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Chondrosarcoma is a highly aggressive primary malignant bone tumor mostly occurring in adults. There are no effective systemic treatments, and patients with this disease have poor survival. miR-181a is an oncomiR that is overexpressed in high-grade chondrosarcoma and promotes tumor progression. Regulator of G-protein signaling 16 (RGS16) is a target of miR-181a. Inhibition of RGS16 expression by miR-181a enhances CXC chemokine receptor 4 signaling, which in turn increases MMP1 and VEGF expression, angiogenesis, and metastasis. Here, we report the results of systemic treatment with anti-miRNA oligonucleotides (AMO) directed against miR-181a utilizing a nanopiece delivery platform (NPs). NPs were combined with a molecular beacon or anti–miR-181a oligonucleotides and are shown to transfect chondrosarcoma cells in vitro and in vivo. Intratumoral injection and systemic delivery had similar effects on miR-181a expression in nude mice bearing chondrosarcoma xenografts. Systemic delivery of NPs carrying anti–miR-181a also restored RGS16 expression, decreased expression of VEGF and MMP1, MMP activity, and tumor volume by 32% at day 38, and prolonged survival from 23% to 45%. In conclusion, these data support that systemic delivery of AMO shows promise for chondrosarcoma treatment.

Lung metastatic burden quantified as number of nodules per lung and area of nodules as a percent of total lung area.

Background Determination of sedation type during gastrointestinal procedures is generally based on risk assessment via the American Society of Anesthesiologists (ASA) classification system, but the reliance of anesthesia risk on clinical factors remains largely uninvestigated. We aim to determine the association between various clinical factors and choice of sedation type during gastrointestinal procedures. Methods This single-center, retrospective cohort study used electronic medical records to identify patients receiving colonoscopy or endoscopy at Rhode Island Hospital. The electronic medical record was queried for history of alcohol abuse, opioid abuse, polysubstance abuse, prescriptions for psychotropic or opioid medications and ASA classification. Logistic regression was used to measure how patient characteristics correlated with sedation type. Results Totally, 2,033 patients were included in the study; 1,080 patients received moderate sedation and 853 received monitored anesthesia care (MAC). Three hundred fifty-four (60.2%) MAC patients had a history of alcohol abuse compared to 234 (39.8%) moderate sedation patients (P < 0.2334); 178 (62.9%) MAC and 105 (37.1%) moderate sedation patients had a history of opioid abuse (P < 0.001); 203 (73.6%) MAC and 73 (26.4%) moderate sedation patients had a history of polysubstance abuse (P < 0.001); and 815 (75.1%) MAC patients had psychiatric comorbidities versus 270 (24.9%) in the moderate sedation group (P < 0.001). In the MAC cohort, alcohol, opioid, polysubstance abuse and psychiatric history were associated with previous failure of moderate sedation (P < 0.0001). Conclusions For a subset of patients, clinical factors including alcohol, opioid, polysubstance abuse and psychiatric history, in addition to ASA classification, play an important role in sedation management.

This study measured therapist behaviors in relation to subsequent habituation within exposure tasks, and also tested their direct and indirect relationships (via habituation) with clinical outcomes of exposure therapy. We observed 459 videotaped exposure tasks with 111 participants in three clinical trials for pediatric obsessive-compulsive disorder (POTS trials). Within exposure tasks, therapist behaviors and patient fear were coded continuously. Outcomes were habituation and post-treatment change in symptom severity, global improvement, and treatment response. More therapist behaviors that encourage approach—and less use of accommodation, unrelated talk, and externalizing language—predicted greater subsequent habituation during individual exposure tasks (exposure-level), and also predicted improved patient clinical outcomes via higher ‘total dose’ of habituation across treatment (patient-level indirect effect). For six of seven therapist behaviors analyzed, the relationship with subsequent habituation within exposure differed by patient fear (low, moderate, or high) at the time the behavior was used. Two therapist behaviors had direct effects in the opposite direction expected; more unrelated talk and less intensifying were associated with greater patient symptom reduction. Results shed light on the “black box” of in-session exposure activities and point to specific therapist behaviors that may be important for clinical outcomes. These behaviors might be best understood in the context of changing patient fear during exposure tasks. Future studies should test whether therapist behaviors can be experimentally manipulated to produce improvement in clinical outcomes.

This study tested whether a new training tool, the Exposure Guide (EG), improved in-session therapist behaviors that have been associated with youth outcomes in prior clinical trials of exposure th...

Summary Hemorrhagic shock induces an aberrant immune response characterized by simultaneous induction of a proinflammatory state and impaired host defenses. The objective of this study was to evaluate the impact of conditionally immortalized neutrophil progenitors (NPs) on this aberrant immune response. We employed a mouse model of hemorrhagic shock, followed by the adoptive transfer of NPs and subsequent inoculation of Staphylococcus aureus to induce pneumonia. We observed that transplant of NPs decreases the proportion of host neutrophils that express programmed death ligand 1 and intercellular adhesion molecule 1 in the context of prior hemorrhage. Following hemorrhage, NP transplant decreased proinflammatory cytokines in the lungs, increased neutrophil migration into the airspaces, and enhanced bacterial clearance. Further, hemorrhagic shock improved NP engraftment in the bone marrow. These results suggest that NPs hold the potential for use as a cellular therapy in the treatment and prevention of secondary infection following hemorrhagic shock., Highlights • Myeloid progenitors restore a competent inflammatory response to pneumonia • Progenitor transplantation promotes clearance of secondary S. aureus pneumonia • Hemorrhagic shock enhances engraftment of transplanted myeloid progenitors, In this article, Cohen and colleagues evaluate the impact of myeloid progenitor transplantation in a “two-hit” mouse model of critical illness. The authors show that progenitor transplantation reverses a dysfunctional host response to secondary Staphylococcus aureus pneumonia induced by prior hemorrhagic shock.

Objective Severe bronchopulmonary dysplasia (sBPD) can lead to long term morbidity. We created a sBPD multidisciplinary team in 2011 to optimize care and improve outcomes. Study design Retrospective chart review of three groups between 2008 and 2016: patients with sBPD born before 2011, patients with sBPD born after 2011, and patients with moderate BPD born after 2011. Results Infants with sBPD after 2011 had a shorter NICU length of stay compared with children born before 2011 (mean 140 days vs 170 days p

Background Online portals have been shown to be a valuable tool for patients to improve compliance with medical treatment in numerous studies across medical specialties. Our aim was to study the effects of the use of web-based applications that allow patients to track their appointments, labs, and provider visit notes on achievement of renal transplantation. Study Design This is a retrospective chart review of patients in 2 outpatient dialysis centers associated with a 719-bed tertiary care academic medical center. Results Nine percent of portal users at 3 years after initiation of hemodialysis were the recipients of kidney transplants vs 9% of nonusers. At 4 years, 23% of users were transplant recipients vs 13% of nonusers. At 5 years, 40% of users were transplant recipients vs 14% of nonusers. There was statistically significant divergence of the curves, with the greatest difference observed at 5 years (p = 0.047). In addition, increased number of logins per month was associated with shortened time to renal transplantation (p = 0.0067). Conclusions Online portal use is associated with a higher likelihood of being approved as a transplantation candidate and increased number of logins is associated with shortened time to renal transplantation.

Mutagenesis is integral for bacterial evolution and the development of antibiotic resistance. Environmental toxins and stressors are known to elevate the rate of mutagenesis through direct DNA toxicity, known as stress-associated mutagenesis, or via a more general stress-induced process that relies on intrinsic bacterial pathways. Here, we characterize the spectra of mutations induced by an array of different stressors using high-throughput sequencing to profile thousands of spectinomycin-resistant colonies of Bacillus subtilis. We found 69 unique mutations in the rpsE and rpsB genes, and that each stressor leads to a unique and specific spectrum of antibiotic-resistance mutations. While some mutations clearly reflected the DNA damage mechanism of the stress, others were likely the result of a more general stress-induced mechanism. To determine the relative fitness of these mutants under a range of antibiotic selection pressures, we used multistrain competitive fitness experiments and found an additional landscape of fitness and resistance. The data presented here support the idea that the environment in which the selection is applied (mutagenic stressors that are present), as well as changes in local drug concentration, can significantly alter the path to spectinomycin resistance in B. subtilis.

Chondrosarcoma is a highly aggressive primary malignant bone tumor mostly occurring in adults. There are no effective systemic treatments, and patients with this disease have poor survival. miR-181a is an oncomiR that is overexpressed in high-grade chondrosarcoma and promotes tumor progression. Regulator of G-protein signaling 16 (RGS16) is a target of miR-181a. Inhibition of RGS16 expression by miR-181a enhances CXC chemokine receptor 4 signaling, which in turn increases MMP1 and VEGF expression, angiogenesis, and metastasis. Here, we report the results of systemic treatment with anti-miRNA oligonucleotides (AMO) directed against miR-181a utilizing a nanopiece delivery platform (NPs). NPs were combined with a molecular beacon or anti–miR-181a oligonucleotides and are shown to transfect chondrosarcoma cells in vitro and in vivo. Intratumoral injection and systemic delivery had similar effects on miR-181a expression in nude mice bearing chondrosarcoma xenografts. Systemic delivery of NPs carrying anti–miR-181a also restored RGS16 expression, decreased expression of VEGF and MMP1, MMP activity, and tumor volume by 32% at day 38, and prolonged survival from 23% to 45%. In conclusion, these data support that systemic delivery of AMO shows promise for chondrosarcoma treatment.

Since stress fractures are common among adolescent athletes, it is important to identify bone assessment tools that accurately identify risk. We investigated the discriminative ability of two imaging technologies to classify at-risk athletes. Findings suggested that peripheral quantitative computed tomography (pQCT) has the ability to distinguish differences in bone structure in injured vs. uninjured limbs. Given the high stress fracture (SFX) prevalence among adolescent girls, an understanding of the most informative assessment tools to identify SFX risks are required. We investigated the discriminative ability of pQCT vs. dual-energy X-ray absorptiometry (DXA) to classify athletes with or without SFX. Twelve adolescent athletes diagnosed with a lower-extremity SFX were compared with 12 matched controls. DXA measured areal bone mineral density (aBMD) and content of the total body, and lumbar spine. Bilateral tibiae were assessed with pQCT. At the metaphysis (3%), total density (ToD), trabecular density (TrD), trabecular area (TrA), and estimated bone strength in compression (BSIc), and at the diaphysis (38% and 66%), total bone area (ToA), cortical density (CoD), cortical area (CoA), estimated bone strength in torsion (SSIp), and peri- and endocortical and muscle area (MuA) were obtained. Cortical bone mass/density around the center of mass and marrow density (estimate of adiposity) were calculated using ImageJ software. General estimated equations adjusting for multiple comparisons (Holm-Bonferroni method) were used to compare means between (1) injured limb of the case athletes vs. uninjured limb of the control athletes and (2) uninjured limb of the case athletes vs. uninjured limbs of the controls and injured vs. uninjured limb of case athletes with a SFX. aBMD and content showed no significant differences between cases and controls. When comparing the injured vs. uninjured leg in the case athletes by pQCT at the 3% tibia, unadjusted TrD, total density, and BSIc were significantly lower (p

5598 Background: Clear Cell Carcinoma (CCC) outside the kidney is a rare tumor that can arise from multiple organs, including the ovary, endometrium and cervix. Extra-renal CCC is chemoresistant and has a poor prognosis. Data suggest that CCC of the gynecologic tract resembles the genomic profile of Renal Cell Carcinoma (RCC), which is responsive to immune checkpoint inhibition (ICI) therapy. We are conducting a two-stage phase 2 trial evaluating immunotherapy for extra-renal CCC. The primary objective is to assess overall rate of response (ORR); Progression-Free (PFS), Overall Survival (OS), and correlative biomarker studies are secondary. Here we present the results of Stage 1. Methods: This is a randomized two-stage non-comparative phase II study evaluating nivolumab (240mg IV every two weeks) alone (N) and in combination with ipilimumab (1mg/kg every six weeks, [N+I]) in patients with relapsed extra-renal CCC after at least one prior chemotherapy (no prior ICI), and measurable disease. Treatment was continued until disease progression or unacceptable toxicity. Stage 1 of this trial called for up to 30 volunteers (15 per arm) after which the study was closed. Consideration to reopen to stage 2 called for two or more responses in either arm. Here we present the completion of Stage 1; the release of results was approved by Brown University Oncology Group (BrUOG) Data Safety and Monitoring Committee. Results: Between July 2018 and October 2021, 30 patients were enrolled and 29 were treated (Table). The majority (83%) had CCC of the ovary (n=24). The ORR with N and N+I was 14.2 and 26.7%, respectively. The 6 month PFS rate was 19.1 and 43.8%; median PFS was 2.7 (95%CI 1.3-5.1) and 5.1 months (95%CI 0.9-NR), respectively. Grade ≥3 treatment-related toxicities occurred in 4 (28.6%) on N and 5 (33.3%) on N+I. There were no treatment-related deaths and no new safety signals. One volunteer enrolled on N+I stopped treatment after two years and remains in CR to date. Conclusions: Although sufficient activity was seen in CCC in both arms, the single-agent activity of N is similar to published reports in platinum-resistant epithelial ovarian cancer and decision made not to pursue it further. However, the combination of ipilimumab and nivolumab warrants additional investigation, and the second stage of this study will enroll 14 more patients to receive N+I. Clinical trial information: NCT03355976. [Table: see text]

PurposeNext generation sequencing has expanded our understanding of many disease processes, including trauma and critical illness. Many studies focus identifying a small set of genes or proteins that are aberrantly expressed. Our objective was to determine whether global differences in pre-mRNA processing entropy, or disorder, could offer novel insights in the setting of critical illness.MethodsWe used an established murine model of trauma that consisted of hemorrhagic shock and cecal ligation and puncture. In our first experiment mice exposed to trauma were compared to controls. In our second experiment, survival 14 days after exposure to trauma was studied. Using deep RNA sequencing we determined entropy values for every pre-mRNA processing event identified. We then used principal component analysis (PCA) to conduct unsupervised classification of the data.ResultsMice exposed to trauma separated from controls using PCA. Similarly, mice that did not survive 14 days post exposure clustered closely together on PCA.ConclusionOur results suggest that there is a substantial difference in global pre-mRNA processing entropy in mice exposed to trauma vs. controls, and that pre-mRNA processing entropy may be helpful in predicting mortality. The method introduced here is easily transferrable to other disease processes and samples.

Background Mesenchymal stem cell–derived extracellular vesicles (EVs) promote angiogenesis in the ischemic myocardium. This study examines the difference in vascular density, myocardial perfusion, molecular signaling, and gene expression between normal diet (ND) and high fat diet (HFD) groups at baseline and following intramyocardial injection of EVs. Methods and Results Intact male Yorkshire swine fed either an ND (n=17) or HFD (n=14) underwent placement of an ameroid constrictor on the left circumflex coronary artery. Subsequently, animals received either intramyocardial injection of vehicle‐saline as controls; (ND‐controls n=7, HFD‐controls, n=6) or EVs; (ND‐EVs n=10, HFD‐EVs n=8) into the ischemic territory. Five weeks later, myocardial function, perfusion, vascular density, cell signaling, and gene expression were examined. EVs improved indices of myocardial contractile function, myocardial perfusion, and arteriogenesis in both dietary cohorts. Interestingly, quantification of alpha smooth muscle actin demonstrated higher basal arteriolar density in HFD swine compared with their ND counterparts; whereas EVs were associated with increased CD31‐labeled endothelial cell density only in the ND tissue, which approached significance. Levels of total endothelial nitric oxide synthase, FOXO1 (forkhead box protein O1) , transforming growth factor‐β, phosphorylated VEGFR2 (vascular endothelial growth factor receptor 2), and phosphorylated MAPK ERK1/ERK2 (mitogen‐activated protein kinase) were higher in ischemic myocardial lysates from ND‐controls compared with HFD‐controls. Conversely, HFD‐control tissue showed increased expression of phosphorylated endothelial nitric oxide synthase, phosphorylated FOXO1, VEGFR2, and MAPK ERK1/ERK2 with respect to ND‐controls. Preliminary gene expression studies indicate differential modulation of transcriptional activity by EVs between the 2 dietary cohorts. Conclusions HFD produces a profound metabolic disorder that dysregulates the molecular mechanisms of collateral vessel formation in the ischemic myocardium, which may hinder the therapeutic angiogenic effects of EVs.

This study tested whether a new training tool, the Exposure Guide (EG), improved in-session therapist behaviors (i.e., indicators of quality) that have been associated with youth outcomes in prior clinical trials of exposure therapy. Six therapists at a community mental health agency (CMHA) provided exposure therapy for 8 youth with obsessive–compulsive disorder (OCD). Using a nonconcurrent multiple baseline design with random assignment to baseline lengths of 6 to 16 weeks, therapists received gold-standard exposure therapy training with weekly consultation (baseline phase) followed by addition of EG training and feedback (intervention phase). The primary outcome was therapist behavior during in-session exposures, observed weekly using a validated coding system. Therapist behavior was evaluated in relation to a priori benchmarks derived from clinical trials. Additional outcomes included training feasibility/acceptability, therapist response to case vignettes and beliefs about exposure, and independent evaluator-rated clinical outcomes. Three therapists reached behavior benchmarks only during the EG (intervention) phase. Two therapists met benchmarks during the baseline phase; one of these subsequently moved away from benchmarks but met them again after starting the EG phase. Across all therapists, the percentage of weeks meeting benchmarks was significantly higher during the EG phase (86.4%) vs. the baseline phase (53.2%). Youth participants experienced significant improvement in OCD symptoms and global illness severity from pre- to posttreatment. Results provide initial evidence that adding the EG to gold-standard training can change in-session therapist behaviors in a CMHA setting.

BACKGROUND Patient-reported outcome (PRO) measures often address quality of life (QOL) and help improve communication and shared decision-making. The home parenteral nutrition patient-reported outcome questionnaire (HPN-PROQ) was developed for patients to self-assess factors that influence QOL. The aim of this study was to establish construct validity. METHOD Responses were analyzed for 77 HPN-dependent patients with chronic and prolonged acute intestinal failure. General linear modeling was conducted to describe patterns of interactions and association between items included in the HPN-PROQ. RESULTS Most patients (78%) had chronic intestinal failure. Mean HPN duration was 3.3 ± 0.6 years. Underlying illness had a moderate or major effect on QOL for 88%; 59% reported their QOL had been negatively impacted by HPN. There was no difference in QOL among chronic patients, depending on how important they rated "being able to do what I want to do" (P = .1), whereas prolonged acute intestinal failure patients had significantly lower QOL if they rated "being able to do what I want to do" extremely vs very important (adjusted P = .02). Confidence with ability to perform HPN procedures was associated with understanding the need for HPN (P < .01). As ratings increased for emotional difficulty in coping with HPN so did HPN impact on QOL (linear trend P < .01). CONCLUSION Construct validity of the HPN-PROQ was evident. The HPN-PROQ considers the unique experience of living with a complex nutrition therapy.

Introduction Post-transplant infections have been studied widely but data on comparisons of deceased donor liver transplants (DDLT) and living donor liver transplants (LDLT), type and timings of infections, and their relations to outcomes are not explored. Material and methods We analysed data from 612 participants of the Adult-to-Adult Living Donor Liver Transplantation Study (A2ALL), a retrospective data set of LDLT and DDLT. We compared the type and timing of the first post-transplant infection in relation to transplant outcomes between the two groups. Results Out of 611 patients, 24.5% experienced the first post-transplant infection, the majority of which were bacterial (35.3%), followed by fungal (11%) and viral infections (4.2%). There was no significant difference in the rate, type or timing of infection between LDLT and DDLT. Patients with late (> 1 year) first infection were 1.8 times more likely to die (95% CI: 1.12-2.98, p = 0.015) and 9 times more likely to have graft failures (95% CI: 3.26-24.8, p < 0.001). DDLT recipients who experienced bacterial infection had a significantly lower survival rate compared to LDLT recipients (p < 0.001). Conclusions Late infection is associated with lower survival in both DDLT and LDLT. Bacterial infection might be more detrimental for DDLT than LDLT. Late infection should be managed aggressively to improve outcomes.

Introduction The present study examined seizure clusters as a primary outcome in patients receiving treatment for PNES. Cluster reduction is examined longitudinally using frequency threshold and statistical definitions of seizure cluster for patients. Possible risk factors for clustering will be examined along with clustering as a risk factor for poorer secondary outcomes. Methods Participants were from a pilot randomized treatment trial for PNES where they received cognitive behavioral therapy-informed psychotherapy (CBT-ip), sertraline, combination therapy, or treatment as usual. Seizure data are from patients' seizure dairies. Results Cluster reduction was observed for those receiving CBT-ip or combination treatment using all definitions of daily clusters and weekly clusters. No risk factors of clustering were observed. Those who were identified as having clusters during the trial had poorer secondary outcomes on several measures at baseline relative to those who were not identified as having clusters. Discussion This is the first study known to the authors to not only examined seizure clusters as a primary outcome for those with PNES, but also the first study to suggest that CBT-ip and combination therapy may be effective in reducing the frequency of clusters.

Preoperative hip joint space width (JSW) of ≤2 mm on plain radiography has been shown to be predictive of intraoperative findings of osteoarthritis, worse functional outcomes, and failure to total hip arthroplasty following hip arthroscopy. However, there is no evidence to suggest that hip joint space greater than 2 mm can definitively rule out the presence of osteoarthritis. We hypothesize that a preoperative JSW of 2 mm or greater does not reliably rule out the presence of high-grade arthritis on hip arthroscopy. Retrospective review of 50 patients who underwent hip arthroscopy between January 11, 2010, and January 3, 2015, at a single institution was performed. Preoperative, standing anteroposterior hip radiographs were reviewed to determine the minimum hip JSW of each operative hip. Operative notes and images were reviewed to determine the Outerbridge classification of cartilage changes on both the acetabulum and femoral head for each patient. High-grade arthritis was defined as a minimum of grade 3 changes on either the femoral head or the acetabulum, which was required for inclusion in the study. The sensitivity of a JSW of 2 mm or less on preoperative radiographs to diagnose a patient with grade 3, grade 4, and grade 3 or 4 arthritis was calculated. Linear regression was used to test for an association between Outerbridge grading and the radiographic minimum JSW. The mean JSW for all patients was 3.5 ± 1.2 mm (range: 0–5.5 mm). Regression found an inverse relationship between joint space and the arthroscopic grading of the articular surfaces (p = 0.0031). However, a preoperative JSW of ≤ 2 mm was only 14.3% sensitive (95% confidence interval [CI] 2.6–51.3%) for predicting Outerbridge grade 3 changes, 7.3% sensitive (95% CI: 2.5–19.4%) for predicting Outerbridge grade 4 changes, and 8.3% sensitive (95% CI: 3.3–20.6%) for predicting Outerbridge grade 3 or 4 changes. The threshold of ≤2 mm of hip JSW on plain radiographs has poor sensitivity for predicting the existence of high-grade arthritis.

Introduction: Clinical care pathways reduce length of stay, variability in practice and costs, yet avoid compromising quality of care or increasing complications. In this study we describe a standardized care pathway, focusing on preoperative and postoperative education as well as immediate postoperative patient care after robotic assisted laparoscopic radical prostatectomy.Methods: A standardized robotic assisted laparoscopic radical prostatectomy care pathway was introduced at our institution in July 2014. A total of 108 men who underwent robotic assisted laparoscopic radical prostatectomy during 2014 were enrolled in this retrospective chart review and were subsequently mailed a quality of life survey. Data regarding length of stay and number of unplanned calls to the urology office or visits to the emergency department were collected from the chart review. The mailed survey was composed of original questions as well as questions adapted from the FACT-P (Functional Assessment of Cancer Therapy-...

Background: Sarcopenia is a condition of clinically relevant loss of muscle mass and function. Acetabular fractures in elderly patients are common and difficult to treat. This study aimed to determine if sarcopenia is common in elderly patients with acetabular fractures and correlates with lower-energy mechanisms of injury, higher rates of complications, and higher mortality than patients with normal muscle mass. Methods: The Rhode Island Hospital Trauma Database was queried for patients who were ≥60 years of age from 2005 to 2014 using the International Classification of Diseases, Ninth Revision, code for closed acetabular fracture, 808.0. Charts were retrospectively reviewed for demographic data, operative intervention, mechanism of injury, mortality, comorbidities, and other factors. Computed tomography (CT) was used to determine the muscle cross-sectional area and to calculate the skeletal muscle index. Results: The database revealed 192 patients coded for acetabular fracture; of these, 181 were correctly diagnosed. Ninety-nine patients had recorded body mass index (BMI) and adequate CT scans to measure the skeletal muscle index. Forty-two patients (42.4%) had sarcopenia, and 57 patients (57.6%) did not have sarcopenia. There were no significant differences in demographic characteristics between the groups with the exception of BMI and sex. BMI was higher in patients who did not have sarcopenia (31.7 kg/m2) than it was in patients with sarcopenia (23.6 kg/m2) (p < 0.001). Male sex was significantly greater (p = 0.0104) in patients with sarcopenia at 76.2% (32 of 42 patients) than in patients without sarcopenia at 50.9% (29 of 57 patients). Fractures in patients without sarcopenia were associated with a higher-energy mechanism of injury in 78.9% of cases compared with 52.4% of cases of patients with sarcopenia (p = 0.005). Sarcopenia was significantly associated (p = 0.0419) with increased 1-year mortality (28.6%) compared with the absence of sarcopenia (12.3%). This association was even stronger if in-hospital mortality was excluded (p = 0.00074). Finally, anterior column fractures were more likely (p = 0.017) to be sustained by patients with sarcopenia at 47.6% (20 patients) than by patients who did not have sarcopenia at 24.6% (14 patients). Conclusions: Sarcopenia is common in elderly patients with acetabular fractures and is associated with lower-energy mechanisms, anterior column fractures, and higher risk of 1-year mortality. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

INTRODUCTION Effective resuscitation of out-of-hospital cardiac arrest (OHCA) patients is challenging. Alternative resuscitative approaches using electromechanical adjuncts may improve provider performance. Investigators applied simulation to study the effect of an experimental automation-assisted, goal-directed OHCA management protocol on EMS providers' resuscitation performance relative to standard protocols and equipment. METHODS Two-provider (emergency medical technicians (EMT)-B and EMT-I/C/P) teams were randomized to control or experimental group. Each team engaged in 3 simulations: baseline simulation (standard roles); repeat simulation (standard roles); and abbreviated repeat simulation (reversed roles, i.e., basic life support provider performing ALS tasks). Control teams used standard OHCA protocols and equipment (with high-performance cardiopulmonary resuscitation training intervention); for second and third simulations, experimental teams performed chest compression, defibrillation, airway, pulmonary ventilation, vascular access, medication, and transport tasks with goal-directed protocol and resuscitation-automating devices. Videorecorders and simulator logs collected resuscitation data. RESULTS Ten control and 10 experimental teams comprised 20 EMT-B's; 1 EMT-I, 8 EMT-C's, and 11 EMT-P's; study groups were not fully matched. Both groups suboptimally performed chest compressions and ventilations at baseline. For their second simulations, control teams performed similarly except for reduced on-scene time, and experimental teams improved their chest compressions (P=0.03), pulmonary ventilations (P

Limited data exist on how to develop resident leadership and communication skills during actual trauma resuscitations.An evaluation tool was developed to grade senior resident performance as the team leader during full-trauma-team activations. Thirty actions that demonstrated the Accreditation Council for Graduate Medical Education core competencies were graded on a Likert scale of 1 (poor) to 5 (exceptional). These actions were grouped by their respective core competencies on 5 × 7-inch index cards. In Phase 1, baseline performance scores were obtained. In Phase 2, trauma-focused communication in-services were conducted early in the academic year, and immediate, personalized feedback sessions were performed after resuscitations based on the evaluation tool. In Phase 3, residents received only evaluation-based feedback following resuscitations.In Phase 1 (October 2009 to April 2010), 27 evaluations were performed on 10 residents. In Phase 2 (April 2010 to October 2010), 28 evaluations were performed on nine residents. In Phase 3 (October 2010 to January 2012), 44 evaluations were performed on 13 residents. Total scores improved significantly between Phases 1 and 2 (p = 0.003) and remained elevated throughout Phase 3. When analyzing performance by competency, significant improvement between Phases 1 and 2 (p0.05) was seen in all competencies (patient care, knowledge, system-based practice, practice-based learning) with the exception of "communication and professionalism" (p = 0.56). Statistically similar scores were observed between Phases 2 and 3 in all competencies with the exception of "medical knowledge," which showed ongoing significant improvement (p = 0.003).Directed resident feedback sessions utilizing data from a real-time, competency-based evaluation tool have allowed us to improve our residents' abilities to lead trauma resuscitations over a 30-month period. Given pressures to maximize clinical educational opportunities among work-hour constraints, such a model may help decrease the need for costly simulation-based training.Therapeutic study, level III.

Background: Among patients undergoing colonoscopy, anticoagulants are usually stopped and are sometimes substituted by a heparin bridge (hep-bridge). We aimed to assess adverse events associated with hep-bridge compared to temporary cessation of anticoagulants (no-bridge). Methods: This was a single-center, retrospective cohort study that included anticoagulated patients undergoing colonoscopy between 2013 and 2016 at a Veterans Affairs Medical Center. In the no-bridge cohort, warfarin was stopped for 5 days and novel anticoagulants for 2 days pre-procedure. In the hep-bridge cohort, anticoagulants were stopped and were substituted by subcutaneous enoxaparin. The primary outcome was post-polypectomy bleeding. Secondary outcomes included cardiovascular events, all-cause adverse events and emergency department or unscheduled ambulatory office visits within 30 days. The predictive values of the HAS-BLED and CHADS2 scores were evaluated. Results: A total of 662 patients were included, of whom 551 underwent polypectomy (mean age 68.6 years; 97.6% male). Four hundred seventy colonoscopies were performed with no-bridge and 192 with hep-bridge. Post-polypectomy bleeding occurred in 6.0% of procedures: 5.7% in the no-bridge cohort compared to 13.0% of hep-bridge procedures (P=0.0038). Cardiovascular or thrombotic events occurred after 2.6% of the no-bridge and 5.2% of the hep-bridge procedures (P=0.1176). Emergency department or unscheduled office visits within 30 days were reported after 18.7% of the no-bridge procedures and 29.7% of the hep-bridge procedures (P

Background Lymphocytes have become the target of cancer interventions through engineering or immune checkpoint antibodies. We previously found decreased lymphocyte counts to be a predictor of mortality and complications in trauma and cardiac surgery patients. We hypothesized lack of lymphocyte count recovery postoperatively would predict outcomes in esophagectomy patients. Methods A retrospective review of all patients undergoing esophagectomy for adenocarcinoma performed over 13 y at our center by a single surgeon after institutional review board approval was performed. Patients were grouped by postoperative lymphocytes counts: never low, low with recovery, and low without recovery. Resolution of lymphopenia was assessed by day 4. Primary end points were overall and recurrence-free survival. Results In total, 198 patients were included with a minimum 6-mo follow-up. Collectively the 5-y recurrence and overall survival rates were 36% and 50%, respectively. Recurrence was significantly higher at 5 y in patients with persistent lymphopenia (43%) compared with those who recovered (14% P = 0.0017) and those who never dropped (0% P = 0.0009). The persistent lymphopenia group had significantly lower survival (45%) compared with the two other groups (67% P = 0.0232). Conclusions There is a significant decrease in the overall and recurrence-free survival in those patients whose lymphocyte count drops without recovery after their esophagectomy. These data imply differences in immune responses to the stress of surgery that can be measured with routine postoperative laboratory values and are indicative of overall outcomes.

Introduction Protocolized automation of critical, labor-intensive tasks for out-of-hospital cardiac arrest (OHCA) resuscitation may decrease Emergency Medical Services (EMS) provider workload. A simulation-based assessment method incorporating objective and self-reported metrics was developed and used to quantify workloads associated with standard and experimental approaches to OHCA resuscitation. Methods Emergency Medical Services-Basic (EMT-B) and advanced life support (ALS) providers were randomized into two-provider mixed-level teams and fitted with heart rate (HR) monitors for continuous HR and energy expenditure (EE) monitoring. Subjects' resting salivary α-amylase (sAA) levels were measured along with Borg perceived exertion scores and multidimensional workload assessments (NASA-TLX). Each team engaged in the following three OHCA simulations: (1) baseline simulation in standard BLS/ALS roles; (2) repeat simulation in standard roles; and then (3) repeat simulation in reversed roles, ie, EMT-B provider performing ALS tasks. Control teams operated with standard state protocols and equipment; experimental teams used resuscitation-automating devices and accompanying goal-directed algorithmic protocol for simulations 2 and 3. Investigators video-recorded resuscitations and analyzed subjects' percent attained of maximal age-predicted HR (%mHR), EE, sAA, Borg, and NASA-TLX measurements. Results Ten control and ten experimental teams completed the study (20 EMT-Basic; 1 EMT-Intermediate, 8 EMT-Cardiac, 11 EMT-Paramedic). Median %mHR, EE, sAA, Borg, and NASA-TLX scores did not differ between groups at rest. Overall multivariate analyses of variance did not detect significant differences; univariate analyses of variance for changes in %mHR, Borg, and NASA-TLX from resting state detected significant differences across simulations (workload reductions in experimental groups for simulations 2 and 3). Conclusions A simulation-based OHCA resuscitation performance and workload assessment method compared protocolized automation-assisted resuscitation with standard response. During exploratory application of the assessment method, subjects using the experimental approach appeared to experience reduced levels of physical exertion and perceived workload than control subjects.

Analyzing the reading grade level of online mental health information is an important first step in ensuring that information is largely accessible by the general public, so as not to perpetuate existing health disparities across socioeconomic groups. The present study systematically examined grade-level readability of mental health information related to various psychiatric diagnoses, obtained from 6 highly utilized mental health websites, using a generalized estimating equations approach. Results suggest that, in general, the readability of mental health information is largely well above the 6th-to-8th grade level recommended by several national health organizations, including the CDC and NIH (Kutner, Greenberg, Jin, & Paulsen, 2006; National Institutes of Health, 2001, 2017), with reading-grade-level estimates from the model ranging from 5.62 to 17.9. Further efforts are required to ensure that writers of online health information do not exacerbate existing health disparities by ignoring these guidelines. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Objective This study measured a variety of within-exposure fear changes and tested the relationship of each with treatment outcomes in exposure therapy. Method We coded 459 videotaped exposure tasks from 111 participants in 3 clinical trials for pediatric obsessive-compulsive disorder (OCD; POTS trials). Within exposures, fear level was observed continuously and alongside exposure process. Fear change metrics of interest were selected for relevance to mechanistic theory. Fear decreases were classified by function; nonhabituation decreases were associated with observed nonlearning processes (e.g., avoidance), whereas habituation decreases appeared to result from an internal and indirect process. Outcomes were posttreatment change in symptom severity, global improvement, and treatment response. Results Greater cumulative habituation across treatment was associated with larger reductions in symptom severity, greater global improvement, and increased odds of treatment response. Fear activation, fear variability, and nonhabituation fear decreases did not predict any outcomes. Exploratory analyses examined fear changes during habituation and nonhabituation exposures; higher peak fear during nonhabituation exposures was associated with attenuated global improvement. Conclusions Habituation is conceptually consistent with multiple mechanistic theories and should continue to be investigated as a practical marker of initial extinction learning and possible moderator of the relationship between fear activation and outcome. Results support the importance of functional and frequent fear measurement during exposures, and discussion considers implications of these findings for future studies aiming to understand learning during exposure and improve exposure delivery. (PsycINFO Database Record

Transcranial motor-evoked potentials (TcMEPs) are used to monitor the descending motor pathway during scoliosis surgery. By comparing potentials before and after correction, surgeons may prevent postoperative functional loss in distal muscles. There is currently no consensus as to which muscles should be monitored. The purpose of this study is to determine the least invasive monitoring protocol with the best localization of potential neurologic deficit. A retrospective review of 125 patients with TcMEP monitoring during surgery for thoracolumbar scoliosis between 2008 and 2015 was conducted. 18 patients had postoperative neurologic consult due to deficit. The remaining 107 patients were a consecutive cohort without postoperative neurologic consult. TcMEPs were recorded from vastus lateralis (VL), tibialis anterior (TA), peroneus longus (PL), adductor hallucis (AH) and abductor pollicis brevis (APB) bilaterally. The effectiveness of each muscle combination was evaluated independently and then compared to other combinations using Akaike Information Criterion (AIC). Monitoring of VL, TA, PL, and AH yielded sensitivity of 77.8% and specificity of 92.5% (AIC=66.7). Monitoring of TA, PL and AH yielded sensitivity of 77.8% and specificity of 94.4% (AIC=62.4). Monitoring of VL, TA and PL yielded sensitivity of 72.2% and specificity of 93.5% (AIC=70.1). Monitoring of TA and PL yielded sensitivity of 72.2% and specificity of 96.3% (AIC=63.9). TcMEP monitoring of TA, PL, and AH provided the highest sensitivity and specificity and best predictive power for postoperative lower extremity weakness.

We sought to determine whether there is any association between a cardiac workload marker, rate pressure product (RPP), working memory, and cortical amyloid-β (Aβ) burden in 63 cognitively normal midlife adults (Mage = 62.8 years; range = 55 to 75 years) at risk for Alzheimer’s disease (AD). The results show a small-to-moderate relationship between increasing cardiac workload (at rest) and neocortical amyloidosis in individuals at the preclinical stage of AD. Moreover, increasing RPP was linearly related to increasing relative impairments on a spatial working memory task (R2 = 0.30), but only for those individuals with neuroimaging evidence suggestive of preclinical AD. These results support a relationship between the aggregation of Aβ protein plaques in the neocortex, increased cognitive impairment, and more inefficient myocardial oxygen use in the absence of significant metabolic demands.

This study confirms previously reported racial differences in Clostridium difficile infection (CDI) rates in the United States and explores the nature of those differences. We conducted a retrospective study using the 2010 Nationwide Inpatient Sample, the largest all-payer database of hospital discharges in the United States. We identified hospital stays most likely to include antibiotic treatment for infections, based on hospital discharge diagnoses, and we examined how CDI rates varied, in an attempt to distinguish between genotypic and environmental racial differences. Logistic regressions for the survey design were used to test hypotheses. Among patients likely to have received antibiotics, white patients had higher CDI rates than black, Hispanic, Asian, and Native American patients ( P < 0.0001). CDI rates increased with higher income levels and were higher for hospitalizations paid by private insurance versus those paid by Medicaid or classified as self-pay or free care ( P < 0.0001). Among patients admitted from skilled nursing facilities, where racial bias in health care access is less, racial differences in CDI rates disappeared ( P = 1.0). Infected patients did not show racial differences in rates of complicated CDI or death ( P = 1.0). Although white patients had greater CDI rates than nonwhite patients, racial differences in CDI rates disappeared in a population for which health care access was presumed to be less racially biased. This provides evidence that apparent racial differences in CDI risks may represent health care access disparities, rather than genotypic differences. CDI represents a deviation from the paradigm that increased health care access is associated with less morbidity.

Objective: To measure unhealthy aerosol materials in an Emergency Department (ED) and identify their sources for mitigation efforts. Background: Based on pilot findings of elevated ED particulate matter (PM) levels, investigators hypothesized that unhealthy aerosol materials derive from exogenous (vehicular) sources at ambulance receiving entrances. Methods: The Aerosol Environmental Toxicity in Healthcare-related Exposure and Risk program was conducted as an observational study. Calibrated sensors monitored PM and toxic gases at Ambulance Triage Exterior (ATE), Ambulance Triage Desk (ATD), and control Public Triage Desk (PTD) on a 3/3/3-day cycle. Cassette sampling characterized PM; meteorological and ambulance traffic data were logged. Descriptive and multiple linear regression analyses assessed for interactions between aerosol material levels, location, temporal variables, ambulance activity, and meteorological factors. Results: Sensors acquired 93,682 PM0.3, 90,250 PM2.5, and 93,768 PM5 measurements over 366 days to generate a data set representing at least 85.6% of planned measurements. PM0.3, PM2.5, and PM5 mean counts were lowest in PTD; 56%, 224%, and 223% higher in ATD; and 996%, 200%, and 63% higher in ATE, respectively (all p < .001). Qualitative analyses showed similar PM compositions in ATD and ATE. On multiple linear regression analysis, PM0.3 counts correlated primarily with location; PM2.5 and PM5 counts correlated most strongly with location and ambulance presence. PM < 2.5 and toxic gas concentrations at ATD and PTD patient care areas did not exceed hazard levels; PM0.3 counts did not have formal safety thresholds for comparison. Conclusions: Higher levels of PM were linked with ED ambulance areas, although their health impact is unclear.

To retrospectively evaluate the safety and efficacy of microwave ablation (MWA) as treatment for single, focal hepatic malignancies.Institutional review board approval was obtained for this HIPAA-compliant study. From December 2003 to May 2012, 64 patients were treated with MWA for a single hepatic lesion, in 64 sessions. Hepatocellular carcinoma (HCC) was treated in 25 patients (geometric mean tumor size, 3.33-cm; 95% CI, 2.65-4.18-cm; range, 1.0-12.0-cm), metastatic colorectal cancer (CRC) was treated in 27 patients (geometric mean tumor size, 2.7-cm; 95% CI, 2.20-3.40-cm; range, 0.8-6.0-cm), and other histological-types were treated in 12 patients (geometric mean tumor size, 3.79-cm; 95% CI, 2.72-5.26-cm; range, 1.7-8.0-cm). Kaplan-Meier (K-M) method was used to analyze time event data. Chi-square and correlation evaluated the relationship between tumor size and treatment parameters.Technical success rate was 95.3% (61/64). Treatment parameters were tailored to tumor size; as size increased more antennae were used (p0.001), treatment with multiple activations increased (p0.028), and treatment time increased (p0.001). There was no statistically significant relationship between time to recurrence and tumor size, number of activations, number of antennae, and treatment time. At one-year, K-M analysis predicted a likelihood of local recurrence of 39.8% in HCC patients, 45.7% in CRC metastases patients, and 70.8% in patients with other metastases. Median cancer specific survivals for patients were 38.3 months for HCC patients, 36.3 months for CRC metastases, and 13.9 months for other histological-types. Complications occurred in 23.4% (15/64) of sessions.In our sample, tumor size did not appear to impact complete ablation rates or local recurrence rates for focal hepatic malignancies treated with MWA.

Editor: In 2012, the American Board of Medical Specialties approved the American Board of Radiology’s application for a dual primary certificate in interventional radiology (IR) and diagnostic radiology (DR) (1). This approval not only designated IR as the 37th primary certificate in the United States, but it also marked a milestone in recognizing that IR is a unique area of medicine that requires a distinct skill set for future trainees. The new primary certificate will result in many vascular and IR (VIR) fellowship positions being converted to integrated IR/DR residency positions. To facilitate recruitment into IR, it would be desirable if medical students could become familiar with IR earlier in their careers. Most U.S. medical school curricula provide minimal exposure to IR; only one third of medical schools offer a radiology clerkship, and most of these are offered as electives (2). Over the past several years, there has been great effort on the part of national societies and individual medical schools to promote medical student IR education. The Society of Interventional Radiology (SIR) has a dedicated medical student weekend, and several institutions have initiated local/regional IR symposiums, providing an introductory overview of the field and various interventions (3). At our institution’s medical school, similar endeavors have been undertaken; we have a well-established interest group, an elective in VIR offered during the clinical years, and a longitudinal clerkship (an outpatient office experience in which students participate in patient consultation, diagnosis, treatment planning, and longitudinal follow-up), and have recently completed the third iteration of a regional IR symposium. Here we discuss a single institution’s

Objective Recent studies in the US and abroad suggest that boys are undergoing puberty at a younger age. It is unknown if this secular trend extends to boys with central precocious puberty (CPP), who sit at the extreme end of the pubertal spectrum, and if neuroimaging should remain a standard diagnostic tool. Study design Retrospective chart review of all boys with CPP seen by Endocrinology at a US pediatric hospital from 2001-2010. Results Fifty boys had pubertal onset at an average age of 7.31 years (95CI 6.83-7.89), though many did not present until nearly one year thereafter, by which time 30% were mid-to-late pubertal. Boys were predominantly non-Hispanic White and 64% were overweight/obese. The majority (64%) of boys had neurogenic CPP (CNS-CPP) with neurofibromatosis type I being the most common diagnosis. Diagnosis of CPP led to discovery of a neurogenic lesion in only 3 of 32 (9%) CNS-CPP cases. The remaining boys, with idiopathic CPP (36%), were indistinguishable from those with CNS-CPP aside from four boys who endorsed a family history of PP (22% vs. 0% among CNS-CPP cases). Importantly, there was no change in the incidence of male CPP after accounting for the increase in clinic volume during this time period. Conclusion In this contemporary Boston-based cohort of 50 boys with CPP, most cases were neurogenic, consistent with older literature. Several idiopathic cases had a family history of PP but were otherwise indistinguishable from CNS-CPP cases. Thus, neuroimaging remains a critical diagnostic tool. We find no evidence for an increase in the prevalence of male CPP.

The purpose of this study was to determine the normal hematological values in cord blood during gestation, the impact of the type of delivery and differences in gender.The database included 10 287 live births of 30-44 weeks gestation from cesarean or vaginal deliveries. Cord blood was collected into bags containing lyophilized heparin. Specimens were stored for 24 h or less and analyzed using the SysmexXE-2100. Data from cesarean births were used to evaluate developmental hematopoietic changes.Increases during maturation occurred in hemoglobin, hematocrit, red blood cell count, and decreases in mean corpuscular volume and mean corpuscular hemoglobin. The number of nucleated red blood cells per 100 white blood cells decreased but absolute counts remained constant. Quantitative counts of white blood cells, neutrophils, monocytes (MON), eosinophils and lymphocytes (LYMP) increased, but percentages of lymphocytes and monocytes decreased. Platelets increased from 30-35 weeks.Reference ranges were established for cord blood. Erythroid and myeloid cells show developmental changes. Mode of delivery has a significant effect on hematologic values. Only a rare parameter showed differences based on gender. The cord blood complete blood cell count has the potential for providing relevant clinical information for managing neonatal patients.

OBJECTIVE: Many states have passed concussion laws that mandate that players undergo medical clearance before returning to play. Few data have been collected on the impact of such laws on emergency department (ED) visits. This study measures the impact of Rhode Island concussion legislation on sports-related concussion visits to a pediatric ED. METHODS: International Classification of Diseases, Ninth Revision, Clinical Modification codes with injury mechanism-associated E-codes were extracted from hospital databases from 2004 to 2011 for both sports-related concussions and sports-related ankle ligamentous injuries (comparison group). Visit rates for sports-related concussions were compared before and after the passage of the state concussion law.Secondary outcome measures included rates of head imaging per ED visit for concussion before and after passage of the law. Times series analysis was used to analyze season-to-season count and rate changes. RESULTS: Overall rate of sports-related concussion visits more than doubled (2.2-fold increase; 95% confidence interval, 1.3-3.6; adjusted P = 0.01) during the fall sports season following the implementation of legislation (2010) relative to the previous year (3.6% vs 1.4%). Rates of sports-related ankle sprain visits tended to increase during the fall sports season but did not achieve statistical significance. Rates of computed tomography scan imaging of the head did not change over time. CONCLUSIONS: The data from this study revealed an increase in pediatric ED visits for sports-related concussions, without a corresponding increase in head imaging, suggesting that the passage of a state concussion law has led to increased vigilance in evaluation of sports-related concussions, without an increase in diagnostic computed tomography scans. Language: en

Bone disease is prevalent among patients with inflammatory bowel disease (IBD), though bone density screening remains underutilized. We used CT scans performed for other indications in IBD patients to identify and monitor osteopenia using CT attenuation values at the lumbar spine. Significant rates of bone disease were detected which would have otherwise gone undiagnosed.Osteoporosis affects about 14-42% of patients with IBD. Though screening is recommended in IBD patients with risk factors, it remains underutilized. In patients with newly diagnosed IBD, we used CT scans performed for other indications to identify and monitor progression of osteopenia.Using the Ocean State Crohn's and Colitis Area Registry, we identified adult patients with one or more abdominal CT scans. Each patient had two age- and gender-matched controls. Radiologists measured attenuation through trabecular bone in the L1 vertebral body recorded in Hounsfield units (HU). Generalized estimating equations were used to measure how HU varied as a function of gender, type of IBD, and age.One hundred five IBD patients were included, and 72.4% were classified as "normal" bone mineral density (BMD) and 27.6% as potentially osteopenic: 8.6% with ulcerative colitis and 19.0% with Crohn's disease. We found a decrease in bone density over time (p 0.001) and that BMD decreases more in Crohn's disease than in ulcerative colitis (p 0.004). Sixty patients had two CT scans, and mean loss of 9.3 HU was noted. There was a non-significant decrease in BMD over time in patients exposed to 31 days of steroids and BMD was stable with 30 days of steroid exposure (p 0.09).Using CT scans obtained for other indications, we found low rates of osteopenia and osteoporosis that may otherwise have gone undiagnosed. Refinement of opportunistic screening may have advantages in terms of cost-savings and earlier detection of bone loss.

Aims The tumour microenvironment is increasingly important in several tumours. We studied the relationship of key players of immune microenvironment with clinicopathological parameters in gastric adenocarcinomas. Methods and results Tissue microarrays were constructed from gastrectomy specimens, 2004-13. Immunohistochemistry was performed for programmed cell death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), tryptophanyl-tRNA synthetase (WARS), guanylate-binding protein 5 (GBP5), tumour-infiltrating lymphocytes (TIL) expressing CD3/CD8/FoxP3/PD1 and mismatch repair proteins (MMRs) MLH1, PMS2, MSH2 and MSH6. Clinicopathological parameters and clinical follow-up were recorded. The study included 86 patients; median follow-up was 34 months (0-148). Tumour types were 45% tubular, 38% diffuse, 17% mixed. PD-L1 was positive in 70%, epithelial IDO in 58%, stromal IDO in 91%, epithelial WARS in 67%, stromal WARS in 100%, epithelial GBP5 in 53% and stromal GBP5 in 71%. MMR-deficiency was found in 22%. There was no difference in biomarker expression by histological subtype, with the exception of fewer diffuse-type being MMR-deficient. Low stromal IDO was associated with decreased progression-free, overall and disease-specific survival. PD-L1-positive tumours were larger with MMR-deficiency and with increasing TILs, and had significantly higher FoxP3TILs. Conclusions PD-L1 is expressed in a large proportion of gastric carcinomas, suggesting that therapy targeting this pathway could be relevant to many patients. PD-L1 expression and MMR-deficiency are associated with increased TILs and larger tumour size, emphasising their role in tumour biology. Higher stromal IDO expression is associated with better prognosis. Finally, we observed that immune modulators WARS and GBP5 are expressed highly in gastric adenocarcinomas, suggesting an important role in tumour pathobiology.

To explore early autonomic cardiac changes in pre-clinical Alzheimer's disease (AD), we have evaluated electrocardiologic measures of vagal tone for 63 adults (ages 55-75) at rest, during cognitive testing, and then again at rest. All subjects had multiple risk factors for AD, and all completed amyloid PET scans (18F-Florbetapir) to determine amyloid positivity (Aβ+). No change in electrocardiographic measures were observed for Aβ+ participants under each testing condition, whereas Aβ-subjects showed an expected increase in vagal tone during the cognitive stress condition. These findings suggest an early relationship between cortical Aβ accumulation, a precursor to AD development, and autonomic cardiac function.

Aims The immune microenvironment is a prognostic factor for various malignancies. The significance of key players of this immune microenvironment, including tumour-infiltrating lymphocytes (TILs) and expression of programmed death-ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase (WARS) in gastrointestinal stromal tumours (GISTs) is largely unknown. Methods and results Tissue microarrays were constructed from pathology files, 1996-2016. Immunohistochemistry for PD-L1, IDO and WARS was correlated with tumour size, mitoses and outcomes. TILs expressing CD3, CD4, CD8, FoxP3 and GBP5 were counted. A total of 129 GISTs were analysed. Mean patient age was 62.5 years; 52.0% were male. Tumour location included 89 stomach (69.0%), 33 small bowel (25.6%) and seven other (5.4%). Mean tumour size was 5.6 cm; mean mitoses were 7.2 per 50 high-power field. Nineteen patients (15.0%) developed disease progression, to abdominal wall (n = 8), liver (n = 6) and elsewhere (n = 5). Median progression-free survival was 56.6 months; five patients died of disease. PD-L1 was positive in 88 of 127 tumour samples (69.0%), 114 of 127 tumours were IDO-positive (89.8%) and 60 of 127 were positive for WARS (47.2%). PD-L1 was associated with increased size (P = 0.01), necrosis (P = 0.018) and mitoses (P = 0.006). Disease progression was not associated with PD-L1 (P = 0.44), IDO (P = 0.14) or WARS (P = 0.36) expression. PD-L1-positive GISTs with CD8+ or CD3+ TILs were significantly smaller than tumours with CD8+ or CD3+ TILs. Conclusions PD-L1 expression was associated with increased size and mitoses. High CD8+ or CD3+ TIL counts were associated with decreased PD-L1/IDO+ GIST size. PD-L1 and IDO could be significant in GIST tumour biology, which invites consideration of immunotherapy as a potential treatment option.