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The aim of this study was to characterize the body composition of patients undergoing neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer (EOC), identify factors associated with sarcopenia at diagnosis, and evaluate the impact of pretreatment sarcopenia and changes in body composition parameters during therapy on perioperative and disease-related outcomes.Patients undergoing NACT for EOC between 2008 and 2020 were identified. Pre-treatment and post-treatment contrast-enhanced CT scans were reviewed to determine skeletal muscle index (SMI) and visceral adipose tissue (VAT) area at the mid-fourth lumbar vertebral level. SMI and VAT were analyzed for association with clinical and treatment variables.174 patients were identified. Mean pretreatment SMI and VAT were 38.3 cmPatients with lower pretreatment SMI tend to undergo less complex surgery than those with higher SMI despite NACT. Decrease in VAT may be a potential indicator of worse OS. Information on body composition can aid in clinical decision making in patients with EOC.

Previous studies demonstrated that accelerometer-based, mechanically timed atrioventricular synchrony (AVS) is feasible using a leadless ventricular pacemaker.The purpose of this study was to determine the performance of a leadless ventricular pacemaker with accelerometer-based algorithms that provide AVS pacing.AccelAV was a prospective, single-arm study to characterize AVS in patients implanted with a Micra AV, which uses the device accelerometer to mechanically detect atrial contractions and promote VDD pacing. The primary objective was to characterize resting AVS at 1 month in patients with complete atrioventricular block (AVB) and normal sinus function.A total of 152 patients (age 77 ± 11 years; 48% female) from 20 centers were enrolled and implanted with a leadless pacemaker. Among patients with normal sinus function and complete AVB (n = 54), mean resting AVS was 85.4% at 1 month, and ambulatory AVS was 74.8%. In the subset of patients (n = 20) with programming optimization, mean ambulatory AVS was 82.6%, representing a 10.5% improvement (P.001). Quality of life as measured by the EQ-5D-3L (EuroQol Five-Dimensions Three-Level questionnaire) improved significantly from preimplant to 3 months (P = .031). In 37 patients with AVB at both 1 and 3 months, mean AVS during rest did not differ (86.1% vs 84.1%; P = .43). There were no upgrades to dual-chamber devices or cardiac resynchronization therapy through 3 months.Accelerometer-based mechanical atrial sensing provided by a leadless pacemaker implanted in the right ventricle significantly improves quality of life in a select cohort of patients with AV block and normal sinus function. AVS remained stable through 3 months, and there were no system upgrades to dual-chamber pacemakers.

Procedures for stress urinary incontinence and benign gynecologic surgery are often performed concurrently, and associated complication rates have previously been unexplored.The aim of this study was to compare postoperative complication rates between women undergoing midurethral sling (MUS) placement at the time of benign gynecologic surgery and those undergoing MUS alone.This was a retrospective matched cohort study of women undergoing MUS with or without concurrent minimally invasive benign gynecologic surgery from January 2010 through December 2020. Eligible women undergoing concurrent surgery were matched to a cohort of women undergoing MUS placement alone. The electronic medical record was queried for demographic and perioperative/postoperative data up to 12 months after surgery.Thirty-eight women met inclusion criteria for the concurrent group, and 152 women were matched accordingly. The overall adverse event rate was 39.5% (95% confidence interval [CI], 0.25-0.55) for the concurrent group and 24.3% (95% CI, 0.18-0.32) for the MUS-only group ( P = 0.05). Adverse events with Clavien-Dindo grade ≤ 2 were higher in the concurrent group (Clavien-Dindo Grade 1: 5% vs 0%, P = 0.04; Clavien-Dindo Grade 2: 16% vs 6%, P = 0.04), as was composite postoperative resource utilization (76% vs 49%, P = 0.003). Mesh exposure ( P = 0.03) and sling lysis/excision rates ( P = 0.02) were higher in the concurrent group. On logistic regression, concurrent surgery cases remained significantly associated with sling mesh erosion (adjusted odds ratio, 12.6; 95% CI, 1.4-116.4).Midurethral sling placement at the time of minimally invasive benign gynecologic surgery is safe but is associated with a higher incidence of postoperative hospital resource utilization and sling mesh extrusion, and a need for revision.

ILLiad, an online interlibrary loan service widely used in libraries, generates detailed reports that support the assessment of interlibrary loan workflows and services. The data generated by these...

Background: The current coronavirus disease 2019 (COVID-19) pandemic began in Ireland with the first confirmed positive case in March 2020. In the early stages of the pandemic clinicians and researchers in two affiliated Dublin hospitals identified the need for a COVID-19 biobanking initiative to support and enhance research into the disease. Through large scale analysis of clinical, regional, and genetic characteristics of COVID-19 patients, biobanks have helped identify, and so protect, at risk patient groups The STTAR Bioresource has been created to collect and store data and linked biological samples from patients with SARS-CoV-2 infection and healthy and disease controls. Aim: The primary objective of this study is to build a biobank, to understand the clinical characteristics and natural history of COVID-19 infection with the long-term goal of research into improved disease understanding, diagnostic tests and treatments. Methods: This is a prospective dual-site cohort study across two tertiary acute university teaching hospitals. Patients are recruited from inpatient wards or outpatient clinics. Patients with confirmed COVID-19 infection as well as healthy and specific disease control groups are recruited. Biological samples are collected and a case report form detailing demographic and medical background is entered into the bespoke secure online Dendrite database. Impact: The results of this study will be used to inform national and international strategy on health service provision and disease management related to COVID-19. In common with other biobanks, study end points evolve over time as new research questions emerge. They currently include patient survival, occurrence of severe complications of the disease or its therapy, occurrence of persistent symptoms following recovery from the acute illness and vaccine responses.

Objectives To identify risk factors for Cesarean delivery and non-reassuring fetal heart tracing (NRFHT) in pregnancies with a small-for-gestational-age (SGA) fetus undergoing induction of labor and to design and validate a prediction model, combining antenatal and intrapartum variables known at the time of labor induction, to identify pregnancies at increased risk of Cesarean delivery. Methods This was a retrospective cohort study of non-anomalous, singleton gestations with a SGA fetus that underwent induction of labor, delivered in a single tertiary referral center between January 2011 and December 2016. SGA was defined as estimated fetal weight (EFW) Results A total of 594 pregnancies were included. Cesarean delivery was performed in 243 (40.9%) pregnancies. Significant risk factors associated with Cesarean delivery, and included in the final model, were maternal age, gestational age at delivery and initial method of labor induction. The bootstrap estimate of the AUC of the final prediction model for Cesarean delivery was 0.82 (95% CI, 0.78-0.86). The model had sensitivity of 64.2%, specificity of 86.9%, positive likelihood ratio (LR) of 4.9 and negative LR of 0.41. The model had good fit (P = 0.617). NRFHT complicated 117 (19.7%) pregnancies. Significant risk factors for NRFHT included EFW 95th percentile or absent/reversed end-diastolic flow) and gestational age at delivery. The final prediction model for NRFHT had an AUC of 0.69 (95% CI, 0.63-0.75) and specificity of 97.0%. Conclusion We identified several significant risk factors for Cesarean delivery and NRFHT among SGA pregnancies undergoing induction of labor. Clinicians may use these risk factors to guide patient counseling and to help anticipate the potential need for operative delivery. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Objectives This study reports on the performance of a leadless ventricular pacemaker with automated, enhanced accelerometer-based algorithms that provide atrioventricular (AV) synchronous ...

Mucosal Associated Invariant T cells are a population of “innate” T cells, which express the invariant T cell receptor (TCR) α chain Vα 7.2-Jα 33 and are capable of robust rapid cytokine secretion, producing a milieu of cytokines including IFN-γ and IL-17. MAIT cells have been reported in multiple human tissues including the gut, periphery and skin. On-going research has highlighted their involvement in numerous inflammatory diseases ranging from rheumatoid arthritis and obesity to psoriasis. Hidradenitis Suppurativa (H.S) is a chronic inflammatory disease of the hair follicles, resulting in painful lesions of apocrine-bearing skin. Several inflammatory cytokines have been implicated in the pathogenesis of H.S including IL-17. The role of MAIT cells in H.S is currently unknown. In this study we show for the first time, that MAIT cells are altered in the peripheral blood of patients with H.S, with reduced frequencies and an IL-17 cytokine bias. We show that CCL20 expression is elevated in lesions of patients with H.S, and MAIT cells can actively traffic towards lesions via CCL20. We show that MAIT cells can accumulate in the lesions from patients with H.S. when compared to adjacent skin, with an IL-17 bias. We show that elevated IL-17, can be linked to the activation of dermal fibroblasts, promoting the expression of chemotactic signals including CCL20 and CXCL1. Finally, we show that targeting the IL-17A transcription factor RORyt robustly reduces IL-17 production by MAIT cells from patients with H.S. Collectively our data details IL-17 producing MAIT cells as a novel player in the pathogenesis of H.S and highlights the potential of RORyt inhibition as a novel therapeutic strategy.

Background: Several studies have previously reported the presence of altered cerebral perfusion during sepsis. However, the role of non-invasive neuromonitoring, and the impact of altered cerebral perfusion, in sepsis patients with delirium remains unclear. Methods: We performed a systematic review of studies that used near-infrared spectroscopy (NIRS) and/or transcranial Doppler (TCD) to assess adults (≥18 years) with sepsis and delirium. From study inception to July 28, 2020, we searched the following databases: Ovid MedLine, Embase, Cochrane Library, and Web of Science. Results: Of 1546 articles identified, 10 met our inclusion criteria. Although NIRS-derived regional cerebral oxygenation was consistently lower, this difference was only statistically significant in one study. TCD-derived cerebral blood flow velocity was inconsistent across studies. Importantly, both impaired cerebral autoregulation during sepsis and increased cerebrovascular resistance were associated with delirium during sepsis. However, the heterogeneity in NIRS and TCD devices, duration of recording (from 10 seconds to 72 hours), and delirium assessment methods (e.g., electronic medical records, confusion assessment method for the intensive care unit), precluded meta-analysis. Conclusion: The available literature demonstrates that cerebral perfusion disturbances may be associated with delirium in sepsis. However, future investigations will require consistent definitions of delirium, delirium assessment training, harmonized NIRS and TCD assessments (e.g., consistent measurement site and length of recording), as well as the quantification of secondary and tertiary variables (i.e., Cox, Mxa, MAPOPT), in order to fully assess the relationship between cerebral perfusion and delirium in patients with sepsis.

BACKGROUND: The MARVEL (Micra Atrial TRacking Using a Ventricular AccELerometer) 2 study assessed the efficacy of atrioventricular (AV) synchronous pacing with a Micra leadless pacemaker. Average atrioventricular synchrony (AVS) was 89.2%. Previously, low amplitude of the Micra-sensed atrial signal (A4) was observed to be a factor of low AVS. OBJECTIVE: The purpose of this study was to identify predictors of A4 amplitude and high AVS. METHODS: We analyzed 64 patients enrolled in MARVEL 2 who had visible P waves on electrocardiogram for assessing A4 amplitude and 40 patients with third-degree AV block for assessing AVS at rest. High AVS was defined as >90% correct atrial-triggered ventricular pacing. The association between clinical factors and echocardiographic parameters with A4 amplitude was investigated using a multivariable model with lasso variable selection. Variables associated with A4 amplitude together with premature ventricular contraction burden, sinus rate, and sinus rate variability (standard deviation of successive differences of P-P intervals [SDSD]) were assessed for association with AVS. RESULTS: In univariate analysis, low A4 amplitude was inversely related to atrial function assessed by E/A ratio and e'/a' ratio, and was directly related to atrial contraction excursion (ACE) and atrial strain (Ɛa) on echocardiography (all P ≤.05). The multivariable lasso regression model found coronary artery bypass graft history, E/A ratio, ACE, and Ɛa were associated with low A4 amplitude. E/A ratio and SDSD were multivariable predictors of high AVS, with >90% probability if E/A

Objectives: Loss of skeletal muscle mass (sarcopenia) has been correlated with adverse postoperative outcomes after primary cytoreduction in patients with epithelial ovarian carcinoma (EOC). We investigated the association between sarcopenia as measured by skeletal muscle index (SMI) prior to and after neoadjuvant chemotherapy (NACT) and post-operative outcomes following interval cytoreduction for EOC. Methods: Patients undergoing NACT for EOC between 2007-2020 were identified through our institutional database. A retrospective review was performed to identify cancer-specific, preoperative, surgical, and post-operative variables. Pretreatment and post-treatment contrast-enhanced CT scans were reviewed by two subspecialty radiologists to determine skeletal muscle index (SMI). SMI was calculated by dividing total psoas and paraspinal muscle area (m2) (measured at the level of L4 vertebrae) by height squared (cm2). Patients were grouped based on SMI into Group 1) patients with >2% decrease in SMI, and Group 2) patients with an increase or less than or equal to 2% decrease in SMI after NACT. SMI was also analyzed as a continuous variable for association with demographic and clinical factors by Kruskal-Wallis test/Spearman's correlation (results summarized as median [25th, 75th percentiles]). Results: A total of 77 patients met the inclusion criteria. Baseline demographic characteristics were consistent between group 1 and 2 patients. Baseline CA125 was significantly higher in group 2 patients (increase or less than or equal to 2% decrease in SMI) (p=0.031). However, change in SMI was not significantly associated with surgical or postoperative outcomes. When analyzed as a continuous variable, SMI was correlated with higher surgical complexity score (SCS); patients with low SCS had a median SMI of 20.7 m2/cm2 vs 23.6 and 23.8 m2/cm2 for intermediate and high SCS, respectively (p=0.01). Length of surgery was also positively correlated with SMI (0.29, (0.05, 0.51), p=0.021) (Table 1). There was no association between SMI and readmission rates, length of hospital stay, postoperative complications, or non-home discharge. Download : Download high-res image (135KB) Download : Download full-size image Conclusions: Higher SMI is predictive of longer operative time and higher SCS in patients undergoing interval debulking, but was not predictive of postoperative outcomes, complications, length of stay, or non-home discharge in this study. These data suggest that SMI may be a surrogate for extent of interval surgical debulking. A larger population of NACT patients is being evaluated to determine more robust correlations in postoperative outcomes.

Background: Hemophagocytic lymphohistiocytosis (HLH) is life-threatening disorder of immune dysregulation involving macrophage and T-cell activation resulting in massive cytokine release causing multi-organ dysfunction. Similar release of cytokine products from fat tissue is associated with obesity-related insulin resistance. Our case presentation is an example of HLH and insulin resistance, two conditions with overlapping pathophysiology, occurring simultaneously. Clinical Presentation: A 17-year-old male, with no history of hyperglycemia, underwent renal transplant due dysplastic kidneys. He received 500mg IV methylprednisolone during surgery followed by a prednisone taper starting at 70mg daily. Serum glucoses post-transplant ranged from 97 to 129 mg/dL. Three weeks post-transplant he was admitted for fever and dehydration. BMI on admission was the 85th percentile. Serum glucose was 371 mg/dL without ketosis. He started on insulin therapy, requiring 60 units per day (0.8 units/kg). It was suspected his new-onset diabetes was due to his immunosuppressant regimen (prednisone 50mg daily, tacrolimus) and/or acute illness. With persistent fevers and negative infectious workup, there was concern for HLH. The diagnosed was confirmed with ferritin level of 65,962 ng/mL (27-265), hemoglobin 6.5 gm/dL, platelets 88,000, triglycerides 765 mg/dL, soluble IL-2 receptor 2,717 u/mL (45 - 1,105). For HLH treatment, he received methylprednisolone 800 mg daily x 3 doses. During this time his insulin requirements increased to 188 units per day (3.6 units/kg). He was transitioned to dexamethasone 20mg daily. His insulin requirements increased over the next 72 hours to 388 units per day (5.2 units/kg). He was found to be positive for Ehrlichiosis, a known precipitant of HLH. Doxycycline therapy was initiated for a 14 day course. One week into his doxycycline course his ferritin had decreased to 999 ng/mL. He remained on dexamethasone 20 mg daily but developed severe hypoglycemia to 29 mg/dL with altered mental status. All insulin therapy was held. Fasting glucoses over the next 4 days ranged from 94-154 mg/dL and post-prandial glucoses 116-288 mg/dL. He discharged home with only short acting insulin for glucoses above 250 mg/dL, which he did not require. Case Lessons: Cytokine release from macrophages is implicated in the pathology of both HLH and insulin resistance associated with obesity. Glucocorticoids used to treat HLH can also exacerbate insulin resistance. Providers should be aware of the risk of hyperglycemia and large insulin requirements in patients with HLH, and the potential for rapid reduction of insulin needs as HLH is successfully treated.

Ketamine, a nonselective NMDA receptor antagonist, is used widely in medicine as an anesthetic agent. However, ketamine’s mechanisms of action lead to widespread physiological effects, some of which are now coming to the forefront of research for the treatment of diverse medical disorders. This paper aims at reviewing recent data on key nonanesthetic uses of ketamine in the current literature. MEDLINE, CINAHL, and Google Scholar databases were queried to find articles related to ketamine in the treatment of depression, pain syndromes including acute pain, chronic pain, and headache, neurologic applications including neuroprotection and seizures, and alcohol and substance use disorders. It can be concluded that ketamine has a potential role in the treatment of all of these conditions. However, research in this area is still in its early stages, and larger studies are required to evaluate ketamine’s efficacy for nonanesthetic purposes in the general population.

This article focuses on two collaborative projects selected by the Howard H. Baker Jr. Center for Public Policy at the University of Tennessee to partner in the US Department of State’s Diplomacy L...

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder marked by massive cytokine release due to macrophage and T-cell activation. Hallmarks of the diagnosis include fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogemia, and elevations in ferritin and soluble IL-2 receptor. Given HLH is associated with critical illness, elevation in inflammatory markers, and treated with glucocorticoids, the development of hyperglycemia during its course is not unexpected. However, detailed descriptions of the severity of hyperglycemia and strategies in insulin management among HLH patients are lacking. We describe 10 years’ experience at a single tertiary pediatric health center with HLH patients who developed insulin dependent hyperglycemia. Objectives: To describe the demographics, clinical and laboratory findings, treatment regimens, and outcomes for children with HLH treated with insulin due to hyperglycemia. Study Design: Retrospective chart review from 2010 through 2019 of youth 0 to 21 years of age who required insulin therapy during or shortly after a hospitalization where they were diagnosed with HLH using established criteria. Descriptive statistics were used to characterize the population of interest. Results: Of 30 patients diagnosed with HLH, 33% (n=10) required insulin therapy. Half (n=5) were female and half (n=5) male. The mean age was 8.4 years (7.8 months - 17 years). The majority (80%) were non-Hispanic white. Mean BMI at admission was 53rd percentile (5th - 87th percentile). Max serum glucose ranged from 267 to 725 mg/dL (mean 421 mg/dL). Marked inflammation was present (max CRP 2.6 - 44.9 mg/dL, max ferritin 1,091 - 90,219 ng/mL). All were treated with dexamethasone, doses ranging from 5 to 11 mg/m2/day and duration from 2 to 70 days. Most (90%) received parenteral nutrition (PN) with a mean max GIR of 8 mg/kg/min (SD=2.7). Intravenous infusions of regular insulin were used in 80% of patients, though 2 patients were later transitioned to long and short acting subcutaneous insulin. Mean duration of IV insulin therapy was 9.5 days (2–24 days); however, 2 patients died while on IV insulin therapy. The majority (70%) needed insulin within 5 days of starting steroids. Two patients (20%) were treated with subcutaneous insulin only (no IV). Only 1 patient was discharged home on insulin therapy. Mean hospital stay was 60 days (10–202 days). Mortality was 50% (n=5). Conclusions: One-third of pediatric HLH patients required insulin during their hospitalization for severe hyperglycemia likely secondary to multiple factors including glucocorticoid use, parenteral nutrition, inflammation, and severe illness. Insulin is typically started within 5 days of initiating steroid therapy, limited to IV infusions, and often is not needed by the time of discharge. Risk of mortality is very high.

Objectives: To examine the relationship between sarcopenia as measured by skeletal muscle index (SMI) on CT and chemotherapy outcomes and pathologic response after neoadjuvant chemotherapy (NACT) in patients with advanced epithelial ovarian carcinoma (EOC). Methods: Our institutional database was retrospectively queried for all women with advanced EOC who underwent NACT between 2007-2020. Demographic and clinical variables including number of NACT cycles, dose reductions, and dose delays were collected. Treatment response by 3-tier pathologic chemotherapy response score (CRS) and residual disease at time of interval cytoreductive surgery were recorded. Pre-treatment and post-treatment contrast enhanced CT scans were reviewed by two subspecialty radiologists to determine baseline and post-treatment SMI. SMI was calculated by dividing total psoas muscle and paraspinal muscle area (m2) (measured at the level of L4 vertebrae by height (cm2) squared. Patients were stratified to account for change in SMI after NACT and grouped into patients with >2% decrease in SMI (group 1) and increase or ≤2% decrease in SMI (group 2). SMI was also analyzed as a continuous variable for association with demographic and clinical factors by Kruskal-Wallis test/Spearman's correlation (results summarized as median [25th, 75th percentiles]). Results: Among 77 patients who met inclusion criteria, there were no significant differences between stage at diagnosis, baseline performance status, frailty scores, number of NACT cycles, histology, or tumor grade between the two groups. However, pretreatment Ca125 was higher in patients in group 2 (p=0.031). When SMI was analyzed as a continuous variable, age at diagnosis was negatively associated with higher SMI (-0.47, (-0.63, -0.28, p= Conclusions: Sarcopenia as measured by SMI is associated with older age and increased number of NACT cycles in our patient population. Additionally, sarcopenia was predictive of lower chemotherapy response at the time of interval cytoreduction. Data collection is ongoing to further delineate the relationship between sarcopenia and response to NACT. Download : Download high-res image (170KB) Download : Download full-size image

This study reports on the performance of a leadless ventricular pacemaker with automated, enhanced accelerometer-based algorithms that provide atrioventricular (AV) synchronous pacing.Despite many advantages, leadless pacemakers are currently only capable of single-chamber ventricular pacing.The prospective MARVEL 2 (Micra Atrial tRacking using a Ventricular accELerometer 2) study assessed the performance of an automated, enhanced accelerometer-based algorithm downloaded to the Micra leadless pacemaker for up to 5 h in patients with AV block. The primary efficacy objective was to demonstrate the superiority of the algorithm to provide AV synchronous (VDD) pacing versus VVI-50 pacing in patients with sinus rhythm and complete AV block. The primary safety objective was to demonstrate that the algorithm did not result in pauses or heart rates of100 beats/min.Overall, 75 patients from 12 centers were enrolled; an accelerometer-based algorithm was downloaded to their leadless pacemakers. Among the 40 patients with sinus rhythm and complete AV block included in the primary efficacy objective analysis, the proportion of patients with ≥70% AV synchrony at rest was significantly greater with VDD pacing than with VVI pacing (95% vs. 0%; p 0.001). The mean percentage of AV synchrony increased from 26.8% (median: 26.9%) during VVI pacing to 89.2% (median: 94.3%) during VDD pacing. There were no pauses or episodes of oversensing-induced tachycardia reported during VDD pacing in all 75 patients.Accelerometer-based atrial sensing with an automated, enhanced algorithm significantly improved AV synchrony in patients with sinus rhythm and AV block who were implanted with a leadless ventricular pacemaker. (Micra Atrial Tracking Using a Ventricular Accelerometer 2 [MARVEL 2]; NCT03752151).

OBJECTIVE: High doses of sodium salicylate (SS) are known to induce tinnitus, general hyperexcitability in the central auditory system, and to cause mild hearing loss. We used the auditory brainstem response (ABR) to assess the effects of SS on auditory sensitivity and temporal processing in the auditory nerve and brainstem. DESIGN: ABRs were evoked using tone burst stimuli varying in frequency and intensity with presentation rates from 11/sec to 81/sec. ABRs were recorded and analyzed prior to and after SS treatment in each animal, and peak 1 and peak 4 amplitudes and latencies were determined along with minimal response threshold. STUDY SAMPLE: Nine young adult CBA/CaJ mice were used in a longitudinal within-subject design. RESULTS: No measurable effects of presentation rate were found on ABR threshold prior to SS; however, following SS administration increasing stimulus rates lowered ABR thresholds by as much as 10 dB and compressed the peak amplitude by intensity level functions. CONCLUSIONS: These results suggest that SS alters temporal integration and compressive nonlinearity, and that varying the stimulus rate of the ABR may prove to be a useful diagnostic tool in the study of hearing disorders that involve hyperexcitability.

BACKGROUND: Micra is a leadless pacemaker that is implanted in the right ventricle and provides rate response via a 3-axis accelerometer (ACC). Custom software was developed to detect atrial contraction using the ACC enabling atrioventricular (AV) synchronous pacing. OBJECTIVE: The purpose of this study was to sense atrial contractions from the Micra ACC signal and provide AV synchronous pacing. METHODS: The Micra Accelerometer Sensor Sub-Study (MASS) and MASS2 early feasibility studies showed intracardiac accelerations related to atrial contraction can be measured via ACC in the Micra leadless pacemaker. The Micra Atrial TRacking Using A Ventricular AccELerometer (MARVEL) study was a prospective multicenter study designed to characterize the closed-loop performance of an AV synchronous algorithm downloaded into previously implanted Micra devices. Atrioventricular synchrony (AVS) was measured during 30 minutes of rest and during VVI pacing. AVS was defined as a P wave visible on surface ECG followed by a ventricular event

Teredinibacter turnerae is a cultivable intracellular endosymbiont of xylotrophic (woodfeeding)bivalves of the Family Teredinidae (shipworms). Although T. turnerae has been isolated from many shipworm taxa collected in many locations, no systematic effort has been made to explore genetic diversity within this symbiont species across the taxonomic and geographical range of its hosts. The mode of symbiont transmission is unknown. Here, we examine sequence diversity in fragments of six genes (16S rRNA, gyrB, sseA, recA, rpoB and celAB) among 25 isolates of T. turnerae cultured from 13 shipworm species collected in 15 locations in the Atlantic, Pacific and Indian Oceans. While 16S rRNA sequences are nearly invariant between all examined isolates (maximum pairwise difference

CNS ATRTs are rare, aggressive tumors occurring in very young children and have a poor prognosis and high morbidity. Even with aggressive multi-modal therapy, the cure rate remains less than 50%. New therapy approaches are desperately needed. The broad objective of this project is to accelerate new treatments for ATRT by employing drug repurposing strategies. A high throughput screening (HTS) assay was developed to interrogate our curated library of FDA-approved and industry-abandoned drugs. Two ATRT cell lines from the Children’s Oncology Group were used for the primary HTS. 3,574 FDA-approved and abandoned drugs were screened using a well-established CellTiter-Glo® Luminescent Cell Viability Assay to determine drug effect on ATRT cell line viability and 122 active drugs were identified. Based on demonstrated systems pharmacology data, drug development and regulatory science considerations, and the ability of agents to cross the blood brain barrier, 9 drugs were selected for in vitro studies. Drug effects on cell proliferation, colony formation, spheroid formation, cell cycle, migration, invasion, and cell signaling pathways will be characterized in human control and ATRT cell lines. Based on resulting mechanistic data, in vitro combination studies will be conducted to determine additive or synergistic anticancer activity in the ATRT cell lines. Building upon our extensive track record of advancing 12 repurposed FDA-approved drugs to cancer experimental therapeutics clinical trials over the past seven years, we will employ innovative drug development and regulatory science strategies to rapidly translate promising new treatments identified through this research to ATRT patients.

Background Prescription charge regimes vary between countries but there is little research on how much people know about these or support values underlying them. Objective To explore, in New Zealand (NZ) and England, the public's knowledge of, and attitudes to, charges and whether knowledge and attitudes varied by demographic characteristics or by values about entitlement to public goods. Method A questionnaire was developed and administered to people over 18 recruited in public places in NZ and England. Results 451 people in NZ and 300 people in England participated. Less than half in each country knew the current prescription charge. In each country 62% of people were unaware of arrangements to protect people from excessive annual charges. Support for free or lower cost medicines for children, people over 65, people on low incomes, people on benefits, and people with chronic health problems was higher in England than in NZ. Support varied by participants' demographic characteristics and, in the case of people on low incomes and people on benefits, by values about universal entitlements. Discussion Gaps in knowledge, particularly about mechanisms to protect people from high costs, are concerning and may lead to people paying excessive charges. There was consensus about the elderly, children and the chronically ill being “deserving” of lower prescription charges, but people who did not believe in universal access to public goods appeared to see people on low incomes or benefits as less “deserving”. In general, public views resembled those underlying the prescription charge regime in their country.

Background In major depression, the neural mechanisms underlying suicide related thoughts and behaviors as well as the expression of other depressive symptoms are incompletely characterized. Evidence indicates that both the striatum and cortical midline structures (CMS) may be involved with both suicide and emotional dysregulation in unipolar illness. The aim of this study was to identify striatal–CMS circuits associated with current depression severity and suicidal ideation (SI) as well as a history of self-harm. Methods Twenty-two male subjects with recurrent unipolar depression were studied using functional MRI. All subjects were unmedicated and without current psychiatric comorbidity. Correlational analyses were used to determine whether striatal–CMS functional connectivity was associated with any of the three clinical variables. Results A network involving the bilateral striatum and anterior CMS was found to be associated with depressive symptom severity. Current SI was associated with a similar but less extensive circuit in the left hemisphere. A distinct striatal motor/sensory network was associated with self-harm behaviors, but not current SI or depression severity. Conclusions The striatal–anterior CMS circuit likely plays a significant role in the expression of depressive symptoms and SI. In contrast, a striatum–motor/sensory cortex network may be a trait marker of suicide-related behaviors. If replicated, this result might eventually lead to the development of a biomarker that would be useful for studies of pharmacologic and/or psychotherapeutic suicide prevention interventions.

The primary aim of this study was to enhance our understanding of the functional architecture of the cortico‐basal ganglia circuitry during motor task execution. Twenty right‐handed female subjects without any history of neuropsychiatric illness underwent fMRI at 3 T. The activation paradigm was a complex motor task completed with the nondominant hand. Analyses of functional connectivity strength were conducted for pairs of structures in input, intrinsic, and output segments of the circuitry. Next, connectivity strengths were correlated with results of neurocognitive testing conducted outside of the scanner, which provided information about both motor and cognitive processes. For input pathways, results indicate that SMA–striatum interactions are particularly relevant for motor behavior and disruptions may impact both motor and cognitive functions. For intrinsic pathways, results indicate that thalamus (VA nucleus) to striatum feedback pathway appears to have an important role during task execution and carries information relevant for motor planning. Together, these findings add to accumulating evidence that the GPe may play a role in higher order basal ganglia processing. A potentially controversial finding was that strong functional connectivity appears to occur across intrinsic inhibitory pathways. Finally, output (thalamus to cortex) feedback was only correlated with motor planning. This result suggests circuit processes may be more relevant for future behaviors than the execution of the current task. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.

The ability to consume wood as food (xylotrophy) is unusual among animals. In terrestrial environments, termites and other xylotrophic insects are the principle wood consumers while in marine environments wood-boring bivalves fulfill this role. However, the evolutionary origin of wood feeding in bivalves has remained largely unexplored. Here we provide data indicating that xylotrophy has arisen just once in Bivalvia in a single wood-feeding bivalve lineage that subsequently diversified into distinct shallow- and deep-water branches, both of which have been broadly successful in colonizing the world's oceans. These data also suggest that the appearance of this remarkable life habit was approximately coincident with the acquisition of bacterial endosymbionts. Here we generate a robust phylogeny for xylotrophic bivalves and related species based on sequences of small and large subunit nuclear rRNA genes. We then trace the distribution among the modern taxa of morphological characters and character states associated with xylotrophy and xylotrepesis (wood-boring) and use a parsimony-based method to infer their ancestral states. Based on these ancestral state reconstructions we propose a set of plausible hypotheses describing the evolution of symbiotic xylotrophy in Bivalvia. Within this context, we reinterpret one of the most remarkable progressions in bivalve evolution, the transformation of the "typical" myoid body plan to create a unique lineage of worm-like, tube-forming, wood-feeding clams. The well-supported phylogeny presented here is inconsistent with most taxonomic treatments for xylotrophic bivalves, indicating that the bivalve family Pholadidae and the subfamilies Teredininae and Bankiinae of the family Teredinidae are non-monophyletic, and that the principle traits used for their taxonomic diagnosis are phylogenetically misleading.

Bipolar II depression is a serious and disabling illness associated with significant impairment and high rates of suicide attempts. However, mechanisms underlying emotional dysregulation in this condition are poorly characterized. The goal of this work was to investigate one component of emotional processing in this disorder, brain activation associated with exposure to emotional faces. Functional MRI was used to study 16 unmedicated male subjects with bipolar II depression and 19 healthy male controls. The activation paradigm exposed subjects to happy, fearful and neutral faces. The two key findings of this study were as follows. First, bipolar subjects demonstrated significantly decreased activation in response to happy facial expression in the left posterior cortical midline structures (CMS) and frontal cortex. Second, depression severity was positively correlated with activation of the posterior CMS and other regions. Our results suggest that mechanisms involving CMS dysfunction may play a role in the neurobiology of bipolar II depression as has been demonstrated for unipolar illness. Further investigations of CMS function in bipolar spectrum disorders are warranted.

Normal human aging is associated with declining motor control and function. It is thought that dysfunction of the cortico-basal ganglia circuitry may contribute to age-related sensorimotor impairment, however the underlying mechanisms are poorly characterized. The aim of this study was to enhance our understanding of age-related changes in the functional architecture of these circuits. Fifty-nine subjects, consisting of a young, middle and old group, were studied using functional MRI and a motor activation paradigm. Functional connectivity analyses and examination of correlations of connectivity strength with performance on the activation task as well as neurocognitive tasks completed outside of magnet were conducted. Results indicated that increasing age is associated with changes in the functional architecture of the cortico-basal ganglia circuitry. Connectivity strength increased between subcortical nuclei and cortical motor and sensory regions but no changes were found between subcortical components of the circuitry. Further, increased connectivity was correlated with poorer performance on a neurocognitive task independently of age. This result suggests that increased connectivity reflects a decline in brain function rather than a compensatory process. These findings advance our understanding of the normal aging process. Further, the methods employed will likely be useful for future studies aimed at disambiguating age-related versus illness progression changes associated with neuropsychiatric disorders that involve the cortico-basal ganglia circuitry.

Who can use the content that a library licenses? What are e-rights? Can licensed digital content be distributed through interlibrary loan? The digital revolution has altered how libraries acquire and distribute content to patrons. Gone are the days in which libraries primarily purchased and owned physical materials. In the internet era, content can be temporarily leased electronically, which has led to unexpected legal issues for librarians and other non-lawyers to navigate (1). In Licensing Digital Content: A Practical Guide for Librarians, Harris provides a plain-language crash course in digital licensing intended to give inexperienced librarians the skills necessary to negotiate a digital license. The guide provides readers with a detailed description of the licensing experience from the development of a licensing needs assessment to the negotiation of the final agreement.

Soy protein contains antioxidant factors, such as isoflavones, which may help prevent heart disease and cancer. Nonetheless, many active men avoid soy protein because of reports that isoflavones lower testosterone levels. However, soy isoflavone effects on testosterone readings in active young adult males have not been reported. This study found that in such men, a 4-week intake of high-isoflavone soy protein (41.5 g/70 kg body weight per day) had no effect on plasma testosterone values. The soy protein intake did elevate plasma total antioxidant status values (a measure of free radical scavenging). By comparison, intake of whey protein or a placebo (cake mix) had no effect on plasma total antioxidant status readings. Thus, soy protein was found to produce an antioxidant effect in active young adult men without lowering testosterone concentrations.

Morphology Download.Introduction: Present implantable cardioverter defibrillators (ICDs) have algorithms that discriminate supraventricular tachycardia (SVT) from ventricular tachycardia (VT). One type of algorithm is based on differences in morphology of ventricular electrograms during VT and SVT. Prior SVT-VT discrimination algorithms have not undergone real-time evaluation in ambulatory patients until they were incorporated permanently into ICDs. This approach may result in incomplete testing of electrogram morphology algorithms because they are influenced by posture, activity, and electrogram maturation. We downloaded software into implanted ICDs to study a novel algorithm that compares morphologies of baseline and tachycardia electrograms based on differences between corresponding coefficients of their wavelet transforms. This comparison is expressed as a match-percent score. Methods and Results: In 23 patients, we downloaded the wavelet algorithm into implanted ICDs to assess the temporal and postural stability of baseline electrograms as measured by this algorithm and its accuracy for SVT-VT discrimination. Median follow-up was 6 months. Software was downloaded into all ICDs without altering other device functions. With few exceptions, percent template match in baseline rhythm was stable with changes in body position, rest versus walking, isometric exercise, and over time (1 and 3 months). Using the nominal match-percent threshold of 70%, sensitivity for detection of 38 VTs was 100%. Specificity for rejection of 65 SVTs was 78%. SVTs were rejected for a total of 2.7 hours. Inappropriate detections of SVT as VT were caused by electrogram truncation, myopotential interference with low-amplitude electrograms, waveform alignment error, and rate-dependent aberrancy. The first three accounted for 69% of inappropriate detections and could have been prevented by optimal programming. The optimal match-percent threshold was 60% to 70% based on a receiver-operator characteristic curve. After shocks, the median time for baseline electrogram morphology to normalize was 85 seconds. Conclusion: The wavelet morphology algorithm has high sensitivity for VT detection. Inappropriate detections of SVT as VT may be reduced by optimal programming. Downloadable software permits evaluation of new algorithms in implanted ICDs.

Date Presented 4/8/2016 Older adults caring for their grandchildren is a phenomenon; little research has focused on ways they cope with parenting stressors. This qualitative study explored coping strategies used by grandparents. Results inform more effective occupation-based interventions to improve quality of life. Primary Author and Speaker: Jennifer-Nicole Wood Additional Authors and Speaker: Kayla Gittens, Callie Merriman, Patrick Hopkins Contributing Authors: Kenneth Guy, Jenene Woods Craig, Kathleen T. Foley

Background Considerable evidence implicates dysfunction of striatal and cortical midline structure (CMS) circuitry in mood disorders. Whether such aberrations exist in bipolar II depression is unknown. Methods Sixteen unmedicated subjects with bipolar II depression and 19 healthy controls were studied using functional MRI and a motor activation paradigm. Analyses of both activation and functional connectivity were conducted. Results A history of suicidal ideation (SI) was negatively correlated with activation of the left putamen while depression severity was positively correlated with activation of the left thalamus. The superior bilateral putamen was simultaneously correlated with depression severity and anti-correlated with SI. Striatal functional connectivity was altered with the bilateral CMS and right inferior parietal lobule. Depression severity was correlated with strength of connectivity between the bilateral striatum and the right lingual gyrus and left cerebellum. Limitations Only males experiencing an episode of major depression were studied. Conclusions Striatal and CMS circuit abnormalities likely contribute to the neurobiology of bipolar II depression. Altered connectivity of the striatum may directly impact depression severity. Further, dissociable components of activation associated with depression severity and suicidal ideation may exist. Finally, the motor activation paradigm used in this study appears to be a useful probe of some neural processes underlying bipolar II depression.

Here we report the complete genome sequence of Teredinibacter turnerae T7901. T. turnerae is a marine gamma proteobacterium that occurs as an intracellular endosymbiont in the gills of wood-boring marine bivalves of the family Teredinidae (shipworms). This species is the sole cultivated member of an endosymbiotic consortium thought to provide the host with enzymes, including cellulases and nitrogenase, critical for digestion of wood and supplementation of the host's nitrogen-deficient diet. T. turnerae is closely related to the free-living marine polysaccharide degrading bacterium Saccharophagus degradans str. 2-40 and to as yet uncultivated endosymbionts with which it coexists in shipworm cells. Like S. degradans, the T. turnerae genome encodes a large number of enzymes predicted to be involved in complex polysaccharide degradation (>100). However, unlike S. degradans, which degrades a broad spectrum (>10 classes) of complex plant, fungal and algal polysaccharides, T. turnerae primarily encodes enzymes associated with deconstruction of terrestrial woody plant material. Also unlike S. degradans and many other eubacteria, T. turnerae dedicates a large proportion of its genome to genes predicted to function in secondary metabolism. Despite its intracellular niche, the T. turnerae genome lacks many features associated with obligate intracellular existence (e.g. reduced genome size, reduced %G+C, loss of genes of core metabolism) and displays evidence of adaptations common to free-living bacteria (e.g. defense against bacteriophage infection). These results suggest that T. turnerae is likely a facultative intracellular ensosymbiont whose niche presently includes, or recently included, free-living existence. As such, the T. turnerae genome provides insights into the range of genomic adaptations associated with intracellular endosymbiosis as well as enzymatic mechanisms relevant to the recycling of plant materials in marine environments and the production of cellulose-derived biofuels. © 2009 Yang et al.

Body surface Laplacian mapping localizes cardiac activity and provides more detailed distributions compared to body surface potential mapping. Systematic comparison of the performance of bipolar and Laplacian ECGs during noise has not been performed. To determine whether Laplacian ECGs (2.5 cm diameter concentric rings) can reduce noise (myopotential and motion artifacts) and improve signal to noise ratio (SNR) compared to bipolar (4 cm spacing) ECGs, Laplacian and bipolar ECGs were recorded from the anterior (precordial V3) and lateral (precordial V6) chest regions in 25 patients undergoing posture changes and in-office exercises. Mean peak-to-peak (Vpp), root mean square noise (Noise(rms)) and SNR were computed across all activities and patients. Sensing performance using an R-wave detector with an auto-adjusting exponentially decaying threshold was assessed. Across all maneuvers, mean Vpp was larger for the bipolar ECG compared to the Laplacian ECG on the anterior (0.65 +/- 0.07 vs. 0.14 +/- 0.07 mV, p

A wide spectrum of CD8 T cell responses can be elicited against antigens (Ag) expressed in the liver, ranging from tolerance to full effector function. Identifying the factors involved would allow us to predict the outcome of liver transplantation and viral hepatitis. To investigate how CD8 T cells respond to liver Ags, we have developed recombinant adeno-associated viral vectors that, when injected into mice, allow de novo Ag expression in a variable number of hepatocytes. Within the first day of Ag expression by at least 70% of hepatocytes, most naïve Ag-specific CD8 T cells were activated in the liver via direct presentation by hepatocytes. CD8 T cell activation in lymph nodes and spleen via cross presentation was detected a day later, suggesting that primary activation of CD8 T cells against hepatocyte-expressed Ag is compartmentalised. These T cells proliferated, developed into CTLs in the first week but were unable to kill all Ag-expressing hepatocytes. Most effector T cells were rapidly deleted while those surviving became exhausted and unresponsive over time. In contrast, when less than 10% of hepatocytes expressed the targeted Ag, CD8 T cell were gradually activated in liver and lymphoid tissues but were not deleted. Instead, they eliminated all Ag-expressing hepatocytes and maintained their effector function overtime. In summary, this study shows that intrahepatic Ag load dictates both the fate and function of CD8 T cells recognising hepatocyte-expressed Ags.