IVF cycle volume among those surveyed. Only 59.6% (n = 34) of clinics surveyed had written policies regarding PAR using oocytes or embryos, whereas 36.8% (n = 21) reported they did not have a policy. Practice type, IVF cycle volume, fertility preservation volume, and prior participation in cases of PAR were not significantly associated with the presence of a policy among respondent clinics. Of those with a policy, 55.9% (n = 19) reported they had used that policy, 59.1% (n = 13) without a policy reported they had considered adopting one, and 63.6% (n = 14) reported they had received a request for PAR services. Only 47.2% (n = 25) of clinics surveyed specified that patients not expected to survive to use oocytes due to terminal illness are eligible for oocyte cryopreservation, whereas 45.3% (n = 24) did not specify. Conclusions/UNASSIGNED:Respondent clinics reported receiving an increasing number of requests for PAR services, but many also lacked PAR policies. Those with policies did not always follow ASRM recommendations. Given the low response rate, these data cannot be interpreted as representative of SART clinics overall. As PAR cases become more common, however, this study highlights poor reporting of PAR and institutional policies toward PAR, suggesting that SART clinics may not be equipped to systematically manage the complexities of PAR.

OBJECTIVES:(1) To demonstrate how a risk assessment tool modified to account for the COVID-19 virus during the current global pandemic is able to provide risk assessment for low-energy geriatric hip fracture patients. (2) To provide a treatment algorithm for care of COVID-19 positive/suspected hip fractures patients that accounts for their increased risk of morbidity and mortality. SETTING:One academic medical center including 4 Level 1 trauma centers, 1 university-based tertiary care referral hospital, and 1 orthopaedic specialty hospital. PATIENTS/PARTICIPANTS:One thousand two hundred seventy-eight patients treated for hip fractures between October 2014 and April 2020, including 136 patients treated during the COVID-19 pandemic between February 1, 2020 and April 15, 2020. INTERVENTION:The Score for Trauma Triage in the Geriatric and Middle-Aged ORIGINAL (STTGMAORIGINAL) score was modified by adding COVID-19 virus as a risk factor for mortality to create the STTGMACOVID score. Patients were stratified into quartiles to demonstrate differences in risk distribution between the scores. MAIN OUTCOME MEASUREMENTS:Inpatient and 30-day mortality, major, and minor complications. RESULTS:Both STTGMA score and COVID-19 positive/suspected status are independent predictors of inpatient mortality, confirming their use in risk assessment models for geriatric hip fracture patients. Compared with STTGMAORIGINAL, where COVID-19 patients are haphazardly distributed among the risk groups and COVID-19 inpatient and 30 days mortalities comprise 50% deaths in the minimal-risk and low-risk cohorts, the STTGMACOVID tool is able to triage 100% of COVID-19 patients and 100% of COVID-19 inpatient and 30 days mortalities into the highest risk quartile, where it was demonstrated that these patients have a 55% rate of pneumonia, a 35% rate of acute respiratory distress syndrome, a 22% rate of inpatient mortality, and a 35% rate of 30 days mortality. COVID-19 patients who are symptomatic on presentation to the emergency department and undergo surgical fixation have a 30% inpatient mortality rate compared with 12.5% for patients who are initially asymptomatic but later develop symptoms. CONCLUSION:The STTGMA tool can be modified for specific disease processes, in this case to account for the COVID-19 virus and provide a robust risk stratification tool that accounts for a heretofore unknown risk factor. COVID-19 positive/suspected status portends a poor outcome in this susceptible trauma population and should be included in risk assessment models. These patients should be considered a high risk for perioperative morbidity and mortality. Patients with COVID-19 symptoms on presentation should have surgery deferred until symptoms improve or resolve and should be reassessed for surgical treatment versus definitive nonoperative treatment with palliative care and/or hospice care. LEVEL OF EVIDENCE:Prognostic Level III. See Instructions for Authors for a complete description of Levels of Evidence.

Background: Recent advances in high-throughput single-cell sequencing technologies have led to their increasingly widespread adoption for clinical applications. However, challenges associated with tissue viability, cell yield, and delayed time-to-capture have created unique obstacles for data processing. Chronic wounds, in particular, represent some of the most difficult target specimens, due to the significant amount of fibrinous debris, extracellular matrix components, and non-viable cells inherent in tissue routinely obtained from debridement. Methods: Here, we examined the feasibility of single cell RNA sequencing (scRNA-seq) analysis to evaluate human chronic wound samples acquired in the clinic, subjected to prolonged cold ischemia time, and processed without FACS sorting. Wound tissue from human diabetic and non-diabetic plantar foot ulcers were evaluated using an optimized 10X Genomics scRNA-seq platform and analyzed using a modified data pipeline designed for low-yield specimens. Cell subtypes were identified informatically and their distributions and transcriptional programs were compared between diabetic and non-diabetic tissue. Results: 139,000 diabetic and non-diabetic wound cells were delivered for 10X capture after either 90 or 180 min of cold ischemia time. cDNA library concentrations were 858.7 and 364.7 pg/µL, respectively, prior to sequencing. Among all barcoded fragments, we found that 83.5% successfully aligned to the human transcriptome and 68% met the minimum cell viability threshold. The average mitochondrial mRNA fraction was 8.5% for diabetic cells and 6.6% for non-diabetic cells, correlating with differences in cold ischemia time. A total of 384 individual cells were of sufficient quality for subsequent analyses; from this cell pool, we identified transcriptionally-distinct cell clusters whose gene expression profiles corresponded to fibroblasts, keratinocytes, neutrophils, monocytes, and endothelial cells. Fibroblast subpopulations with differing fibrotic potentials were identified, and their distributions were found to be altered in diabetic vs. non-diabetic cells. Conclusions: scRNA-seq of clinical wound samples can be achieved using minor modifications to standard processing protocols and data analysis methods. This simple approach can capture widespread transcriptional differences between diabetic and non-diabetic tissue obtained from matched wound locations.

The neuropeptide Y (NPY) system is emerging as a promising therapeutic target for neuropsychiatric disorders by intranasal delivery to the brain. However, the vast majority of underlying research has been performed with males despite females being twice as susceptible to many stress-triggered disorders such as posttraumatic stress disorder, depression, anorexia nervosa, and anxiety disorders. Here, we review sex differences in the NPY system in basal and stressed conditions and how it relates to varied susceptibility to stress-related disorders. The majority of studies demonstrate that NPY expression in many brain areas under basal, unstressed conditions is lower in females than in males. This could put them at a disadvantage in dealing with stress. Knock out animals and Flinders genetic models show that NPY is important for attenuating depression in both sexes, while its effects on anxiety appear more pronounced in males. In females, NPY expression after exposure to stress may depend on age, timing, and nature and duration of the stressors and may be especially pronounced in the catecholaminergic systems. Furthermore, alterations in NPY receptor expression and affinity may contribute to the sex differences in the NPY system. Overall, the review highlights the important role of NPY and sex differences in manifestation of neuropsychiatric disorders.

Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). However, the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. Here, we find that inflicting acute lung injury (ALI) to mice doubles their incidence of AAA and accelerates macrophage-driven proteolytic damage of the aortic wall. ALI-induced HMGB1 leaks and is captured by arterial macrophages thereby altering their mitochondrial metabolism through RIPK3. RIPK3 promotes mitochondrial fission leading to elevated oxidative stress via DRP1. This triggers MMP12 to lyse arterial matrix, thereby stimulating AAA. Administration of recombinant HMGB1 to WT, but not Ripk3^-/- mice, recapitulates ALI-induced proteolytic collapse of arterial architecture. Deletion of RIPK3 in myeloid cells, DRP1 or MMP12 suppression in ALI-inflicted mice repress arterial stress and brake MMP12 release by transmural macrophages thereby maintaining a strengthened arterial framework refractory to AAA. Our results establish an inter-organ circuitry that alerts arterial macrophages to regulate vascular remodeling.