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Minimally invasive approaches to major liver resection have been limited by presumed difficulty of the operation. While some concerns arise from mastering the techniques, factors such as tumor size and liver parenchymal features have anecdotally been described as surrogates for operative difficulty. These factors have not been systematically studied for minimally invasive right hepatectomy (MIRH). Seventy-five patients who underwent MIRH during 2007–2016 by the senior author were evaluated; these were compared to control group of open right hepatectomy. Demographics, operative, and post-operative variables were collected. Operative times and estimated blood loss, two objective parameters of operative difficulty were correlated to volume of hepatic resection, parenchymal transection diameter and liver parenchymal features using regression analysis. Thirty-eight (50.6%) resections were performed for malignant indications. Average tumor size was 5.7 cm (±3.6), mean operative time was 196 min (±74), and mean EBL was 220 mL (±170). Average transection diameter was 10.1 cm (±1.7). There was no correlation between operative difficulty with parenchymal transection diameter or presence of steatosis. Blood loss was higher with increased right hepatic lobe volume and body mass index. This analysis of a very defined anatomical resection suggests that the often quoted radiographic and pathologic features indicative of a challenging procedure were not significant in determining operative difficulty.

Background Results from the MemoryGel Breast Implants Core Clinical Study suggest these devices are safe and effective at 10 years after implantation. Although clinical trials are essential for measuring the safety and effectiveness of a device, real-world evidence can supplement clinical trials by providing information on outcomes observed in diverse clinical settings for a more heterogeneous population, without fixed treatment patterns, and without continuous patient monitoring, such that follow-up is more representative of normal clinical practice. Objectives The aim of this study was to measure real-world outcomes, including safety and effectiveness, in patients who underwent primary breast augmentation with smooth MemoryGel implants. Methods This was a case series looking at patients, age 22 years and older, who underwent primary breast augmentation at a single site between December 2006 and December 2016 and who had a minimum of 2 years of follow-up. Descriptive statistics were used to summarize baseline characteristics and outcomes. Kaplan-Meier models were used to estimate safety outcomes for capsular contracture (Baker grade III/IV), infection, and rupture. Results A total of 50/777 (6.4%) patients reported a complication, with an average time to complication of 3.9 years (range, 19 days-11.8 years) postprocedure. Kaplan-Meier estimates of the 10-year cumulative incidence of capsular contracture (Baker grade III/IV), infection, and rupture were 4.7%, 0.1%, and 1.6%, respectively. Conclusions Analyses of a large population from a single site provide further support for the long-term safety and effectiveness of MemoryGel breast implants in a primary augmentation cohort. Level of Evidence: 4

Aortic aneurysms occur concomitantly with malignancy in approximately 1.0-17.0% of patients. There is little published information regarding the effects of subsequent oncological therapies on aortic aneurysm growth. The aim of this study was to determine the effects of chemoradiation therapies on the natural progression of small abdominal aortic aneurysm (AAA), thoracic aortic aneurysm, and thoracoabdominal aortic aneurysm.Patients with aortic aneurysms with and without malignancy between 2005 and 2017 were identified within institutional databases using Current Procedural Terminology and International Classification of Disease codes. Inclusion criteria included complete chemotherapy documentation, a minimum of 3 multiplanar axial/coronal imaging or ultrasonography before, during, and after receiving therapy or 2 studies for patients without malignancy. Propensity matching, Cox and linear regression, and Kaplan-Meier survival analyses were performed.A total of 159 (172 aneurysms) patients with malignancy and 127 (149 aneurysms) patients without malignancy were included. Average patient demographics were 74.4 ± 9.8-years-old, Caucasian (66.8%), male (70.3%), with hypertension (71.1%), current smoking (24.5%), coronary atherosclerotic disease (26.2%), and AAA (71.0%). The most common malignancy was lung cancer (48.4%) with most chemotherapy regimens including a platinum-based alkylating agent and concurrent antimetabolite (56.0%). The overall median follow-up time was 28.2 (range 3.1-174.4) months. Aortic aneurysms in patients without malignancy grew to larger sizes (4.43 ± 0.96 vs. 4.14 ± 1.00, P = 0.008) with similar median growth rates (0.12 vs. 0.12 cm/year, P = 0.090), had more atypical morphologic features (14.1% vs. 0.6%, P 0.001), more frequently underwent repair (22.1% vs. 8.7%, P = 0.001), and more frequently required emergency repair for rupture (5.4% vs. 0.0%, P = 0.087). Cox regression identified initial aortic size ≥4.0 cm (hazard ratio [HR] 3.028), AAA (HR 2.146), chronic aortic findings (3.589), and the use of topoisomerase inhibitors (HR 2.694). Linear regression demonstrated increased growth rates predicted by antimetabolite chemotherapy (β 0.170), initial aortic size (β 0.086), and abdominal aortic location (β 0.139, all P 0.002).Small aortic aneurysms with concomitant malignancies are discovered at smaller initial sizes, grow at similar rates, require fewer interventions, and have fewer ruptures and acute dissections than patients without malignancy. Antimetabolite therapies modestly accelerate aneurysmal growth, and patients receiving topoisomerase inhibitors may require earlier repair. Patients with concomitant disease can be confidently treated according to standard institutional aneurysm surveillance protocols. Overall, we recommend treatment of the malignancy before small aortic aneurysm repair as these aneurysms behave similarly to those in patients without malignancy.

Existing research suggests patients with blood group O are less likely to develop pancreatic ductal adenocarcinoma (PDAC) compared to those with non-O blood groups, and that survival from PDAC may be affected by ABO blood type. This study assessed survival outcomes in PDAC patients who underwent pancreatoduodenectomy (PD) in one health system.From 2010 to 2017, demographic, operative, chemotherapy and survival data for patients undergoing PD at Emory Healthcare were reviewed. Patients with blood type AB were excluded due to small sample size. The relationship between ABO blood group and survival was analyzed using Kaplan-Meier survival curves and multivariate cox proportional regression analysis.Of 449 PDAC patients assessed, 204 (45.4%), 60 (13.4%) and 185 (41.2%) were blood groups A, B and O, respectively. Patients were well matched in clinicopathologic characteristics. Median survival did not differ by blood group (p = 0.82), and this relationship remained insignificant on cox regression analysis (p = 0.15). On multivariate analysis, lymph node positivity (p 0.001) and increasing age (p = 0.001) were associated with reduced survival.In contrast to recent reports, this larger study found that blood group did not impact overall survival among patients undergoing PD for PDAC.

Objective Image-guided breast biopsies are safe, efficient, and reliable. However, patients are often anxious about these procedures, particularly those who have never undergone a prior biopsy. Methods This prospective IRB-approved study surveyed 163 patients undergoing their first breast biopsy. Participants provided informed consent and completed a short written survey prior to and immediately after their procedure. Level of anxiety as well as anticipated and actual levels of pain prior to and following the procedure were assessed using a 0–10-point Likert scale. Correlation, bivariate, and regression analyses were performed. Results Regarding the biopsy experience, 133/163 (81.6%) of patients reported it as better than expected. Anxiety decreased significantly from a prebiopsy mean score of 5.52 to a postbiopsy mean score of 2.25 (P < 0.001). Average and greatest pain experienced during the procedure had mean scores of 2.03 and 2.77, respectively, both significantly lower compared to preprocedural expectation (mean 4.53) (P < 0.001). Lower pain scores were reported in US-guided procedures compared to stereotactic- and MRI-guided biopsies (P < 0.001). No significant differences in pain scores were seen in those undergoing single versus multiple biopsies, or when benign, elevated-risk, or malignant lesions were sampled. Positive correlations were seen with prebiopsy anxiety levels and procedural pain as well as with anticipated pain and actual procedural pain. Conclusion Image-guided biopsies are often better tolerated by patients than anticipated. We stress the benefit of conveying this information to patients prior to biopsy, as decreased anxiety correlates with lower levels of pain experienced during the procedure.

Background The amount of IV fluids sufficient to prevent post-operative acute kidney injury (AKI) during pancreaticoduodenectomy (PD) is unknown. We assessed the restrictive IOIVF use in PD on the rate of post-operative AKI, delayed gastric emptying and ileus, and pancreatic fistulas (POPF). Methods Patients who underwent PD between 2012 and 2017 were reviewed. Univariate and multivariate analyses looked for association between pre- and intra-operative factors on AKI, ileus and POPF. Results Of 395 included patients, 97, 172, and 126 patients received less than 1000 mL (ultra-restrictive), 1000 mL to less than 2000 mL (restrictive), and 2000 mL and greater (nonrestrictive) normalized total IOIVF respectively. Of these 23 (24.2%), 34(20.4%), and 21(17.4%) developed AKI respectively, most of them mild. There was no difference in odds of developing AKI, ileus, or pancreatic fistula among fluid groups. While there was no difference in Clavien-Dindo III-IV complications, the incidence of Clavien-Dindo type I-II complications was lower in the restricted fluid groups. Discussion Restricted fluids did not lead to higher AKI rates but were associated with fewer low-grade complications.

Background Limited literature is available on the postoperative development of impaired glucose tolerance (IGT) and new-onset diabetes mellitus (NODM) following Distal Pancreatectomy (DP). We aimed to study the post-surgical clinical evolution of IGT/DM and its association with preoperative glycemic profiles of patients undergoing DP. Methods Pre- and postoperative glycemic laboratories were measured in patients undergoing DP by the senior author from 2007–2017. Multivariate risk factor analysis was performed to determine risk factors for new-onset IGT/DM after DP. Kaplan–Meier curves were constructed for development of NODM postoperatively. Results Of 216 included patients, n = 63, n = 68 and n = 85 were preoperatively diagnosed with no-diabetes (No-DM), pre-diabetes (Pre-DM), and diabetes (DM), respectively. At 2-year follow-up, n = 37, n = 80 and n = 99 were classified as No-DM, Pre-DM or DM, respectively. Pre-diabetics had a higher risk of developing postoperative dysglycemia (RR 2.230, 95% CI 1.732–2.870, p = 0.001). Preoperative OGTT>130, HbA1c >6.0, and chronic pancreatitis were risk factors for postoperative DM. Conclusion 40% of patients undergoing DP were unaware of their dysglycemic status (pre-DM or DM) pre-operatively. At 2-year follow-up, 36% non-diabetic and 57% pre-diabetic patients had developed NODM. Appropriate pre-operative diabetic assessment is warranted for all patients undergoing pancreatic resections.

Bile cultures (BC) have routinely been used to guide empiric antibiotic therapy for developing postoperative infections. The ability of BCs to predict sensitivity and resistance patterns (SRP) of site of infection cultures (SOIC) remains controversial. The aim was to assess the concordance of pathogens and SRPs between paired BC/SOICs.Medical records of consecutive patients undergoing pancreaticoduodenectomy were reviewed between 2014 and 2018. BC/SOIC pathogens and SRPs were compared on a patient-by-patient basis and concordance (K) was assessed.Common patient characteristics of 522 included patients were 65-years-old, Caucasian (75.5%), male (54.2%), malignant indication (79.3%), and preoperative biliary stent (59.0%). Overall, 275 (89.6%) BCs matured identifiable isolates with 152 (55.2%) demonstrating polymicrobial growth. Ninety-two (17.6%) SOICs were obtained: 48 and 44 occurred in patients with and without intraoperative BCs. Stents were associated with bacteriobilia (85.7%, K = 0.947, p 0.001; OR 22.727, p 0.001), but not postoperative infections (15.2%; K = 0.302, p 0.001; OR 1.428, p = 0.122). Forty-eight patients demonstrated paired BC/SOICs to evaluate. Pathogenic concordance of this group was 31.1% (K = 0.605, p 0.001) while SRP concordance of matched pathogens was 46.7% (K = 0.167, p = 0.008).Bile cultures demonstrate poor concordance with the susceptibility/resistance patterns of postoperative infections following pancreaticoduodenectomy and may lead to inappropriate antibiotic therapies.

Objective Parenchymal breast cysts are considered to be rare in men and are sparsely described in the literature. The purpose of this study was to review our institution’s experience with male breast cysts in an effort to improve overall understanding and management of this rare entity. Methods An institutional review board–exempt retrospective study was performed. Radiology reports for males who underwent mammogram and/or breast ultrasound at any of our institution’s primary or satellite locations from January 1995 to January 2020 were screened to find males with breast cysts. If cysts were reported and images were available, case review was performed to confirm parenchymal breast cyst(s) and patient characteristics were collated. Results Of 5425 male cases presenting for breast imaging, 19 (0.4%) cases of male breast cysts were confirmed, with a mean patient age of 41.6 years (range: 2–81 years). The most common indication leading to cyst discovery was a palpable lump, corresponding to the site of the cyst in 5 (26.3%) patients and near the site where cyst(s) were ultimately discovered in 7 (36.8%) patients. There were 8 (42.1%) instances of cysts without concurrent gynecomastia. Three (15.8%) men underwent needle sampling. There were no cases of atypia or malignancy on needle biopsy or on subsequent clinical follow-up, with median clinical follow-up of 70.3 months (range: 3.3–259.4 months). Conclusion Male breast parenchymal cysts are rare, but their prevalence is likely underestimated. If detected incidentally or upon targeted evaluation, biopsy may be averted if classic benign cyst features are identified.

There is a growing literature of evidence that the use of acellular dermal matrices (ADMs) in abdominal wall reconstruction (AWR) for high-risk patients provides superior complication profiles when compared with standard synthetic mesh. Here we compare Fortiva, Strattice, and Alloderm ADMs in AWR.In a prospectively maintained database, all patients undergoing AWR between January 2003 and November 2016 were reviewed. Hernia recurrence and surgical site occurrence (SSO) were our primary and secondary endpoints. Kaplan-Meier survival curves and logistic regression models were used to evaluate risks for hernia recurrence and SSO.A total of 229 patients underwent AWR with 1 of 3 ADMs. Median follow-up time was 20.9 months (1-60 months). Cumulative recurrence rates for each mesh were 6.9%, 11.2%, and 22.0% (P = 0.04), for Fortiva, Strattice, and Alloderm groups. Surgical site occurrence for each mesh was 56.9%, 49.0%, and 49.2%, respectively. Seroma was significantly lower in the Fortiva group (1.4%; P = 0.02). Independent risk factors hernia recurrence included body mass index of 30 kg/m(2) or higher and hypertension. Adjusted risk factors included oncologic resection for hernia recurrence (odds ratio, 5.3; confidence interval, 1.1-97.7; P = 0.11) and a wound class of contaminated or dirty/infected for SSO (odds ratio, 3.6; confidence interval, 1.0-16.6; P = 0.07).Acellular dermal matrices provide a durable repair with low overall rate of recurrence and complications in AWR. The recurrence and complication profiles differ between brands. With proper patient selection and consideration, ADMs can be used confidently for a variety of indications and wound classifications.

Cilia are critical to numerous biological functions, both in development and everyday homeostatic processes. Diseases arising from genetic mutations that cause cilia dysfunction are termed ciliopathies. Several ubiquitously expressed splicing factors have been implicated in the condition Retinitis Pigmentosa (RP), a group of diseases characterised by the progressive degeneration of the retina. In many types of RP the disease affects the modified primary cilium of the photoreceptor cells and thus, these types of RP are considered ciliopathies. Here, we discuss sequence variants found within a number of these splicing factors, the resulting phenotypes, and the mechanisms underpinning disease pathology. Additionally, we discuss recent evidence investigating why RP patients with mutations in globally expressed splicing factors present with retina-specific phenotypes.

Background:. In the United States, 2-stage expander-to-implant–based breast reconstruction accounts for more than half of all breast reconstruction procedures. Tissue expansion technology has undergone significant advancements in the past few decades. Previous reports suggest that the most common perioperative complications associated with breast tissue expanders are infection and skin flap necrosis. However, little clinical data are available for CPX4 Breast Tissue Expanders. The aim of the study was to measure real-world outcomes related to safety and effectiveness of the tissue expansion process, in patients who underwent primary breast reconstruction following the use of CPX4 Breast Tissue Expanders. Methods:. This was a single-arm retrospective cohort design looking at patients who underwent 2-stage, expander-to-implant–based primary breast reconstruction at a single site between April 2013 and December 2016 and who had a minimum of 2 years follow-up. Descriptive statistics were used to summarize baseline characteristics and safety outcomes. Results:. A total of 123 patients were followed for an average of 3.73 ± 0.94 years. At least 1 complication during the time of tissue expansion, before the permanent implant, was reported in 39/123 (31.7%) patients [51/220 implants (23.2%)]. The most frequently reported complications were delayed wound healing (13.8%) and cellulitis/infection (9.7%). Conclusion:. Analyses of real-world data from a single site provide further support for the safety and effectiveness of the CPX4 Breast Tissue Expander for women undergoing 2-stage expander-to-implant primary breast reconstruction.

Background The use of neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC) has increased in recent years. Limited data exists on the impact of NAC on biliary microbiome. Methods Patients who underwent pancreaticoduodenectomy (PD) for PDAC between 2014 and 2017 were reviewed. Patients were stratified into two groups based on their NAC status for comparison. Results Of 168 patients included, 63 (37.5%) received NAC. Patients who received NAC exhibited significantly increased growth of Gram-negative anaerobic bacteria (p = 0.043). Patients in the non-NAC group were more likely to grow pathogens resistant to ampicillin-sulbactam (47% vs 21%, p = 0.007), cefazolin (49% vs 28%, p = 0.040), cefoxitin (42% vs 11%, p = 0.009) and cefuroxime (26% vs 4%, p = 0.019). NAC status did not impact infectious postoperative outcomes, including SSIs. Conclusion Patients who did not receive NAC were more likely to grow pathogens resistant to cephalosporins. Perioperative antibiotic prophylaxis should be tailored to cover Gram-negative organisms and enterococci.

Synthetic mesh and acellular dermal matrix reinforcement during complex abdominal wall reconstruction (CAWR) have significantly improved outcomes. In an attempt to further improve outcomes, we combined both into a single biosynthetic by suturing a synthetic mesh on top of porcine acellular dermal matrix. Our aim was to review our experience with this new technique. Patients undergoing CAWR with the biosynthetic mesh were reviewed from a prospective database from 2015 to 2018. A total of 39 patients were 56.3 ± 10.9 years old, white (59.0%), and female (74.4%), with 31.9 ± 7.4 kg/m of body mass index. Eight repairs were performed on patients classified as greater than or equal to modified Ventral Hernia Working Group (mVHWG) class 3a, and 41.0% followed a concurrent resection of previously placed mesh. The biosynthetic mesh was placed as an underlay (51.3%) or inlay (46.2%) with primary closure in 51.3% and component separation in 12.8%. Recurrence at 3 years of follow-up occurred in 3 patients (7.7%). Complications within 60 days occurred in 6 patients (15.4%), including 4 soft tissue infections-one requiring explantation, with a total of 2 patients (5.1%) requiring explantation overall. Type 2 diabetes, previous mesh removal, component separation, and mVHWG class 3b independently predicted noninfectious complications. Male sex and mVHWG class 3b independently predicted surgical site infection. No predictors were found for recurrence. Biosynthetic mesh does not seem to increase the risk of early complications and may reduce recurrences and improve long-term outcomes after CAWR.

Literature is varied regarding risk factors associated with diabetes development after major pancreatic resection. The aim was to develop and validate a scoring index that preoperatively predicts the development of diabetes after pancreaticoduodenectomy and distal pancreatectomy.In this prospective study, perioperative fasting and postprandial (OGTT, oral glucose tolerance test) plasma glucose, glycated hemoglobin A1c (HbA1c), insulin, and c-peptide were measured in select consecutive patients undergoing pancreaticoduodenectomy and distal pancreatectomy by the senior author, from 2007 to 2018. American Diabetes Association definitions were used for glycemic classifications. Statistical analyses included multivariate generalized estimated equation for factor identification and variable weighting; area under the receiver operating curve (ROC) c-statistic for predictive ability, and survival analysis risk score grouping.Of 1,083 included patients with preoperative normoglycemia (253; 23.4%), prediabetes (362; 33.4%), and diabetes (468; 43.2%), the overall postoperative incidence of each diabetic class at 120 months was 152 (14.0%), 466 (43.0%), and 465 (42.9%), respectively. The development and validation groups included 1,023 and 60 patients, respectively. Five factors were identified predicting diabetes development, with a total possible score of 8. The C-statistics for development and validation groups were 0.727 (CI 0.696 to 0.759, p 0.001) and 0.823 (CI 0.718 to 0.928, p0.001), respectively. At a cut point of 3 (sensitivity 0.691, specificity 0.644) the Post-pancreatectomy Diabetes Index (PDI) independently predicted diabetes in development (odds ratio [OR] 4.298, relative risk [RR] 2.486, CI 1.238 to 5.704, p0.001) and validation (OR 6.970, RR 2.768, CI 2.182 to 22.261, p0.001) groups. The PDI similarly predicted pre-diabetes in development (OR 1.961, RR 1.325, CI 1.202 to 2.564, p0.001) and validation (OR 4.255, RR 1.798, CI 1.247 to 14.492, p = 0.021) groups.The Post-pancreatectomy Diabetes Index predicts the development of diabetes and pre-diabetes in patients undergoing major pancreatectomy using routine endocrine laboratories and pre-surgical clinical data.

Tumor cells upregulate a plethora of proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment. Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how alterations in pH modulate the interactions between immune cells and tumors cells could help elucidate opportunities for new therapeutic approaches. To determine how pH modification impacts immune cell-mediated killing of tumor cells, co-culture experiments were conducted with GFP+ SW480 colorectal cancer cells and either NK-92 natural killer cells or TALL-104 T cells at various pHs in a 48-well plate. Manipulation of pH occurred using the compounds lactic acid and sodium bicarbonate. We observed that both NK-92 cells and TALL-104 cells exhibited decreasing amounts of cell killing in response to decreasing pH. Next, to determine if therapeutic manipulation of pH via alteration of pH pump activity could overcome the negative changes in immune cell activity associated with pH, we added Cariporide, a selective NHE1 inhibitor, to the co-culture experiments. Treatment with Cariporide bolstered T cell killing in a dose-dependent manner, however the doses used did not impact natural killer cell-mediated killing. Given the importance of cell signaling on immune function, and because we saw potentially significant changes in immune killing with Cariporide, we then evaluated how changes in pH using Cariporide affected these signaling molecules. Colorectal cancer cells (HCT116, HT29, KM12C) were treated with Cariporide at 5 µm and 10 µm doses and cancer cell culture supernatants were collected and frozen down at -80 °C. Cytokine, chemokine, and growth factor levels were analyzed using a Luminex 200 multiplexing instrument. Overall cytokine levels showed a decreasing trend in response to increasing doses of Cariporide. There were notable decreases in the levels of IL-8/CXCL8, VEGF, CCL3/MIP-1 alpha, and M-CSF with increasing doses of Cariporide. All of these factors, as well as extracellular acidosis, are known to promote epithelial mesenchymal transition (EMT), thus, promoting metastatic dissemination. A therapeutic that targets factors that lead to EMT could help prevent metastasis. Moreover, we saw that pH impacts the function of immune cells and this is relevant in the context of a highly acidic TME. Therapeutically modifying the pH of the TME using Cariporide treatment may be a way to improve immune response and prevent EMT. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response. Citation Format: Kelsey E. Huntington, Aaron W. Maxwell, Anna Louie, Shengliang Zhang, Lanlan Zhou, Wafik S. El-Deiry. Decreasing colorectal cancer extracellular pH dampens immune cell killing and is partially ameliorated by treatment with NHE1 inhibitor Cariporide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2736.

Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.

Background: Poor sleep quality is a common complaint, affecting over one third of people in the United States. While sleep quality is thought to be related to slow-wave sleep (SWS), there has been little investigation to address whether modulating slow-wave oscillations (SWOs) that characterize SWS could impact sleep quality. Here we examined whether closed-loop transcranial alternating current stimulation (CL-tACS) applied during sleep impacts sleep quality and efficiency. Methods: CL-tACS was used in 21 participants delivered at the same frequency and in phase with endogenous SWOs during sleep. Sleep quality was assessed in the morning following either verum or sham control stimulation during sleep, with order counterbalanced within participants. Results: Higher sleep quality and efficiency were found after verum stimulation nights compared to control. The largest effects on sleep quality were found immediately following an adaptation night in the laboratory for which sleep quality was reduced. Conclusions: Applying CL-tACS at the same frequency and phase as endogenous SWOs may offer a novel method to improve subjective sleep quality after a night with poor quality sleep. CL-tACS might be helpful for increasing sleep quality and efficiency in otherwise healthy people, and in patients with clinical disorders that involve sleep deficits.

Complementary integrative health therapies have a perioperative role in the reduction of pain, analgesic use, and anxiety, and increasing patient satisfaction. However, long implementation lags have been quantified. The Consolidated Framework for Implementation Research (CFIR) can help mitigate this translational problem.We reviewed evidence for several nonpharmacological treatments (CFIR domain: characteristics of interventions) and studied external context and organizational readiness for change by surveying providers at 11 Veterans Affairs (VA) hospitals (domains: outer and inner settings). We asked patients about their willingness to receive music and studied the association between this and known risk factors for opioid use (domain: characteristics of individuals). We implemented a protocol for the perioperative use of digital music players loaded with veteran-preferred playlists and evaluated its penetration in a subgroup of patients undergoing joint replacements over a 6-month period (domain: process of implementation). We then extracted data on postoperative recovery time and other outcomes, comparing them with historic and contemporary cohorts.Evidence varied from strong and direct for perioperative music and acupuncture, to modest or weak and indirect for mindfulness, yoga, and tai chi, respectively. Readiness for change surveys completed by 97 perioperative providers showed overall positive scores (mean0 on a scale from -2 to +2, equivalent to2.5 on the 5-point Likert scale). Readiness was higher at Durham (+0.47) versus most other VA hospitals (range +0.05 to +0.63). Of 3307 veterans asked about willingness to receive music, approximately 68% (n = 2252) answered "yes." In multivariable analyses, a positive response (acceptability) was independently predicted by younger age and higher mean preoperative pain scores (4 out of 10 over 90 days before admission), factors associated with opioid overuse. Penetration was modest in the targeted subset (39 received music out of a possible 81 recipients), potentially reduced by device nonavailability due to diffusion into nontargeted populations. Postoperative recovery time was not changed, suggesting smooth integration into workflow.CFIR-guided implementation of perioperative music was feasible at a tertiary VA hospital, with moderate penetration in a high-risk subset of patients. Use of digital music players with preferred playlists was supported by strong evidence, tension for change, modest readiness among providers, good acceptability among patients (especially those at risk for opioid overuse), and a protocolized approach. Further study is needed to identify similar frameworks for effective knowledge-translation activities.

Background Minimally invasive approaches for major hepatectomy have been marred by significant rates of conversion and associated morbidity. This study aimed to determine risk factors for conversion as well as postoperative morbidity in patients undergoing minimally invasive right-sided hepatectomy (MIRH). Methods Data for patients undergoing MIRH between 2008 and 2017 at Emory University were reviewed. Risk factors for conversion were determined using multivariate regression analysis. Outcomes of conversion patients were compared with those who underwent successful MIRH or elective open surgery. Results Unplanned conversion occurred in 7 (6.25%) of 112 patients undergoing MIRH. Primary reason for conversion was difficult dissection secondary to inflammation and severe adhesions. No preoperative clinical factor was identified that predicted conversions. Converted cases had higher EBL and pRBC transfusion compared to non-converted cases however morbidity was similar to those undergoing primary open surgery. Conclusion Difficult dissection and adhesions remained the only clinically applicable parameter leading to unplanned conversions. While these did offset benefits of a successful minimally invasive approach, it did not increase risk of postoperative complications compared with planned open surgery.

With current emphasis on improving cost-quality relationship in medicine, it is imperative to evaluate cost-value relationships for surgical procedures. Previously the authors demonstrated comparable clinical outcomes for minimally invasive right hepatectomy (MIRH) and open right hepatectomy (ORH). MIRH had significantly higher intraoperative cost, though overall costs were similar.MIRH was decoded into its component critical steps using value stream mapping, analyzing each associated cost. MIRH technique was prospectively modified, targeting high cost steps and outcomes were re-examined. Records were reviewed for elective MIRH before (pre-MIRH n = 50), after (post MIRH n = 25) intervention and ORH (n = 98), between January 1, 2008 and November 30, 2016.Average overall cost was significantly lower for post-standardization MIRH (post-MIRH $21 768, pre-MIRH $28 066, ORH $33 020; p 0.001). Average intraoperative blood loss was reduced with MIRH (167, 292 and 509 mL p 0.001). Operative times were shorter (147, 190 and 229 min p 0.001) and LOS was reduced for MIRH (3, 4, 7 days p 0.002).Using a common quality improvement tool, the authors established a model for cost effective clinical care. These tools allow surgeons to overcome personal or traditional biases such as stapler choices, but most importantly eliminate non-value added interventions for patients.

Background Scrotal inguinal hernias represent a challenging surgical pathology. Although some advanced laparoscopists can repair these hernias through a minimally invasive approach, open repair is considered the technique of choice for most surgeons. The purpose of this study is to show our results of robotic-assisted laparoscopic repair of scrotal inguinal hernias. Patients and methods We reviewed the charts of 14 patients with inguinoscrotal hernias who underwent robotic-assisted transabdominal preperitoneal (TAPP) hernia repair. Mean follow-up was 7 months. The European Registry for Abdominal Wall Hernia Quality of Life score, a 90-point scale, was utilized to quantify patient reported outcomes. Results Robotic TAPP repair was successful in all 14 patients. Average case duration was 100 minutes (78 to 140 min) for unilateral hernias and 208 minutes (166 to 238 min) for bilateral hernias. Trainees were involved in 93% (13/14) of cases. There were no recurrences. Three patients developed postoperative seromas. The mean European Registry for Abdominal Wall Hernia Quality of Life score was 3.7 (0 to 10). Conclusions Scrotal hernias can be safely repaired using robotic-assisted TAPP methods with low morbidity and favorable patient reported outcomes.

Major depressive disorder is associated with lower medial prefrontal cortex volumes. The role that gender might play in moderating this relationship and what particular medial prefrontal cortex subregion(s) might be implicated is unclear. Magnetic resonance imaging was used to assess dorsal, ventral, and anterior cingulate regions of the medial prefrontal cortex in a normative sample of male and female adults. The Depression, Anxiety, and Stress Scale (DASS) was used to measure these three variables. Voxel-based morphometry was used to test for correlations between medial prefrontal gray matter volume and depressive traits. The dorsal medial frontal cortex was correlated with greater levels of depression, but not anxiety and stress. Gender moderates this effect: in males greater levels of depression were associated with lower dorsal medial prefrontal volumes, but in females no relationship was observed. The results indicate that even within a non-clinical sample, male participants with higher levels of depressive traits tend to have lower levels of gray matter volume in the dorsal medial prefrontal cortex. Our finding is consistent with low dorsal medial prefrontal volume contributing to the development of depression in males. Future longitudinal work is needed to substantiate this possibility.

Although many approaches have been tried in the attempt to reduce the devastating impact of stroke, tissue plasminogen activator for thromboembolic stroke is the only proved, effective acute stroke treatment to date. Vasopressin, an acute-phase reactant, is released after brain injury and is partially responsible for the subsequent inflammatory response via activation of divergent pathways. Recently there has been increasing interest in vasopressin because it is implicated in inflammation, cerebral edema, increased intracerebral pressure, and cerebral ion and neurotransmitter dysfunctions after cerebral ischemia. Additionally, copeptin, a byproduct of vasopressin production, may serve as a promising independent marker of tissue damage and prognosis after stroke, thereby corroborating the role of vasopressin in acute brain injury. Thus, vasopressin antagonists have a potential role in early stroke intervention, an effect thought to be mediated via interactions with aquaporin receptors, specifically aquaporin-4. Despite some ambiguity, vasopressin V1a receptor antagonism has been consistently associated with attenuated secondary brain injury and edema in experimental stroke models. The role of the vasopressin V2 receptor remains unclear, but perhaps it is involved in a positive feedback loop for vasopressin expression. Despite the encouraging initial findings we report here, future research is required to characterize further the utility of vasopressin antagonists in treatment of stroke.

Background Limited literature is available on the development of impaired glucose tolerance and diabetes mellitus after pancreaticoduodenectomy. The primary aim was to define the diabetic phenotype and correlate preoperative glycemic laboratory results to new-onset diabetes after pancreaticoduodenectomy. Study Design In this prospective study, perioperative fasting and postprandial (oral glucose tolerance test) plasma glucose, glycated hemoglobin, insulin, and c-peptide were measured in consecutive patients undergoing pancreaticoduodenectomy by the senior author from 2006 to 2017. American Diabetes Association definitions were used for glycemic classifications. Multivariate risk factor analysis was performed. Results Of 774 identified patients, 371 diabetics were excluded and 403 patients were included: 167 and 236 were preoperatively classified as nondiabetic and prediabetic, respectively. The incidence rates of diabetes at 120 months post pancreaticoduodenectomy were 9.0% (nondiabetics), 22.0% (prediabetics), and 16.6% (overall). Patients in whom diabetes developed demonstrated a 3-fold larger difference between oral glucose tolerance test and fasting glucose (Δ), and 2-fold larger Δinsulin and Δc-peptide values. Tiered multivariate analysis identified glycated hemoglobin >5.4% with a relative risk (RR) of 2.944 (p = 0.047) as an independent predictor of impaired glucose tolerance and diabetes mellitus. Analysis of patients stratified by preoperative classification identified fasting glucose >95 mg/dL (nondiabetics, RR 1.925; p = 0.002), and glycated hemoglobin ≥5.4% (prediabetics, RR 3.125; p = 0.040) as independent risk factors for diabetes. Compared with nondiabetics, prediabetics classified by any laboratory results demonstrated an RR of 2.471 (p = 0.001) for diabetes developing postoperatively. There was no association between primary pathology, advancing age, or BMI and increased risk of diabetes development. Conclusions Diabetes will develop after pancreaticoduodenectomy in approximately 16.6% of patients. A preoperative glycated hemoglobin >5.4% independently predicts new-onset diabetes. Pre- and postoperative endocrine analysis remains paramount for proper patient risk stratification.

Purpose: Molecular breast imaging (MBI) is a nuclear medicine technology that uses dual-head cadmium zinc telluride (CZT) gamma cameras to image functional uptake of a radiotracer, Tc-99m sestamibi, in the breast. An important factor in adoption of MBI in the screening setting is reduction of the necessary administered dose of Tc-99m sestamibi from the typically used dose of 740 MBq to approximately 148 MBq, such that MBI’s whole-body effective dose is comparable to that of screening mammography. Methods that increase MBI count sensitivity may allow a proportional reduction in the necessary administered dose. Our objective was to evaluate the impact of two count sensitivity improvement methods on image quality by evaluating count sensitivity, spatial resolution, and lesion contrast in phantom simulations. Methods: Two dual-head CZT-based MBI systems were studied: LumaGem and Discovery NM 750b. Two count sensitivity improvement methods were implemented: registered collimators optimized for dedicated breast imaging and widened energy acceptance window optimized for use with CZT. System sensitivity, spatial resolution, and tumor contrast-to-noise ratio (CNR) were measured comparing standard collimation and energy window setting [126–154 keV (+10%, −10%)] with optimal collimation and a wide energy window [110–154 keV (+10%, −21%)]. Results: Compared to the standard collimator designs and energy windows for these two systems, use of registered optimized collimation and wide energy window increased system sensitivity by a factor of 2.8–3.6. Spatial resolution decreased slightly for both systems with new collimation. At 3 cm from the collimator face, LumaGem’s spatial resolution was 4.8 and 5.6 mm with standard and optimized collimation; Discovery NM 750b’s spatial resolution was 4.4 and 4.6 mm with standard and optimized collimation, respectively. For both systems, at tumor depths of 1 and 3 cm, use of optimized collimation and wide energy window significantly improved CNR compared to standard settings for tumors 8.0 and 9.2 mm in diameter. At the closer depth of 1 cm, optimized collimation and wide energy window also significantly improved CNR for 5.9 mm tumors on Discovery NM 750b. Conclusions: Registered optimized collimation and wide energy window yield a substantial gain in count sensitivity and measurable gain in CNR, with some loss in spatial resolution compared to the standard collimator designs and energy windows used on these two systems. At low-count densities calculated to represent doses of 148 MBq, this tradeoff results in adequate count density and lesion contrast for detection of lesions ≥8 mm in the middle of a typical breast (3 cm deep) and lesions ≥6 mm close to the collimator (1 cm deep).

To report our findings from a prospective pilot study evaluating the accuracy of molecular breast imaging (MBI) in assessing tumor response to neoadjuvant therapy (NT) for breast cancer.Twenty patients with newly diagnosed invasive breast cancer who were scheduled to receive NT underwent MBI before beginning and after completing NT before surgery. MBI was performed using a dual-detector cadmium-zinc-telluride gamma camera system mounted on a modified mammography gantry after patients had received an intravenous injection of 20 mCi of 99mTc sestamibi. Tumor extent was measured on MBI, and tumor-to-background (T/B) ratios of radiotracer uptake were determined through region-of-interest analysis. Pathologic measurement of tumor size was used as a standard and compared with post-NT tumor size derived from MBI.Three patients in whom post-NT MBI could not be performed because of scheduling problems were excluded from analysis. Eighteen cancers were diagnosed in 17 patients. A correlation coefficient of r = 0.681 (P = 0.002) was found between MBI and residual tumor size. The average T/B ratio on MBI decreased from a pretreatment value of 3.0 to a posttreatment value of 1.4. The relative decrease in T/B ratio did not appear to be predictive of response.Measurements of tumor size by MBI and T/B ratios are limited in their predictive value regarding the pathologic extent of residual disease in women treated with NT for breast cancer. Alternate tumor-specific radiopharmaceuticals should be evaluated to provide information to improve planning and monitoring of breast cancer treatment.

We develop a model of repeated conflict that features probabilistic winner-take-all outcomes and compare its dynamics to the dynamics generated by a similar deterministic model in which combatants divide the conflict spoils. While these models generate the same behavior in a one-shot game, in a repeated setting the winner-take-all model generates richer dynamics than the dynamics generated by the deterministic model, which are new to the economics literature on conflict. As in real-world conflicts, the winner-take-all model generates changes in the relative dominance of combatants, full mobilization of fighting resources, and endogenous surrender. We evaluate the implications for the literature.

Agonists of somatostatin receptor subtype 2 (sst(2)) have been proposed as therapeutics for the treatment of proliferative diabetic retinopathy and exudative age-related macular degeneration. An HTS screen identified 2-quinolones as weak agonists of sst(2), and these were optimized to provide small molecules with sst(2) binding and functional potency comparable to peptide agonists. Agonist 21 was shown to inhibit rat growth hormone secretion following systemic administration and to inhibit ocular neovascular lesion formation after local administration.

Australia has been a leader in doctoral education over the last two decades. Proponents of the doctor of education (EdD), among others, in the early 1990s led the development of a range of awards termed “professional doctorates” (Maxwell & Shanahan, 1996), which were intended to contrast with the traditional PhD. The latter was then considered more academic, the former more professional, in orientation. A professional doctorate holder would not normally aspire for employment in a university though a good case can be made for professional doctorate holders to be hired by universities. A body of Australian professional doctoral literature has developed in Australia (see, e.g., Brennan, 1995; Ellis, 2006; Lee, Brennan, & Green, 2009; Malloch, 2010; Maxwell, 2011; Maxwell, Hickey, & Evans, 2005; Maxwell & Shanahan, 1996, 1998, 2001; McWilliam, 2003; Neumann, 2005; Pearson, 2006; Stock, 2013; Trigwell, Shannon, & Maurizi, 1997; Voudouris & Hunter, 2011). Some international comparative studies have been undertaken (e.g., Kot & Hendel, 2012; Servage, 2009; Whitechurch, 2009). A key doctoral education meeting place for 20 years has been the Quality in Postgraduate Research series of conferences held in Adelaide (see http://www.qpr.edu.au/).

The present studies used a psychophysical approach to examine the effect of cannabinoids on temporal processing. Rats trained to discriminate 2- and 8-s (Experiment 1, n=72) and 4- and 16-s (Experiment 2, n=60) intervals were tested with intermediate durations. Psychophysical functions for time, relating the probability of judging a duration as “long” as a function of the actual stimulus durations, were characterized by measures of central tendency (point of subjective equality, PSE) and variability (Weber fraction, WF). The potent cannabinoid agonist, WIN55,212-2 (1–3 mg/kg), produced a dose-related decrease in sensitivity to time (i.e. increase in WF) without systematically affecting PSE (Experiments 1 and 2). The central cannabinoid CB1 antagonist, SR141716A (1–3 mg/kg), did not alter either the WF or PSE (Experiments 1 and 2). Coadministration of SR141716A with WIN55,212-2 blocked the effect of the agonist on WF (Experiment 2), suggesting that the WF effect is mediated by actions at cannabinoid CB1 receptors. Computational modeling with an information processing theory of timing suggests that the reduction in sensitivity to time can be attributed to a disorder of attention.

OBJECTIVE. The purpose of this study was to assess the diagnostic performance of supplemental screening molecular breast imaging (MBI) in women with mammographically dense breasts after system modifications to permit radiation dose reduction. SUBJECTS AND METHODS. A total of 1651 asymptomatic women with mammographically dense breasts on prior mammography underwent screening mammography and adjunct MBI performed with 300-MBq (99m)Tc-sestamibi and a direct-conversion (cadmium zinc telluride) gamma camera, both interpreted independently. The cancer detection rate, sensitivity, specificity, and positive predictive value of biopsies performed (PPV3) were determined. RESULTS. In 1585 participants with a complete reference standard, 21 were diagnosed with cancer: two detected by mammography only, 14 by MBI only, three by both modalities, and two by neither. Of 14 participants with cancers detected only by MBI, 11 had invasive disease (median size, 0.9 cm; range, 0.5-4.1 cm). Nine of 11 (82%) were node negative, and two had bilateral cancers. With the addition of MBI to mammography, the overall cancer detection rate (per 1000 screened) increased from 3.2 to 12.0 (p0.001) (supplemental yield 8.8). The invasive cancer detection rate increased from 1.9 to 8.8 (p0.001) (supplemental yield 6.9), a relative increase of 363%, while the change in DCIS detection was not statistically significant (from 1.3 to 3.2, p =0.250). For mammography alone, sensitivity was 24%; specificity, 89%; and PPV3, 25%. For the combination, sensitivity was 91% (p0.001); specificity, 83% (p0.001); and PPV3, 28% (p = 0.70). The recall rate increased from 11.0% with mammography alone to 17.6% (p0.001) for the combination; the biopsy rate increased from 1.3% for mammography alone to 4.2% (p0.001). CONCLUSION. When added to screening mammography, MBI performed using a radiopharmaceutical activity acceptable for screening (effective dose 2.4 mSv) yielded a supplemental cancer detection rate of 8.8 per 1000 women with mammographically dense breasts.

▪ Abstract There has been substantial evidence for more than three decades that the major psychiatric illnesses such as schizophrenia, bipolar disorder, autism, and alcoholism have a strong genetic basis. During the past 15 years considerable effort has been expended in trying to establish the genetic loci associated with susceptibility to these and other mental disorders using principally linkage analysis. Despite this, only a handful of specific genes have been identified, and it is now generally recognized that further advances along these lines will require the analysis of literally hundreds of affected individuals and their families. Fortunately, the emergence in the past three years of a number of new approaches and more effective tools has given new hope to those engaged in the search for the underlying genetic and environmental factors involved in causing these illnesses, which collectively are among the most serious in all societies. Chief among these new tools is the availability of the entire human genome sequence and the prospect that within the next several years the entire complement of human genes will be known and the functions of most of their protein products elucidated. In the meantime the search for susceptibility loci is being facilitated by the availability of single nucleotide polymorphisms (SNPs) and by the beginning of haplotype mapping, which tracks the distribution of clusters of SNPs that segregate as a group. Together with high throughput DNA sequencing, microarrays for whole genome scanning, advances in proteomics, and the development of more sophisticated computer programs for analyzing sequence and association data, these advances hold promise of greatly accelerating the search for the genetic basis of most mental illnesses while, at the same time, providing molecular targets for the development of new and more effective therapies.