Stenting for Inferior Vena Cava Stenosis After Liver Transplant.

OBJECTIVE. A case series analysis and meta-analysis were performed to assess the efficacy of stenting for inferior vena cava (IVC) stenosis after liver transplant; a secondary analysis assessed demographic factors as potential predictors of all-cause mortality. MATERIALS AND METHODS. Liver transplant recipients treated for symptomatic IVC stenosis at a major medical center from 1996 to 2017 were assessed. The main medical databases were searched for studies evaluating stenting in liver transplant recipients with IVC stenosis. Cox proportional hazards regression analysis was used to determine predictors of survival (age, sex, reason for transplant, stent size and number, publication year). Univariate and multivariable models were constructed. Because patients in the case series and meta-analysis had similar demographics and outcomes, the results were pooled. RESULTS. The case series included 40 patients (31 treated with stents; nine, without stents). Meta-analysis of 5277 records identified 17 eligible studies involving 73 patients. Stenting was effective in resolving the gradient in 100% of patients and in relieving symptoms in 85% of patients. Primary stent patency at latest follow-up (median, 556 days) was seen in 113 of 118 stents (96%; some patients had multiple stents). Reason for transplant was the only significant predictor of all-cause mortality; patients with hepatocellular carcinoma had a higher hazard of death than those undergoing transplant for other reasons (hazard ratio = 3.23; 95% CI, 1.40-7.42; p = 0.006). CONCLUSION. Stenting for IVC stenosis after liver transplant is clinically effective and durable, with 96% of stents showing long-term patency and 85% of patients experiencing symptom relief.

Corpora amylacea in prostatectomy tissue and associations with molecular, histological, and lifestyle factors.

BACKGROUND: Corpora amylacea are amyloid bodies commonly found adjacent to damaged prostate epithelium. Little is known about their formation or function. The current study sought to characterize corpora amylacea in prostate tissue and to describe their relationship with clinical, histological, molecular, and lifestyle factors, especially with chronic inflammation which is associated with aggressive disease. METHODS: We studied a cohort of 355 men with prostate cancer and tissue specimens from the Health Professionals Follow-Up Study. Pathologists examined H&E slides and undertook a standardized review for histologic data and inflammation. Trained observers counted corpora amylacea within the benign and predominately tumor areas. Immunohistochemistry biomarkers were available from tissue microarrays. We used multivariable logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) to assess associations of chronic inflammation, clinical, histological, molecular, and lifestyle factors with the presence of corpora amylacea. RESULTS: Corpora amylacea were present in benign tissue area for 298 men (84%). Specimens with moderate-to-severe chronic inflammation were more likely to have corpora amylacea in benign regions (OR = 5.4 95%CI 1.9, 15.6). Moreover, corpora amylacea were more common in men with higher body mass index (OR = 1.13 95%CI 1.01, 1.26). In contrast, Gleason grade (OR = 0.4 95%CI 0.2, 0.8), proliferation index (OR = 0.6 95%CI 0.3, 1.2) and the presence of the TMPRSS2:ERG fusion (OR = 0.4 95%CI 0.2, 0.8) were inversely associated with corpora amylacea presence. TURP specimens were less likely to have corpora amylacea than prostatectomy specimens (OR = 0.12 95%CI 0.03, 0.47). Age, PSA, stage, biomarkers of angiogenesis and PTEN, and vasectomy were not significantly associated with corpora amylacea. CONCLUSION: Corpora amylacea were common among men with prostate cancer and were associated with pro-inflammatory factors, some markers of less aggressive disease, and lack of the TMPRSS2:ERG fusion.

Familial Risk and Heritability of Cancer Among Twins in Nordic Countries.

IMPORTANCE: Estimates of familial cancer risk from population-based studies are essential components of cancer risk prediction. OBJECTIVE: To estimate familial risk and heritability of cancer types in a large twin cohort. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 80,309 monozygotic and 123,382 same-sex dizygotic twin individuals (N = 203,691) within the population-based registers of Denmark, Finland, Norway, and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50,990 individuals who died of any cause, and 3804 who emigrated and were lost to follow-up. EXPOSURES: Shared environmental and heritable risk factors among pairs of twins. MAIN OUTCOMES AND MEASURES: The main outcome was incident cancer. Time-to-event analyses were used to estimate familial risk (risk of cancer in an individual given a twin's development of cancer) and heritability (proportion of variance in cancer risk due to interindividual genetic differences) with follow-up via cancer registries. Statistical models adjusted for age and follow-up time, and accounted for censoring and competing risk of death. RESULTS: A total of 27,156 incident cancers were diagnosed in 23,980 individuals, translating to a cumulative incidence of 32%. Cancer was diagnosed in both twins among 1383 monozygotic (2766 individuals) and 1933 dizygotic (2866 individuals) pairs. Of these, 38% of monozygotic and 26% of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5% (95% CI, 4%-6%) higher in dizygotic (37%; 95% CI, 36%-38%) and an absolute 14% (95% CI, 12%-16%) higher in monozygotic twins (46%; 95% CI, 44%-48%) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32%). For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33% (95% CI, 30%-37%). Significant heritability was observed for the cancer types of skin melanoma (58%; 95% CI, 43%-73%), prostate (57%; 95% CI, 51%-63%), nonmelanoma skin (43%; 95% CI, 26%-59%), ovary (39%; 95% CI, 23%-55%), kidney (38%; 95% CI, 21%-55%), breast (31%; 95% CI, 11%-51%), and corpus uteri (27%; 95% CI, 11%-43%). CONCLUSIONS AND RELEVANCE: In this long-term follow-up study among Nordic twins, there was significant excess familial risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus. This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.

ABO blood group alleles and prostate cancer risk: Results from the breast and prostate cancer cohort consortium (BPC3).

BACKGROUND: ABO blood group has been associated with risk of cancers of the pancreas, stomach, ovary, kidney, and skin, but has not been evaluated in relation to risk of aggressive prostate cancer. METHODS: We used three single nucleotide polymorphisms (SNPs) (rs8176746, rs505922, and rs8176704) to determine ABO genotype in 2,774 aggressive prostate cancer cases and 4,443 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). Unconditional logistic regression was used to calculate age and study-adjusted odds ratios and 95% confidence intervals for the association between blood type, genotype, and risk of aggressive prostate cancer (Gleason score ≥8 or locally advanced/metastatic disease (stage T3/T4/N1/M1). RESULTS: We found no association between ABO blood type and risk of aggressive prostate cancer (Type A: OR = 0.97, 95%CI = 0.87-1.08; Type B: OR = 0.92, 95%CI =n0.77-1.09; Type AB: OR = 1.25, 95%CI = 0.98-1.59, compared to Type O, respectively). Similarly, there was no association between "dose" of A or B alleles and aggressive prostate cancer risk. CONCLUSIONS: ABO blood type was not associated with risk of aggressive prostate cancer.

Multicenter double-blinded randomized controlled trial of standard abdominal wound edge protection with surgical dressings versus coverage with a sterile circular polyethylene drape for prevention of surgical site infections: a CHIR-Net trial (BaFO; NCT01181206).

OBJECTIVE: To determine whether circular plastic wound edge protectors (CWEPs) significantly reduce the rate of surgical site infections (SSIs) in comparison to standard surgical towels in patients undergoing laparotomy. BACKGROUND: SSIs cause substantial morbidity, prolonged hospitalization, and costs and remain one of the most frequent surgical complications. CWEPs have been proposed as a measure to reduce the incidence of SSIs. METHODS: In this randomized controlled, multicenter, 2-arm, parallel-group design, patient- and observer-blinded trial patients undergoing open elective abdominal surgery were assigned to either intraoperative wound coverage with a CWEP or standard coverage with surgical towels. Primary endpoint was superiority of intervention over control in terms of the incidence of SSIs within a 30-day postoperative period. RESULTS: Between September 2010 and November 2012, 608 patients undergoing laparotomy were randomized at 16 centers across Germany. Three patients in the device group and 11 patients in the control group did not undergo laparotomy. Patients' and procedural characteristics were well balanced between the 2 groups. Forty-eight patients discontinued the study prematurely, mainly because of relaparotomy (control, n=9; intervention, n=9) and death (control, n=4; intervention, n=7). A total of 79 patients experienced SSIs within 30 days of surgery, 27 of 274 (9.9%) in the device group and 52 of 272 (19.1%) in the control group (odds ratio=0.462, 95% confidence interval: 0.281-0.762; P=0.002). Subgroup analyses indicate that the effect could be more pronounced in colorectal surgery, and in clean-contaminated/contaminated surgeries. CONCLUSIONS: Our trial shows that CWEPs are effective at reducing the incidence of SSIs in elective and clean or clean-contaminated open abdominal surgery.

A Curricular Model for Simulation Within Orthopaedic Residency Training.

Introduction: American Board of Orthopaedic Surgery/American Council on GraduateMedical Education Residency Review Committee training requirements have necessitated the need for the adoption of simulation education into existing programmatic requirements. Current guidelines focus only on interns at a potentially significant cost to programs; both in total dollar amount and time. Methods: The authors aim to provide a model that can maximize utility for all resident levels, manage cost by maximizing the use of cadaveric material, and allow integration of varied industry support. Results: The Oregon Health & Science University Orthopaedic education program has developed a high-fidelity training curriculum that (1) is applicable to both junior and senior residents (2) has minimized the cost per resident with the reuse of cadaveric specimens and (3) has nurtured partnerships with industry stakeholders to reduce bias in training by collaborating with most major industry representatives. Conclusion: The simulation curriculum outlined in this manuscript may serve as a reference for other programs and institutions to develop their own residency educational curriculum models.

Innovative growth and development of a neurological surgery residency cadaveric spine-simulation training program: a single-institution experience.

OBJECTIVE: Cadaveric and dry 3D model-based simulation training is a valuable educational tool for neurosurgical residents. Such simulation training is an opportunity for residents to hone technical skills and decision-making and enhance their neuroanatomy knowledge. The authors describe the growth and development of the Oregon Health & Science University Department of Neurological Surgery resident-focused, hands-on, spine-simulation surgery courses and provide details of course evaluations, layout, and setup. METHODS: A four-part spine surgical simulation series, including two human cadaveric and two dry 3D model-based courses, was created to provide resident spine procedure training. Residents participated in the spine simulation series (2017-2021) and completed annual course curriculum and anonymous post-course evaluations. Evaluations included both Likert scale items and free-text responses. Responses to Likert scale items were analyzed in Python. Free-text responses were quantified using the Valence Aware Dictionary for Sentiment Reasoner. Descriptive statistics were calculated and plotted using Python's seaborn and matplotlib library modules. RESULTS: The analysis included 129 spine (occipitocervical, thoracolumbar, and spine model fusion I and II) simulation course evaluations. Likert responses demonstrated high average responses for evaluation questions (4.67 ± 0.90 and above). The average compound sentiment value was 0.58 ± 0.28. CONCLUSIONS: This is the first time Likert responses and sentiment analysis have been used to demonstrate how neurosurgical residents positively value a hands-on spine simulation training. Simulation is an essential component of neurosurgical resident education training. The authors encourage other neurosurgical education programs to develop and leverage spine simulation as a teaching tool.

Stimulation of the Premotor Cortex Enhances Interhemispheric Functional Connectivity in Association with Upper Limb Motor Recovery in Moderate-to-Severe Chronic Stroke.

Background: Transcranial direct current stimulation (tDCS) targeting the primary motor cortex is modestly effective for promoting upper-limb motor function following stroke. The premotor cortex (PMC) represents an alternative target based on its higher likelihood of survival and dense motor-network connections. Objective: The objective of this study was to determine whether ipsilesional PMC tDCS affects motor network functional connectivity (FC) in association with reduction in motor impairment, and to determine whether this relationship is influenced by baseline motor severity. Methods: Participants with chronic stroke were randomly assigned to receive active-PMC or sham-tDCS with rehabilitation for 5 weeks. Resting-state functional magnetic resonance imaging was acquired to characterize change in FC across motor-cortical regions. Results: Our results indicated that moderate-to-severe participants who received active-tDCS had greater increases in PMC-to-PMC interhemispheric FC compared to those who received sham; this increase was correlated with reduction in proximal motor impairment. There was also an increase in intrahemispheric dorsal premotor cortex-primary motor cortex FC across participants regardless of severity or tDCS group assignment; this increase was correlated with a reduction in proximal motor impairment in only the mild participants. Conclusions: Our findings have significance for developing targeted brain stimulation approaches. While participants with milder impairments may inherently recruit viable substrates within the ipsilesional hemisphere, stimulation of PMC may enhance interhemispheric FC in association with recovery in more impaired participants. Trial Registration: ClinicalTrials.gov Identifier: NCT01539096; Registration date: February 21, 2012.

Innovative growth and development of a neurological surgery residency cadaveric skull base simulation training program: A single institution experience.

OBJECTIVE: Neurosurgical cadaveric and simulation training is a valuable opportunity for residents and fellows to develop as neurosurgeons, further neuroanatomy knowledge, and develop decision-making and technical expertise. The authors describe the growth and development of Oregon Health & Science University (OHSU) Department of Neurological Surgery (NSG) resident hands-on simulation skull base course and provide details of course layout and setup. METHODS: A three-part surgical simulation series was created to provide training in cadaveric skull base procedures. Course objectives were outlined for participants. Residents participated in NSG hands-on simulation courses (years 2015-2020) and completed annual course curriculum and anonymous course evaluations, which included free text reviews. Courses were evaluated by Likert scale analysis within Python, and free text was quantified using Valence Aware Dictionary for sEntiment Reasoning (VADER). Descriptive statistics were calculated and plotted using Python's Seaborn and Matplotlib library modules. RESULTS: Analysis included 162 skull base (anterior fossa, middle fossa and lateral, and endoscopic endonasal-based) simulation course evaluations. Resident responses were overwhelmingly positive. Likert responses demonstrated high average responses for each question (4.62 ± 0.56 and above). A positive attitude about simulation courses is supported by an average compound sentiment value of 0.558 ± 0.285. CONCLUSION: This is the first time Likert responses and sentiment analysis have been used to demonstrate how neurosurgical residents view a comprehensive, multi-year hands-on simulation training program. We hope the information presented serves as a guide for other institutions to develop their own residency educational curriculum in cadaveric skull base procedures.

Clinical and Imaging Characteristics Associated with Color Vision Impairment in Lewy Body Disease.

BACKGROUND: Color vision impairment (CVI) has been reported in dementia with Lewy bodies (DLB) and prodromal Lewy body disease (pro-LBD). OBJECTIVE: In order to better characterize the diagnostic value of CVI testing, we compared the prevalence of CVI in patients with with Lewy body disease compared to Alzheimer's disease (AD), and we examined clinical and imaging characteristics associated with CVI in patients with DLB and suspected pro-LBD. METHODS: We retrospectively reviewed medical records, dopamine transporter (DaT-SPECT) imaging, and volumetric MRI from patients with AD, DLB, and suspected pro-LBD who underwent an online Farnsworth D-15 color vision test. RESULTS: 111 patients (62 DLB, 25 pro-LBD, and 24 AD) were included with a median age of 75 years. Newly diagnosed CVI was present in 67% of patients with DLB, 44% of patients with pro-LBD, and 18% of patients with AD. In patients with DLB, CVI was associated with lower Montreal Cognitive Assessment (MoCA) scores and lower sub-scores in visuospatial/executive function, naming, and language. In a multivariable logistic regression model, a diagnosis of DLB or pro-LBD compared to AD, and a lower composite MoCA score in visuospatial/executive function, naming, and language were associated with CVI controlling for age and gender. Among 17 DLB patients who underwent volumetric MRI, patients with CVI (n = 9) demonstrated lower normative volumetric percentiles in the right transverse superior temporal lobe. CONCLUSION: We provide further evidence that CVI can help differentiate DLB from AD, and we suggest that CVI may be an indicator of cognitive decline and disease progression in DLB.

Perineural Invasion and Risk of Lethal Prostate Cancer.

Background: Prostate cancer has a propensity to invade and grow along nerves, a phenomenon called perineural invasion (PNI). Recent studies suggest that the presence of PNI in prostate cancer has been associated with cancer aggressiveness.Methods: We investigated the association between PNI and lethal prostate cancer in untreated and treated prostate cancer cohorts: the Swedish Watchful Waiting Cohort of 615 men who underwent watchful waiting, and the U.S. Health Professionals Follow-Up Study of 849 men treated with radical prostatectomy. One pathologist performed a standardized histopathologic review assessing PNI and Gleason grade. Patients were followed from diagnosis until metastasis or death.Results: The prevalence of PNI was 7% and 44% in the untreated and treated cohorts, respectively. PNI was more common in high Gleason grade tumors in both cohorts. PNI was associated with enhanced tumor angiogenesis, but not tumor proliferation or apoptosis. In the Swedish study, PNI was associated with lethal prostate cancer [OR 7.4; 95% confidence interval (CI), 3.6-16.6; P < 0.001]. A positive, although not statistically significant, association persisted after adjustment for age, Gleason grade, and tumor volume (OR 1.9; 95% CI, 0.8-5.1; P = 0.17). In the U.S. study, PNI predicted lethal prostate cancer independent of clinical factors (HR 1.8; 95% CI, 1.0, 3.3; P =0.04).Conclusions: These data support the hypothesis that perineural invasion creates a microenvironment that promotes cancer aggressiveness.Impact: Our findings suggest that PNI should be a standardized component of histopathologic review, and highlights a mechanism underlying prostate cancer metastasis. Cancer Epidemiol Biomarkers Prev; 26(5); 719-26. ©2017 AACR.

Sniffing out significant "Pee values": genome wide association study of asparagus anosmia.

OBJECTIVE:  To determine the inherited factors associated with the ability to smell asparagus metabolites in urine. DESIGN:  Genome wide association study. SETTING:  Nurses' Health Study and Health Professionals Follow-up Study cohorts. PARTICIPANTS:  6909 men and women of European-American descent with available genetic data from genome wide association studies. MAIN OUTCOME MEASURE:  Participants were characterized as asparagus smellers if they strongly agreed with the prompt "after eating asparagus, you notice a strong characteristic odor in your urine," and anosmic if otherwise. We calculated per-allele estimates of asparagus anosmia for about nine million single nucleotide polymorphisms using logistic regression. P values <5×10-8 were considered as genome wide significant. RESULTS:  58.0% of men (n=1449/2500) and 61.5% of women (n=2712/4409) had anosmia. 871 single nucleotide polymorphisms reached genome wide significance for asparagus anosmia, all in a region on chromosome 1 (1q44: 248139851-248595299) containing multiple genes in the olfactory receptor 2 (OR2) family. Conditional analyses revealed three independent markers associated with asparagus anosmia: rs13373863, rs71538191, and rs6689553. CONCLUSION:  A large proportion of people have asparagus anosmia. Genetic variation near multiple olfactory receptor genes is associated with the ability of an individual to smell the metabolites of asparagus in urine. Future replication studies are necessary before considering targeted therapies to help anosmic people discover what they are missing.

Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists.

2-Aminooxazolines were discovered as a novel structural class of TAAR1 ligands. Starting from a known adrenergic compound 1, structural modifications were made to obtain highly potent and selective TAAR1 ligands such as 12 (RO5166017), 18 (RO5256390), 36 (RO5203648), and 48 (RO5263397). These compounds exhibit drug-like physicochemical properties, have good oral bioavailability, and display in vivo activity in a variety of animal models relevant for psychiatric diseases and addiction.

Design of novel aminopyrrolidine factor Xa inhibitors from a screening hit.

Starting from a hit identified by focused screening, 3-aminopyrrolidine factor Xa inhibitors were designed. The binding mode as determined by X-ray structural analysis as well as the pharmacokinetic behaviour of selected compounds is discussed.