Faculty Bibliography

Learning, memory, and emotional regulation are all modulated by sleep. Sleep influences on neural circuit function and plasticity occur in all mammalian brain regions examined to date, including the noncanonical olfactory system, suggesting sleep disruption could have wide-ranging consequences on behavior and cognition. New evidence suggests that sleep disturbances during early development can have particularly insidious and long-lasting consequences. In particular, work from our lab and others suggests that early-life adverse events can disrupt sleep across the life span, thus contributing to a variety of negative cognitive and behavioral outcomes. These findings raise the possibility that interventions targeting sleep may have therapeutic value for children or adults exposed to early-life adverse events. Here, we describe sleep and sleep ontogeny and then describe the role of sleep in normal and pathological brain function. Finally, we explore how early-life adverse events and sleep disturbances may reciprocally interact to produce a range of psychopathological outcomes.
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BACKGROUND:Unicondylar knee arthroplasty (UKA) has superior functional outcomes compared to total knee arthroplasty (TKA) with good mid-term and long-term survival data from high-volume institutions. We sought to quantify the risk of complications, re-operation/revision, hospital re-admission for any reason, and mortality of knee arthroplasty patients in the US patient population using 2 large databases. METHODS:UKA and TKA patients who were identified in the 2002-2011, 5% sample of Medicare data and 2004-2012 (June) MarketScan Commercial and Medicare Supplemental Databases were followed to evaluate the risk of complications, hospital re-admission for any reason, and mortality within 90 days of surgery. Survival probability defined by re-operation was calculated using the Kaplan-Meier method at 0.5, 2, 5, 7, and up to 10 years post-operatively. RESULTS:Compared to UKA, complication rates for TKA patients were significantly higher, including wound complication, pulmonary embolism, stiffness, peri-prosthetic joint infection, myocardial infarction, re-admission, and death. Age was found to be a significant risk factor (P < .05) for all complications in the Medicare cohort, except stiffness (P = .839), and all complications in the MarketScan cohort, except re-admission (P = .418), whereas gender had a variable effect on complications based on age. Survivorship of UKA was lower than TKA at all time points. Additionally, younger age adversely affected implant survival. By 7 years post-surgery, UKA survivorship in the Medicare and MarketScan cohorts was 80.9% and 74.4%, respectively. In contrast, TKA survivorship for the same cohorts was 95.7% and 91.9% by the same time point. CONCLUSION/CONCLUSIONS:Patients undergoing UKA have fewer post-operative complications and re-admissions than those undergoing TKA. However, patients undergoing UKA have a higher rate of re-operation and revision at up to 10 years of follow-up. It appears that age, as well as surgeon and hospital volume significantly impacts implant survivorship while gender does not have a relation. LEVEL OF EVIDENCE/METHODS:Level III.

BACKGROUND:Little work investigates the effect of behavioral health system efforts to increase use of evidence-based practices or how organizational characteristics moderate the effect of these efforts. The objective of this study was to investigate clinician practice change in a system encouraging implementation of evidence-based practices over 5 years and how organizational characteristics moderate this effect. We hypothesized that evidence-based techniques would increase over time, whereas use of non-evidence-based techniques would remain static. METHOD/METHODS:Using a repeated cross-sectional design, data were collected three times from 2013 to 2017 in Philadelphia's public behavioral health system. Clinicians from 20 behavioral health outpatient clinics serving youth were surveyed three times over 5 years (n = 340; overall response rate = 60%). All organizations and clinicians were exposed to system-level support provided by the Evidence-based Practice Innovation Center from 2013 to 2017. Additionally, approximately half of the clinicians participated in city-funded evidence-based practice training initiatives. The main outcome included clinician self-reported use of cognitive-behavioral and psychodynamic techniques measured by the Therapy Procedures Checklist-Family Revised. RESULTS:Clinicians were 80% female and averaged 37.52 years of age (SD = 11.40); there were no significant differences in clinician characteristics across waves (all ps > .05). Controlling for organizational and clinician covariates, average use of CBT techniques increased by 6% from wave 1 (M = 3.18) to wave 3 (M = 3.37, p = .021, d = .29), compared to no change in psychodynamic techniques (p = .570). Each evidence-based practice training initiative in which clinicians participated predicted a 3% increase in CBT use (p = .019) but no change in psychodynamic technique use (p = .709). In organizations with more proficient cultures at baseline, clinicians exhibited greater increases in CBT use compared to organizations with less proficient cultures (8% increase vs. 2% decrease, p = .048). CONCLUSIONS:System implementation of evidence-based practices is associated with modest changes in clinician practice; these effects are moderated by organizational characteristics. Findings identify preliminary targets to improve implementation.

Background: Factors associated with need for surgical intervention (SI)following endoscopic therapy for iatrogenic luminal perforations are not well known. We aim to identify predictors of need for SI amongst patients undergoing attempted endoscopic closure following iatrogenic luminal perforation.
Method(s): We conducted a retrospective review of iatrogenic perforations that underwent endoscopic closure attempts in 7 North American referral centers. Data was collected including patient demographics, index perforation procedure, attempted closure procedures and need for surgical repair. Univariate and multivariable logistic regression analyses were performed.
Result(s): A total of 144 iatrogenic perforation cases were reviewed. Only 22 patients (15.3%)required SI following endoscopic closure attempts. Perforations occurred after upper endoscopy (67), colonoscopy (35), surgical endoscopy (17), and ERCP (25)interventions as defined in Figure 1. Notably none of the surgical endoscopy cases required surgical intervention. The most common perforation locations included: duodenum (35; 24.3%), esophagus (32; 22.2%), colon (32; 22.2%), and stomach (20; 13.9%). Perforation was recognized during the index procedure in 128 patients (88.9%). Needle decompression was needed in 9 cases (6.3%). Twelve patients (8.3%)underwent more than one endoscopic closure session. Multiple endoscopic closure modalities were used in 24 cases (16.7%). Most common modalities used included: through-the-scope clips (TTS, 58; 40.3%), stents (42; 29.2%), over-the-scope clips (OTSC, 37; 25.7%), and endoscopic suturing (27; 18.8%). On univariate analysis, needle decompression was a significant predictor of need for SI (27.3% vs. 2.5%); while stent use (9.1% vs. 32.8%), technical (31.8% vs. 94.3%)and immediate clinical success (27.3% vs. 95.1%)were inversely associated (Table 1). On multivariable analysis, index colonoscopy-related perforation, needle decompression and need for multiple endoscopic closure modalities were significant predictors of need for SI; while use of TTS clips and immediate clinical success were inversely associated (Table 1). None of the other examined factors predicted the need for SI, outlined in Table 1.
Conclusion(s): The need for surgical intervention after attempted endoscopic closure of iatrogenic perforations is low. Needle decompression, index colonoscopy-related perforation, and use of multiple endoscopic closure modalities were predictors of need for surgical intervention. [Figure presented]Univariate and multivariable analyses of need for surgical intervention after attempted endoscopic closure of iatrogenic perforations
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Background: The full-thickness resection device (FTRD)was recently introduced in the US and has made endoscopic resection of difficult lesions and those with deep wall origin/infiltration possible using non-exposure resection technique. Although initial studies were promising, outcome results of FTRD in the literature are scarce.
Aim(s): To study the feasibility, effciacy, and safety of FTRD for the resection of colonic lesions.
Method(s): Patients who underwent endoscopic full-thickness resection (EFTR)using the FTRD for lower GI lesions at 24 U.S. tertiary-care centers between 10/17 and 10/18 were included in this retrospective study. Outcomes were technical success (defined as en-block resection)and R0 histologic margin. Chi square test was used to assess the association between lesion type, size, and location with the two outcomes.
Result(s): A total of 79 patients (mean age 65 yr, 39.2% F)underwent resection of colonic lesions using the FTRD. The most common indication was difficult adenoma (defined as non-lifting, recurrent, residual or involving appendiceal orifice/diverticular opening)in 48 (60.8 %)patients, followed by adenocarcinoma in 17 (21.5%), and sub-epithelial lesions in 10 (12.7 %). Lesion location was in the proximal colon in 46 (58.2%)patients, followed by distal colon in 17 (21.5%), and rectum in 16 (20.3%). Mean pre-resection lesion diameter and total procedure time were 15.3 +/- 6.5 mm and 63 +/-32 min, respectively. Majority of patients underwent MAC sedation and received no prophylactic antibiotics. Most patients, 72.2%, were discharged post-procedurally. Technical success was achieved in 67 (84.8 %)patients. For the 12 patients with technical failure, 5 underwent hot snare resection, 2 endoscopic submucosal dissection, 1 was managed surgically, while 4 had no further interventions. R0 resection was achieved in 88.9% of patients. A total of 9 (11.4%)adverse events occurred. Mild, moderate, and severe AE had a frequency of 6 (7.6%), 1 (1.3%), and 2 (2.5%), respectively. Most common AE was FTRD mechanical failure in 5 cases (6.3%), with one leading to perforation requiring surgery (severe event). Bleeding was reported in 3 cases (3.8%), with one case requiring endoscopic intervention 2-days post-procedure. One patient, despite being on pre and post procedure antibiotics, developed appendicitis 10-days post-procedure and was managed surgically (severe event). Technical success and R0 resection were not significantly associated with lesion type, size, or location.
Conclusion(s): Results from this first U.S multicenter study suggest that EFTR is a feasible, safe, and effective technique for EFTR of difficult colonic lesions. Surgical management can be avoid in the vast majority of cases. Although adverse events are not uncommon, severe complications are rare. [Figure presented][Figure presented]
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Background: Prior data from Asian countries showed comparable outcomes of endoscopic submucosal dissection (ESD)vs surgery in patients with early gastric cancer (EGC)meeting standard and expanded criteria. Data from comparative studies using strict criteria in North American population are lacking.
Method(s): We conducted a multicenter retrospective study from 16 North American centers. All patient underwent ESD and/or gastrectomy for EGC between 12/2004 and 2/2018, with follow-up until 10/2018. Patients who did not meet either standard or expanded criteria, those with evidence of lymph node or distant metastasis at time of diagnosis, those without curative resection, and those with follow-up time of less than 6 months were excluded. Primary outcomes were overall survival (OS), cancer-specific survival (CSS)and recurrence-free survival (RFS). Kaplan-Meier using log-rank analysis was used to compare outcomes between ESD and surgery groups. Factors associated with outcomes were analyzed using Cox hazards regression and linear regression analyses.
Result(s): There were 393 patients with EGC who underwent ESD or gastrectomy from 14 US and 2 Canadian centers. Of these, 318 patients were excluded due to unfulfilled standard or expanded criteria (n=254), evidence of lymph node metastasis (n=1), no data on lymphovascular invasion (n=1), non-R0 resection (n=17)and follow-up time of less than 6 months (n=45). A total of 75 patients were analyzed (38 treated with ESD and 37 treated with surgery). Patients treated with surgery had a higher proportion of pedunculated lesions (P=0.02), undifferentiated tumors (P =0.01), EGCs fulfilling expanded criteria (P <0.0001)and longer follow-up time (P=0.0004)(Table 1). OS (P= 1.00), CSS (P=1.00)and RFS (P=1.00)were not statistically different between ESD vs surgery groups. There was no subsequent nodal or distant metastasis in either group. A single patient in the surgery group died of an etiology not related to gastric cancer at 7.9 years after gastrectomy. There were no deaths in the ESD group. One patient with moderately differentiated adenocarcinoma in the gastric antrum, treated with curative ESD, developed a gastric cardiac neuroendocrine tumor at 7.2 years (Table 2). The metachronous lesion was treated with a repeat curative endoscopic resection. There was no demographic, procedural or histological factor associated with OS, CSS or RFS.
Conclusion(s): The standard and expanded criteria for gastric ESD are clinically applicable to a North American population. ESD provides comparable oncologic outcomes and is thus an alternative treatment option to surgery. Recurrence after ESD is uncommon, and can be managed successfully using follow-up and repeat endoscopic treatment. [Figure presented][Figure presented]
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Background: Factors associated with successful endoscopic therapy for iatrogenic gastrointestinal luminal perforations are not well known. We aim to evaluate safety and efficacy outcomes of endoscopic closure of perforations and identify factors associated with successful closure.
Method(s): We conducted a multicenter retrospective study from 7 North American referral centers. All patients underwent attempted endoscopic closure of iatrogenic perforations. Primary outcomes evaluated were technical success and immediate clinical success (less than 14 days). Secondary outcomes were adverse events, length of hospital stay, and long term clinical success (more than 14 days). Cases were analyzed based on immediate clinical success status. Univariate and multivariable analyses were performed.
Result(s): A total of 144 iatrogenic perforation cases were reviewed. Collectively, a total of 163 endoscopic closure procedures were performed with median follow up 192 days. Technical and immediate clinical success were achieved in 122/144 cases (84.7%). Mean perforation size was 11.28 mm. Perforation occurrence: 67 during upper endoscopy (diagnostic, dilation, EMR, stent placement/removal and endoscopic US), 35 during colonoscopy (diagnostic, EMR, stent placement/removal, dilation and EUS), 17 during surgical endoscopy (ESD, POEM)and 25 during ERCP. Univariate analysis of patient demographics, index perforation procedure details, closure procedure details, and need for surgical intervention are reported in Table 1. Factors associated with immediate clinical success with respective (OR [95% CI], p<0.05)were morning timing (AM)of index procedure 3.34(1.23-9.09), fellow involvement in index procedure 0.37(0.14-0.97), antibiotic use 5.13(1.45-18.12), needle decompression 0.11(0.03-0.45), use of stent 4.63(1.02-20.88)and technical success of closure procedure 16.7(5.58-50.24). None of the perforations that occurred during surgical endoscopy cases had clinical failure of closure. Patients with immediate clinical success had shorter hospital stay (5.7 vs. 9.3 days)and achieved higher long term clinical success (96.2% vs. 7.7%)compared to those with immediate clinical failure. In the multivariable model, technical success 22.20(3.99-123.6)was the only positive predictor of immediate clinical success; while needle decompression 0.11(0.02-0.76)was the only negative predictor. The overall adverse event rate for endoscopic closure procedures was 13.9%, outlined in Table 1.
Conclusion(s): Endoscopic closure techniques are safe and effective for treatment of iatrogenic perforations. Technical success of the endoscopic closure procedure is a positive predictor of immediate clinical success. Needle decompression is negative predictor of successful closure. Patients that achieve immediate clinical success have shorter hospitalizations and higher rates of long term clinical success. [Figure presented]
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Background: In Western countries, most patients with early gastric cancer (EGC)are still being treated with gastrectomy. Endoscopic submucosal dissection (ESD)is a widely accepted treatment option for EGC in Asia and has become increasingly performed in the West. To date, outcomes data on gastric ESD in the Western settings have been limited to small, single-center studies, with a lack of data coming from North America.
Aim(s): To evaluate gastric ESD outcomes across various centers in North America.
Method(s): This was a retrospective analysis of prospectively collected data on consecutive patients with gastric epithelial neoplasia who underwent ESD between 1/2008 to 10/2018 at 19 centers. Primary end point was the rate of en bloc resection. Secondary outcomes included: (1)rate of complete (R0)and curative resection, (2)adverse event rates, and (3)rates of recurrence and gastric cancer-related death.
Result(s): Of 253 patients who were referred for gastric ESD, ESD was not technically feasible in 6 cases (1 due to deeply invasive cancer and 5 due to severe submucosal fibrosis from prior endoscopic resection). In 247 patients (mean age 69 yrs; 56% male; 50% Caucasian), including 143 (58%)adenomas, 67 (27%)EGC, and 28 (11%)neuroendocrine tumors (NET), ESD was attempted. Median procedure time was 90 min (IQR 55 - 124). In 38% of cases, ESD was performed in an outpatient setting. En-bloc resection rates for all lesions, EGCs, adenomas, and NETs were 92%, 94%, 89%, and 90%, respectively. R0 resection rates for all lesions, EGC, adenomas, and NET were 81%, 76%, 87%, and 70%, respectively. Curative resection according to Japanese criteria was achieved in 76% (16/21)of EGCs fulfilling the standard criteria and 69% (25/36)of EGCs fulfilling the expanded criteria. Intraprocedural perforation occurred in 8%(n=21). Of these, all but two cases were treated successfully with endoscopic therapy. Two cases (0.8%)required surgery due to perforation, and both occurred during the early phase of the learning curve. Delayed bleeding occurred in 8 cases (3%). No delayed perforation or procedure-related deaths were observed. In the EGC cohort, local recurrence was observed in 4 cases (11%)and all were following non-curative resection. In the gastric adenoma group, there were 5 (6.7%)local recurrences after ESD (1.8% after R0 resection vs 44% after non-R0 resection, p=0.001). After a median follow-up of about 12 months post-operatively, no metastatic recurrences or gastric cancer-related deaths were observed.
Conclusion(s): This large multicenter study demonstrated high rates of en bloc and R0 resections of gastric neoplasia in North America, comparable to that of Eastern centers. We recommend ESD as treatment of choice for gastric neoplasia including lesions fulfilling standard and expanded criteria for EGC. [Figure presented][Figure presented]
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Choline is critical for normative function of 3 major pathways in the brain, including acetylcholine biosynthesis, being a key mediator of epigenetic regulation, and serving as the primary substrate for the phosphatidylethanolamine N-methyltransferase pathway. Sufficient intake of dietary choline is critical for proper brain function and neurodevelopment. This is especially important for brain development during the perinatal period. Current dietary recommendations for choline intake were undertaken without critical evaluation of maternal choline levels. As such, recommended levels may be insufficient for both mother and fetus. Herein, we examined the impact of perinatal maternal choline supplementation (MCS) in a mouse model of Down syndrome and Alzheimer's disease, the Ts65Dn mouse relative to normal disomic littermates, to examine the effects on gene expression within adult offspring at ∼6 and 11 mo of age. We found MCS produces significant changes in offspring gene expression levels that supersede age-related and genotypic gene expression changes. Alterations due to MCS impact every gene ontology category queried, including GABAergic neurotransmission, the endosomal-lysosomal pathway and autophagy, and neurotrophins, highlighting the importance of proper choline intake during the perinatal period, especially when the fetus is known to have a neurodevelopmental disorder such as trisomy.-Alldred, M. J., Chao, H. M., Lee, S. H., Beilin, J., Powers, B. E., Petkova, E., Strupp, B. J., Ginsberg, S. D. Long-term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.

Skilled object retrieval requires coordination of the perceptual and motor systems. Coordination is especially challenging when body position is changing and visual search is required to locate the target. In three experiments, we used a "pivot paradigm" to induce changes in body position: Participants were passively pivoted 180° toward a target placed at varied locations to the left and right of the center of a reaching board. Experiment 1 showed that 6- to 15-month-old infants (n = 41) plan prehension so quickly that they retrieve targets mid-turn and scale their reaches to target location relative to turn direction. Experiment 2 characterized planning mid-turn reaching in 6- to 8-month-olds (n = 5) wearing a head-mounted eye tracker. Reach planning depended on when the target appeared in the field of view-not on target fixation. Experiment 3 used head-mounted eye tracking and motion tracking to assess perceptual-motor coordination in adults (n = 13). Adults displayed more mid-turn reaching than infants. But like infants, adults scaled reaching to target location relative to turn direction, and contact time depended on when the target came into view-not on target fixation. Findings show that fast, efficient perceptual-motor coordination supports flexibility in infant prehension, and constraints on coordination are similar across the lifespan.