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Background: At-risk alcohol use is associated with increased adverse health consequences, yet is undertreated in healthcare settings. People residing in rural areas need improved access to services; however, few interventions are designed to meet the needs of rural populations. Mobile interventions can provide feasible, low-cost, and scalable means for reaching this population and improving health, and behavioral economic approaches are promising. Methods: We conducted a pilot randomized controlled trial focused on acceptability and feasibility of a mobile behavioral economic intervention for 75 rural-residing adults with at-risk alcohol use. We recruited participants from a large healthcare system and randomized them to one of four virtually-delivered conditions reflecting behavioral economic approaches: episodic future thinking (EFT), volitional choice (VC), both EFT and VC, or enhanced usual care control (EUC). The intervention included a telephone-delivered induction session followed by two weeks of condition-consistent ecological momentary interventions (EMIs; 2x/day) and ecological momentary assessments (EMAs; 1x/day). Participants completed assessments at baseline, post-intervention, and two-month follow-up, and provided intervention feedback. Results: All participants completed the telephone-delivered session and elected to receive EMI messages. Average completion rate of EMAs across conditions was 92.9%. Among participants in active intervention conditions, 89.3% reported the induction session was helpful and 80.0% reported it influenced their future drinking. We also report initial alcohol use outcomes. Discussion: The behavioral economic intervention components and trial procedures evaluated here appear to be feasible and acceptable. Next steps include determination of their efficacy to reduce alcohol use and public health harms.

Background: Guidelines suggest that active surveillance (AS) may be considered for select patients with favorable intermediate-risk (fIR) prostate cancer. Objective: To compare the outcomes between fIR prostate cancer patients included by Gleason score (GS) or prostate-specific antigen (PSA). Most patients are classified with fIR disease due to either a 3 + 4 = 7 GS (fIR-GS) or a PSA level of 10–20 ng/ml (fIR-PSA). Previous research suggests that inclusion by GS 7 may be associated with worse outcomes. Design, setting, and participants: We conducted a retrospective cohort study of US veterans diagnosed with fIR prostate cancer from 2001 to 2015. Outcome measurements and statistical analysis: We compared the incidence of metastatic disease, prostate cancer–specific mortality (PCSM), all-cause mortality (ACM), and receipt of definitive treatment between fIR-PSA and fIR-GS patients managed with AS. Outcomes were compared with those of a previously published cohort of patients with unfavorable intermediate-risk disease using cumulative incidence function and Gray’s test for statistical significance. Results and limitations: The cohort included 663 men; 404 had fIR-GS (61%) and 249 fIR-PSA (39%). There was no evidence of difference in the incidence of metastatic disease (8.6% vs 5.8%, p = 0.77), receipt of definitive treatment (77.6% vs 81.5%, p = 0.43), PCSM (5.7% vs 2.5%, p = 0.274), and ACM (16.8% vs 19.1%, p = 0.14) between the fIR-PSA and fIR-GS groups at 10 yr. On multivariate regression, unfavorable intermediate-risk disease was associated with higher rates of metastatic disease, PCSM, and ACM. Limitations included varying surveillance protocols. Conclusions: There is no evidence of difference in oncological and survival outcomes between men with fIR-PSA and fIR-GS prostate cancer undergoing AS. Thus, presence of GS 7 disease alone should not exclude patients from consideration of AS. Shared decision-making should be utilized to optimize management for each patient. Patient summary: In this report, we compared the outcomes of men with favorable intermediate-risk prostate cancer in the Veterans Health Administration. We found no significant difference between survival and oncological outcomes.

Introduction: The Brief Addiction Monitor-Revised (BAM-R) is a widely used, 17-item assessment of substance use, risk, and protective factors associated with recovery from substance use disorders. Despite wide adoption in the U.S. Department of Veterans Affairs (VA) and recommendations for use in measurement-based care (MBC), administration may not be feasible in many MBC settings due to time constraints. The purpose of this study was to derive a shortened version of the BAM-R for use in fast-paced healthcare settings. Methods: BAM-R data from 32,002 Veterans were obtained through the VA's Corporate Data Warehouse. We used logistic regression models to identify items for removal based on prediction of two clinical outcomes (90-day substance use disorder (SUD) treatment retention and 12-month mortality) and item-level sensitivity to change during substance use treatment. Results: Although no intake BAM-R items predicted SUD treatment retention or mortality, effect sizes for item-level sensitivity to change during substance use treatment varied from small to large. Seven items were judged as relevant for MBC of SUD. Among all BAM-R items, Heavy Alcohol Use, Self-Help, Drug Use, Craving, and Mood items demonstrated the greatest magnitude of sensitivity to change. Conclusions: Although additional research is recommended before a shortened BAM-R can be implemented in non-specialty MBC settings, we identified 5 BAM-R items with perceived clinical utility and scores that demonstrated evidence of sensitivity to change. Shortening the BAM-R increases feasibility of use, though more work is needed to optimize measurement for SUD MBC.

Background: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. Objectives: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. Methods: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD or no established CVD, male ≥ 55 or female ≥ 60 years, and one additional CVRF. The primary endpoint was an ordinal COVID-19 severity outcome including need for hospitalization, supplemental oxygen, intensive care unit (ICU), mechanical ventilation, ICU or mechanical ventilation plus vasopressors, and death. Secondary endpoints included incident adverse CV events. Ordinal logistic regression models estimated associations of CVD/CVRF with COVID-19 severity. Effect modification by recent cancer therapy was evaluated. Results: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54–74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11–1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all p

Summary: Background: Metastatic renal cell carcinoma (mRCC) is a heterogenous disease with poor 5-year overall survival (OS) at 14%. Patients with mRCC to endocrine organs historically have prolonged OS. Pancreatic metastases are uncommon overall, with mRCC being the most common etiology of pancreatic metastases. In this study, we report the long-term outcomes of patients with mRCC to the pancreas in two separate cohorts. Methods: We performed a multicenter, international retrospective cohort study of patients with mRCC to the pancreas at 15 academic centers. Cohort 1 included 91 patients with oligometastatic disease to the pancreas. Cohort 2 included 229 patients with multiples organ sites of metastases including the pancreas. The primary endpoint for Cohorts 1 and 2 was median OS from time of metastatic disease in the pancreas until death or last follow up. Findings: In Cohort 1, the median OS (mOS) was 121 months with a median follow up time of 42 months. Patients who underwent surgical resection of oligometastatic disease had mOS of 100 months with a median follow-up time of 52.5 months. The mOS for patients treated with systemic therapy was not reached. In Cohort 2, the mOS was 90.77 months. Patients treated with first-line (1L) VEGFR therapy had mOS of 90.77 months; patients treated with IL immunotherapy (IO) had mOS of 92 months; patients on 1L combination VEGFR/IO had mOS of 74.9 months. Interpretations: This is the largest retrospective cohort of mRCC involving the pancreas. We confirmed the previously reported long-term outcomes in patients with oligometastatic pancreas disease and demonstrated prolonged survival in patients with multiple RCC metastases that included the pancreas. In this retrospective study with heterogeneous population treated over 2 decades, mOS was similar when stratified by first-line therapy. Future research will be needed to determine whether mRCC patients with pancreatic metastases require a different initial treatment strategy. Funding: Statistical analyses for this study were supported in part by the University of Colorado Cancer Center Support Grant from the NIH/NCI, P30CA046934-30.

A comprehensive evaluation of the clear cell renal cell carcinoma (ccRCC) immune landscape was found using 584 RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), we identified 17 key dysregulated immune-associated genes in ccRCC based on association with clinical variables and important immune pathways. Of the numerous findings from our analyses, we found that several of the 17 key dysregulated genes are heavily involved in interleukin and NF-kB signaling and that somatic copy number alteration (SCNA) hotspots may be causally associated with gene dysregulation. More importantly, we also found that key immune-associated genes and pathways are strongly upregulated in ccRCC. Our study may lend novel insights into the clinical implications of immune dysregulation in ccRCC and suggests potential immunotherapeutic targets for further evaluation.

Summary: Background: Breakthrough SARS-CoV-2 infections following vaccination against COVID-19 are of international concern. Patients with cancer have been observed to have worse outcomes associated with COVID-19 during the pandemic. We sought to evaluate the clinical characteristics and outcomes of patients with cancer who developed breakthrough SARS-CoV-2 infections after 2 or 3 doses of mRNA vaccines. Methods: We evaluated the clinical characteristics of patients with cancer who developed breakthrough infections using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19; NCT04354701). Analysis was restricted to patients with laboratory-confirmed SARS-CoV-2 diagnosed in 2021 or 2022, to allow for a contemporary unvaccinated control population; potential differences were evaluated using a multivariable logistic regression model after inverse probability of treatment weighting to adjust for potential baseline confounding variables. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) are reported. The primary endpoint was 30-day mortality, with key secondary endpoints of hospitalization and ICU and/or mechanical ventilation (ICU/MV). Findings: The analysis included 2486 patients, of which 564 and 385 had received 2 or 3 doses of an mRNA vaccine prior to infection, respectively. Hematologic malignancies and recent receipt of systemic anti-neoplastic therapy were more frequent among vaccinated patients. Vaccination was associated with improved outcomes: in the primary analysis, 2 doses (aOR: 0.62, 95% CI: 0.44–0.88) and 3 doses (aOR: 0.20, 95% CI: 0.11–0.36) were associated with decreased 30-day mortality. There were similar findings for the key secondary endpoints of ICU/MV (aOR: 0.60, 95% CI: 0.45–0.82 and 0.37, 95% CI: 0.24–0.58) and hospitalization (aOR: 0.60, 95% CI: 0.48–0.75 and 0.35, 95% CI: 0.26–0.46) for 2 and 3 doses, respectively. Importantly, Black patients had higher rates of hospitalization (aOR: 1.47, 95% CI: 1.12–1.92), and Hispanic patients presented with higher rates of ICU/MV (aOR: 1.61, 95% CI: 1.06–2.44). Interpretation: Vaccination against COVID-19, especially with additional doses, is a fundamental strategy in the prevention of adverse outcomes including death, among patients with cancer. Funding: This study was partly supported by grants from the National Cancer Institute grant number P30 CA068485 to C-YH, YS, SM, JLW; T32-CA236621 and P30-CA046592 to C.R.F; CTSA 2UL1TR001425-05A1 to TMW-D; ACS/FHI Real-World Data Impact Award, P50 MD017341-01, R21 CA242044-01A1, Susan G. Komen Leadership Grant Hunt to MKA. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH).

The application of induced pluripotent stem cells (iPSCs) in advanced therapies is increasing at pace, but concerns remain over their clinical safety profile. We report the first-ever application of doggybone DNA (dbDNA) vectors to generate human iPSCs. dbDNA vectors are closed-capped linear double-stranded DNA gene expression cassettes that contain no bacterial DNA and are amplified by a chemically defined, current good manufacturing practice (cGMP)-compliant methodology. We achieved comparable iPSC reprogramming efficiencies using transiently expressing dbDNA vectors with the same iPSC reprogramming coding sequences as the state-of-the-art OriP/EBNA1 episomal vectors but, crucially, in the absence of p53 shRNA repression. Moreover, persistent expression of EBNA1 from bacterially derived episomes resulted in stimulation of the interferon response, elevated DNA damage, and increased spontaneous differentiation. These cellular activities were diminished or absent in dbDNA-iPSCs, resulting in lines with a greater stability and safety potential for cell therapy.

Background: Muscle-invasive bladder cancer (MIBC) remains undertreated despite multiple potentially curative options. Both radical cystectomy (RC) with or without neoadjuvant chemotherapy and trimodal therapy (TMT), including transurethral resection of bladder tumor followed by chemoradiotherapy, are standard treatments. Objective: To evaluate real-world clinical outcomes of RC with neoadjuvant chemotherapy (RC-NAC), RC without NAC, TMT with National Comprehensive Cancer Network guideline–preferred radiosensitizing chemotherapy including cisplatin or mitomycin-C and 5-fluorouracil (pTMT), and TMT with nonpreferred chemotherapy (npTMT). Design, setting, and participants: US veterans with nonmetastatic MIBC (T2-4aN0-3M0) were studied. Outcome measurements and statistical analysis: Overall mortality (OM) was evaluated with multivariable Cox proportional hazard model. Bladder cancer-specific mortality (BCSM) was evaluated with multivariable Fine-Gray regression. Salvage cystectomy rates were obtained by chart review. Results and limitations: Overall 2306 patients were included: 1472 (64%) with RC without NAC, 506 (22%) with RC-NAC, 163 (7%) with pTMT, and 165 (7%) with npTMT. On multivariable analysis, pTMT was associated with similar OM (hazard ratio [HR] 1.19; 95% confidence interval [CI] 0.94–1.50; p = 0.15) and BCSM (HR 1.34; 95% CI 0.99–1.83; p = 0.06) to RC-NAC; npTMT was associated with worse OM (HR 1.30; 95% CI 1.04–1.61; p = 0.02) and BCSM (HR 1.45; 95% CI 1.09–1.94; p = 0.01). RC without NAC was associated with similar OM (HR 1.08; 95% CI 0.95–1.24; p = 0.24) and BCSM (HR 1.02; 95% CI 0.86–1.21; p = 0.79). When stratified by age, among patients ≥65 yr of age, treatment with pTMT was associated with similar OM (HR 1.14; 95% CI 0.87–1.50; p = 0.35) and BCSM (HR 1.11; 95% CI 0.76–1.62; p = 0.60). Among patients

Purpose: Chemoradiation (CRT) is a definitive treatment option for muscle-invasive bladder cancer (MIBC). Despite its effectiveness, CRT is underused, in part owing to concerns of tolerability and the need for integrated multidisciplinary care. We investigated factors associated with and the impact of treatment discontinuation in patients with MIBC treated with CRT. Methods and Materials: In the US Veterans Affairs’ national database, we identified patients with urothelial histology, MIBC (T2-4a/N0-3/M0) diagnosed between 2000 and 2018 and treated with definitive-intent CRT. The primary endpoint of discontinued radiation was evaluated in a multivariable logistic regression. Secondary endpoints of 30-day and 90-day mortality, overall mortality, and nonbladder cancer mortality were evaluated in multivariable models. Results: Of 369 veterans with MIBC who underwent CRT, 30 patients (8.1%) did not complete radiation. The most common reasons for treatment discontinuation included comorbidities or infections necessitating hospital admission (63.3%) and treatment intolerance or declining performance status (26.7%). In multivariable logistic regression, variables associated with radiation discontinuation were creatinine clearance ≤ 50 (odds ratio [OR], 3.93; 95% CI, 1.63-9.50; P = .002), incomplete transurethral resection of bladder tumor (TURBT) (OR, 3.16; 95% CI, 1.15-8.63; P = .02), and nonpreferred chemotherapy (OR, 3.31; 95% CI, 1.31-8.36; P = .01). In the cohort that discontinued radiation, 30-day mortality was 33.3% and 90-day mortality was 50.0%, with the majority of deaths attributed to nonbladder cancer causes. No patient or tumor variables were associated with either endpoint. In the cohort that completed radiation, 30-day mortality was 2.7% and 90-day mortality was 6.8%. In multivariable analysis, radiation discontinuation was associated with worse overall mortality (hazard ratio [HR], 2.48; 95% CI, 1.36-4.50; P = .003) and worse nonbladder cancer mortality (HR, 2.32; 95% CI, 1.24-4.34; P = .008). Conclusions: With a low rate of treatment discontinuation, CRT is an effective and feasible treatment option for the typically elderly and comorbid population of patients with MIBC. In addition to identified predictors of treatment discontinuation (poor renal function, incomplete TURBT, etc.), further research is required to develop evidence-based guidelines for optimal patient selection.

Summary: Hepatitis C virus (HCV) is a leading cause of liver-associated disease and liver cancer. Of the major HCV subtypes, patients infected with subtype 1b have been associated with having a higher risk of developing chronic infection and hepatocellular carcinoma. However, underlying reasons for this increased disease severity remain unknown. Here, we provide an evolutionary rationale, based on a comparative study of fitness landscape and in-host evolutionary models of the E2 glycoprotein of HCV subtypes 1a and 1b. Our analysis demonstrates that a higher chronicity rate of 1b may be attributed to lower fitness constraints, enabling 1b viruses to more easily escape antibody responses. More generally, our results suggest that differences in evolutionary constraints between HCV subtypes may be an important factor in mediating distinct disease outcomes. Our analysis also identifies antibodies that appear escape-resistant against both subtypes 1a and 1b, providing directions for designing HCV vaccines having cross-subtype protection.

Summary: Knowledge of the epitopes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targeted by T cells in recovered (convalescent) individuals is important for understanding T cell immunity against coronavirus disease 2019 (COVID-19). This information can aid development and assessment of COVID-19 vaccines and inform novel diagnostic technologies. Here, we provide a unified description and meta-analysis of SARS-CoV-2 T cell epitopes compiled from 18 studies of cohorts of individuals recovered from COVID-19 (852 individuals in total). Our analysis demonstrates the broad diversity of T cell epitopes that have been recorded for SARS-CoV-2. A large majority are seemingly unaffected by current variants of concern. We identify a set of 20 immunoprevalent epitopes that induced T cell responses in multiple cohorts and in a large fraction of tested individuals. The landscape of SARS-CoV-2 T cell epitopes we describe can help guide immunological studies, including those related to vaccines and diagnostics. A web-based platform has been developed to help complement these efforts.

Summary: Explosion of gene therapy approaches for treating rare monogenic and common liver disorders created an urgent need for disease models able to replicate human liver cellular environment. Available models lack 3D liver structure or are unable to survive in long-term culture. We aimed to generate and test a 3D culture system that allows long-term maintenance of human liver cell characteristics.The in vitro whole-organ “Bioreactor grown Artificial Liver Model” (BALM) employs a custom-designed bioreactor for long-term 3D culture of human induced pluripotent stem cells-derived hepatocyte-like cells (hiHEPs) in a mouse decellularized liver scaffold. Adeno-associated viral (AAV) and lentiviral (LV) vectors were introduced by intravascular injection.Substantial AAV and LV transgene expression in the BALM-grown hiHEPs was detected. Measurement of secreted proteins in the media allowed non-invasive monitoring of the system.We demonstrated that humanized whole-organ BALM is a valuable tool to generate pre-clinical data for investigational medicinal products.

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a common comorbid disorder in patients suffering from substance use disorder (SUD). Individuals with co-occurring SUD and ADHD are more likely than SUD patients without ADHD to have developed SUD at a younger age, be polysubstance users, and need inpatient treatment more often. The present study investigates whether individuals with polysubstance use disorder who remain abstinent for a year after entering treatment have a more substantial reduction in ADHD symptoms than those who relapsed and controls. Material and methods: Subjects were SUD patients (N=115) and healthy controls (N=34). ADHD symptoms were assessed using the adult ADHD Self-Report Scale (ASRS). Substance use was assessed by self-reports on the Alcohol Use Disorders Identification Test (AUDIT) and the Drug Use Disorders Identification Test (DUDIT). Participants were defined as having relapsed if they had an AUDIT scoreâ¥8 or a DUDIT scoreâ¥2 for women andâ¥6 for men. Results: Patients who remained abstinent for one year reported a substantial reduction of ADHD symptoms compared to patients who relapsed and controls. Conclusions: Abstinence alleviates ADHD symptoms among patients with polysubstance use disorder. We suggest that confirmation of an ADHD diagnosis should follow a period of abstinence to avoid identification of false-positive cases. Keywords: Polysubstance, Recovery, ADHD, Substance use disorder

The class Ia anti-arrhythmic drug ajmaline is used clinically to unmask latent type I ECG in Brugada syndrome (BrS) patients, although its mode of action is poorly characterised. Our aims were to identify ajmaline's mode of action in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), and establish a simple BrS hiPSC platform to test whether differences in ajmaline response could be determined between BrS patients and controls. Control hiPSCs were differentiated into spontaneously contracting cardiac clusters. It was found using multi electrode array (MEA) that ajmaline treatment significantly lengthened cluster activation-recovery interval. Patch clamping of single CMs isolated from clusters revealed that ajmaline can block both INa and IKr. Following generation of hiPSC lines from BrS patients (absent of pathogenic SCN5A sodium channel mutations), analysis of hiPSC-CMs from patients and controls revealed that differentiation and action potential parameters were similar. Comparison of cardiac clusters by MEA showed that ajmaline lengthened activation-recovery interval consistently across all lines. We conclude that ajmaline can block both depolarisation and repolarisation of hiPSC-CMs at the cellular level, but that a more refined integrated tissue model may be necessary to elicit differences in its effect between BrS patients and controls.

Let W1 and W2 be independent n×n complex central Wishart matrices with m1 and m2 degrees of freedom respectively. This paper is concerned with the extreme eigenvalue distributions of double-Wishart matrices (W1+W2)−1W1, which are analogous to those of F matrices W1W2−1 and those of the Jacobi unitary ensemble (JUE). Defining α1=m1−n and α2=m2−n with m1, m2≥n, we derive new exact distribution formulas in terms of (α1+α2)-dimensional matrix determinants, with entries involving derivatives of Legendre polynomials. This provides a convenient exact representation, while facilitating a direct large-n analysis with α1 and α2 fixed (i.e., under the so-called “hard-edge” scaling limit). The analysis is based on new asymptotic properties of Legendre polynomials and their relation with Bessel functions that are here established. Specifically, we present limiting formulas for the smallest and largest eigenvalue distributions as n→∞ in terms of α1- and α2-dimensional determinants respectively, which agrees with expectations from known universality results involving the JUE and the Laguerre unitary ensemble (LUE). We also derive finite-n corrections for the asymptotic extreme eigenvalue distributions under hard-edge scaling, giving new insights on universality by comparing with corresponding correction terms derived recently for the LUE. Our derivations are based on elementary algebraic manipulations and properties of Legendre polynomials, differing from existing results on double-Wishart and related models which often involve Fredholm determinants, Painlevé differential equations, or hypergeometric functions of matrix arguments.

The potential of induced pluripotent stem cells (iPSCs) in disease modeling and regenerative medicine is vast, but current methodologies remain inefficient. Understanding the cellular mechanisms underlying iPSC reprogramming, such as the metabolic shift from oxidative to glycolytic energy production, is key to improving its efficiency. We have developed a lentiviral reporter system to assay longitudinal changes in cell signaling and transcription factor activity in living cells throughout iPSC reprogramming of human dermal fibroblasts. We reveal early NF-κB, AP-1, and NRF2 transcription factor activation prior to a temporal peak in hypoxia inducible factor α (HIFα) activity. Mechanistically, we show that an early burst in oxidative phosphorylation and elevated reactive oxygen species generation mediates increased NRF2 activity, which in turn initiates the HIFα-mediated glycolytic shift and may modulate glucose redistribution to the pentose phosphate pathway. Critically, inhibition of NRF2 by KEAP1 overexpression compromises metabolic reprogramming and results in reduced efficiency of iPSC colony formation.

Accurate focusing is a critical challenge of whole slide imaging, primarily due to inherent tissue topography variability. Traditional line scanning and tile-based scanning systems are limited in their ability to acquire a high degree of focus points while still maintaining high throughput. This review examines limitations with first-generation whole slide scanning systems and explores a novel approach that employs continuous autofocus, referred to as independent dual sensor scanning. This "second-generation" concept decouples image acquisition from focusing, allowing for rapid scanning while maintaining continuous accurate focus. The technical concepts, merits, and limitations of this method are explained and compared to that of a traditional whole slide scanning system.

Context: Whole slide imaging (WSI) for digital pathology involves the rapid automated acquisition of multiple high-power fields from a microscope slide containing a tissue specimen. Capturing each field in the correct focal plane is essential to create high-quality digital images. Others have described a novel focusing method which reduces the number of focal planes required to generate accurate focus. However, this method was not applied dynamically in an automated WSI system under continuous motion. Aims: This report measures the accuracy of this method when applied in a rapid continuous scan mode using a dual sensor WSI system with interleaved acquisition of images. Methods: We acquired over 400 tiles in a "stop and go" scan mode, surveying the entire z depth in each tile and used this as ground truth. We compared this ground truth focal height to the focal height determined using a rapid 3-point focus algorithm applied dynamically in a continuous scanning mode. Results: Our data showed the average focal height error of 0.30 (±0.27) μm compared to ground truth, which is well within the system′s depth of field. On a tile by tile assessment, approximately 95% of the tiles were within the system′s depth of field. Further, this method was six times faster than acquiring tiles compared to the same method in a non-continuous scan mode. Conclusions: The data indicates that the method employed can yield a significant improvement in scan speed while maintaining highly accurate autofocusing.

Ixodes scapularis and Ixodes pacificus are vectors of a range of pathogens of public health significance in North America. These ticks transmit pathogens to and from wild animal reservoir host species, but also bite humans and expose them to the pathogens. We describe the geographical and temporal distribution of the pathogen Babesia odocoilei, the causative agent of cervid babesiosis. Ixodes spp. ticks collected through active and passive surveillance were submitted to the National Microbiology Laboratory of the Public Health Agency of Canada for analysis of the presence of B. odocoilei from 2018 to 2021. Generalized linear models were constructed to evaluate the temporal change of B. odocoilei prevalence across Canada. Babesia odocoilei-positive I. scapularis are widespread across south-central and eastern regions of Canada, with an overall prevalence of 12.0 % in both nymphs (CI 95 % : 11.4-12.6) and adults (CI 95 % : 11.9-12.1) collected in passive surveillance and 13.2 % (CI 95 % : 12.9-13.5) and 10.0 % (CI 95 % : 9.8-10.2) in nymphs and adult, respectively, collected in active surveillance. A single I. pacificus tick tested positive in active surveillance out of 29 ticks collected in British Columbia, while no B odocoilei-positive I. scapularis were found in passive surveillance among the 11 adult ticks tested. Although B. odocoilei infection prevalence of adult I. scapularis was significantly higher in 2019 (14.1 %) than in 2018 (7.4 %), it remained stable from 2019 to 2021, suggesting that this pathogen may already be well established in endemic tick populations. The results provided in this article represent, to date, the most comprehensive picture of B. odocoilei distribution and prevalence in ticks in Canada and highlight the interest of maintaining One Health surveillance approaches to give added insight into disease transmission cycles for less well-characterized microorganisms., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024. Published by Elsevier GmbH.)

Competing Interests: Disclosure The authors have stated that they have no conflicts of interest.

Background: Doppler echocardiographic (echo) assessment of residual mitral regurgitation (MR) after transcatheter edge-to-edge repair (TEER) is challenging and often subjective. This study aimed to evaluate the accuracy and feasibility of standardized quantitative echo methods for assessment of MR severity after MitraClip repair by comparing measurements against a reference MR severity obtained from patient-specific in silico models., Methods: Post-procedure hemodynamics were simulated under five different MitraClip configurations in previously validated patient-specific in silico models for the treatment of functional MR. The residual regurgitant volume was calculated as in clinical practice using four quantitative virtual echo methods: pulsed Doppler, volumetric, proximal isovelocity surface area (PISA) and vena contracta area (VCA). Multiple permutations were performed for each method. Virtual echo MR results were evaluated against reference MR values directly extracted from the 5 patient-specific in silico models., Results: The echo methods with the greatest accuracy were the three-dimensional (3D) volumetric method (r = 0.957, bias -0.8 ± 1.2 ml, p = 0.01), the 3D VCA method wherein velocity time integrals were evaluated for each jet assessed (r = 0.919, bias -1.5 ± 1.7 ml, p = 0.03), and the 3D PISA method integrating surface areas throughout systole (r = 0.98, bias -2.0 ± 0.9 ml, p = 0.003). The pulsed Doppler and 2D volumetric methods had technical limitations that may result in a high underestimation or overestimation of the MR severity after TEER. In the case of multiple regurgitant jets, a more accurate MR assessment was obtained when all significant jets were evaluated., Conclusions: Clinically, the 3D volumetric, 3D VCA and 3D PISA methods gave the most accurate MR quantification after TEER. Three-dimensional echo technologies harbor the potential of becoming the non-invasive imaging tool of choice for MR quantification after complex transcatheter mitral interventions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: People with obesity are a highly heterogeneous group. Characterizing this heterogeneity may help to improve public health by offering adapted interventions and treatments to more homogeneous sub-groups among obese patients. This research aims to (1) identify distinct clusters of people with obesity based on demographic, behavioural, and clinical factors in the province of Quebec (Canada) and (2) assess the association of these clusters with selfperceived health., Methods: We conducted a sex specific cluster analysis (multiple correspondence analysis and hierarchical clustering) of adults with body mass index (BMI) ≥ 30 kg/m 2  from the 2015-2016 Canadian Community Health Survey in Quebec. Clusters were based on demographic, clinical, and behavioural characteristics. The clusters were tested for association with poor selfperceived health using logistic regression., Results: Three clusters of individuals with obesity were identified. These were (1) young individuals, (2) people with higher levels of depression and anxiety, and (3) older adults with high comorbidity. Those with high levels of depression and anxiety (9% of men vs. 13% of women) were associated with the poorest selfperceived health., Conclusions: People with obesity in Quebec can be categorized into three clusters based on demographic, clinical, and behavioural characteristics. The findings of this study draw attention to the need to examine the coexistence of obesity with depression and anxiety, particularly as it relates to selfperceived health., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Transcatheter mitral leaflet approximation with MitraClip has proven to be a viable treatment option for heart failure patients with functional mitral regurgitation (MR). PASCAL is a similar clip device, but it has design features that differentiate it from MitraClip. The effects of the different clip designs are largely unknown. In this study, using a patient-specific, mitral valve-left ventricle heart model, we performed finite-element (FE) simulations to provide a head-to-head comparison of the post-operative effects that PASCAL and MitraClip have on mitral valve (MV) geometry and biomechanics in a functional MR patient. The two devices were modeled as approximations of the real devices, and three implantation configurations were simulated for each device. The results showed that for this patient case, PASCAL caused less MV deformation than MitraClip. Additionally, PASCAL implantation reduced the stresses and strains in the MV leaflets compared to pre-repair conditions, while MitraClip implantation caused them to increase. Although complete coaptation was not achieved, both devices improved leaflet coaptation and were viable MR treatment options. The FE simulations in this study can be used to quantify biomechanics involved in clip treatments and improve our understanding of complex interactions between human hosts and percutaneous clip devices., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Hesitance and resistance to COVID-19 vaccination poses a serious challenge to achieving adequate vaccine uptake in the general population. Cross-sectional data from the early months of the pandemic indicates that approximately one-third of adults in multiple nations are hesitant or resistant to a vaccine for COVID-19. Using longitudinal data, we tracked changes in attitudes to COVID-19 vaccination during the pandemic., Study Design: This is a quantitative, longitudinal design., Method: Nationally representative samples of the adult general population of the Republic of Ireland (N = 1041) and the United Kingdom (N = 2025) were assessed for their attitudes towards COVID-19 vaccination at three points from March to August 2020., Results: Statistically significant increases in resistance to COVID-19 vaccination were observed in Irish (from 9.5% to 18.1%) and British (from 6.2% to 10%) adults., Conclusion: Resistance to vaccination has significantly increased in two European nations as the pandemic has progressed. Growing resistance to COVID-19 vaccination will pose a challenge to public health officials responsible for ensuring sufficient vaccine coverage., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Subclavian/axillary (TAx) access has become the most frequently used alternative access route for transcatheter aortic valve replacement (TAVR). Transcarotid (TC) TAVR has grown in popularity recently. Comparative data between these 2 contemporary access methods is lacking., Methods: Data were extracted from The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (TVT) Registry™ (June 2015 to October 2019) for patients undergoing TAVR by TC or TAx access with the SAPIEN 3 and SAPIEN 3 Ultra (Edwards Lifesciences, Irvine, CA) transcatheter heart valves. Procedural, index hospitalization, and 30-day outcomes were analyzed for TC vs TAx groups after 1:2 propensity matching of patient baseline characteristics., Results: The study included 3903 cases, of which 801 TC and 3102 TAx procedures were compared. After 1:2 propensity matching, TC TAVR was associated with similar 30-day mortality (4.3% vs 5.2%, P = .34) but a significantly lower risk of stroke (4.2% vs 7.4%; hazard ratio, 0.56; 95% confidence interval, 0.38-0.83; P = .003) compared with TAx access. Other outcomes that favored TC over TAx included shorter procedure time (117.0 vs 132.4 minutes; P < .001) and fluoroscopy time (16.6 vs 21.6 min; P < .001), lower contrast volume (78.5 vs 96.7 mL; P < .001), shorter length of stay in the intensive care unit (24.3 vs 25.0 hours; P = .02) and hospital (2.0 vs 3.0 days; P = .002), and more patients discharged to home (82.9% vs 74.6%; P < .001)., Conclusions: TC TAVR is associated with similar mortality and a significant reduction in stroke compared with the TAx approach. If femoral access is precluded, TC may be a safe, or at times, preferred avenue of transcatheter valve delivery., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Plasma cell-free DNA (cfDNA) variant analysis is commonly used in many cancer subtypes. Cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) has shown high sensitivity for cancer detection. To date, studies have not compared the sensitivity of both methods in a single cancer subtype., Methods: cfDNA from 40 metastatic RCC (mRCC) patients was subjected to targeted panel variant analysis. For 34 of 40, cfMeDIP-seq was also performed. A separate cohort of 38 mRCC patients were used in cfMeDIP-seq analysis to train an RCC classifier., Results: cfDNA variant analysis detected 21 candidate variants in 11 of 40 mRCC patients (28%), after exclusion of 2 germline variants and 6 variants reflecting clonal hematopoiesis. Among 23 patients with parallel tumor sequencing, cfDNA analysis alone identified variants in 9 patients (39%), while cfDNA analysis focused on tumor sequencing variant findings improved the sensitivity to 52%. In 34 mRCC patients undergoing cfMeDIP-seq, cfDNA variant analysis identified variants in 7 (21%), while cfMeDIP-seq detected all mRCC cases (100% sensitivity) with 88% specificity in 34 control subjects. In 5 patients with cfDNA variants and serial samples, variant frequency correlated with response to therapy., Conclusion: cfMeDIP-seq is significantly more sensitive for mRCC detection than cfDNA variant analysis. However, cfDNA variant analysis may be useful for monitoring response to therapy.

Recent studies have highlighted the occurrence and distribution of Ixodes scapularis ticks infected with Borrelia burgdorferi sensu stricto (s.s.) around the city of Ottawa, Ontario, Canada, and the need for strategies to mitigate the risk of human exposure and infection. We conducted a field study from July to October 2018 to examine the effectiveness of ecotonal woodchip borders as an environmental control method to suppress the density of host-seeking ticks along recreational trails in Ottawa. We used an experimental design with ten 100-m trail replicates randomized to intervention or control groups, and monitored questing tick density at weekly intervals in mid-summer and early fall. We compared questing tick density between woodchip-treated and untreated trails using a mixed-effects Poisson regression model. Of the 138 I. scapularis ticks collected, there were 86 adult and nymphal ticks, 37 (43 %) of which were positive for B. burgdorferi s.s. A total of 58 Haemaphysalis leporispalustris were also collected. Mean combined adult and nymphal I. scapularis density was 1.15 (1.40 standard deviation; SD) per 100 m in the control group compared to 0.28 (0.56 SD) per 100 m in the intervention group, reflecting a 75 % reduction in questing tick density on trail replicates treated with woodchip borders (p < 0.001). An effect of the intervention was observed in both sampling periods. This study indicates that woodchip borders may be an effective strategy to suppress questing tick density along trail margins where recreational trail users are more active, thereby reducing the likelihood of tick encounters., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Survivorship care for patients with prostate cancer requires careful consideration of unique disease-specific factors, including the prolonged natural disease history, the potential for competing health risks, and the consequences of long-term androgen deprivation therapy. However, current prostate cancer survivorship research is unfortunately limited by the lack of a robust supportive evidence base, variability in the definitions and measurement of survivorship outcomes, and a heavy reliance on expert opinion. As a result, the conduct of quality prostate cancer survivorship research is of increasing importance for patients, medical providers, and other key stakeholders. This manuscript harmonizes a path forward for improving prostate cancer survivorship by defining prostate cancer survivorship and survivorship research, as well as by highlighting key research priorities and cooperative mechanisms for survivorship studies within prostate cancer, with a particular focus on men with advanced disease., (Copyright © 2019. Published by Elsevier Inc.)

Background: Mitral regurgitation (MR) is present in a large proportion of patients who undergo transcatheter aortic valve replacement (TAVR). However, existing clinical data on the impact of TAVR on early post-procedural MR severity are contradictory. Using a comprehensive computational engineering methodology, this study aimed to evaluate quantitatively the structural and hemodynamic impact of TAVR on aortic-mitral continuity and MR severity in a rigorously developed and validated patient-specific left heart (LH) computer model with aortic stenosis and concomitant functional MR., Methods: TAVR procedure was virtually simulated using a self-expandable valve (SEV) at three implantation heights. Pre- and post-TAVR LH dynamics as well as intra-operative biomechanics were analyzed., Results: No significant differences in early MR improvement (<10%) were noted at the three implantation depths when compared to the pre-TAVR state. The high deployment model resulted in the highest stress in the native aortic leaflets, lowest stent-tissue contact force, highest aortic-mitral angle, and highest MR reduction for this patient case. When comparing SEV vs. balloon-expandable valve (BEV) performance at an optimal implantation height, the SEV gave a higher regurgitant volume ⋅ than the pre-TAVR model (40.49 vs 37.59 ml), while the BEV model gave the lowest regurgitant volume (33.84 vs 37.59 ml)., Conclusions: Contact force, aortic-mitral angle, and valve annuli compression were identified as possible mechanistic parameters that may suggest avenues for acute MR improvement. Albeit a single patient parametric study, it is our hope that such detailed engineering analysis could shed some light into the underlying biomechanical mechanisms of TAVR impact on MR.

The mammalian Na + /H + exchanger isoform 1 (NHE1) is an integral membrane protein that regulates intracellular pH (pH i ) by removing a single intracellular proton in exchange for one extracellular sodium ion. It is involved in cardiac hypertrophy and ischemia reperfusion damage to the heart and elevation of its activity is a trigger for breast cancer metastasis. NHE1 has an extensive 500 amino acid N-terminal membrane domain that mediates transport and consists of 12 transmembrane segments connected by intracellular and extracellular loops. Intracellular loops are hypothesized to modulate the sensitivity to pH i . In this study, we characterized the structure and function of intracellular loop 5 (IL5), specifically amino acids 431-443. Mutation of eleven residues to alanine caused partial or nearly complete inhibition of transport; notably, mutation of residues L432, T433, I436, N437, R440 and K443 demonstrated these residues had critical roles in NHE1 function independent of effects on targeting or expression. The nuclear magnetic resonance (NMR) solution spectra of the IL5 peptide in a membrane mimetic sodium dodecyl sulfate solution revealed that IL5 has a stable three-dimensional structure with substantial alpha helical character. NMR chemical shifts indicated that K438 was in close proximity with W434. Overall, our results show that IL5 is a critical, intracellular loop with a propensity to form an alpha helix, and many residues of this intracellular loop are critical to proton sensing and ion transport., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Sunitinib might optimize the feasibility of partial nephrectomy (PN) for complex renal tumors with imperative indications. We compared the renal functional outcomes of patients with complex renal masses who had undergone sunitinib before PN with those of patients who had not required neoadjuvant sunitinib before PN., Patients and Methods: We performed a multicenter retrospective analysis of patients with renal cell carcinoma who had undergone PN for a complex renal mass (R.E.N.A.L. nephrometry score, 10-12) and imperative indications from January 2012 to July 2014. Neoadjuvant sunitinib was used in cases for which PN was not considered feasible. The cohort was divided into those patients who had undergone PN without neoadjuvant sunitinib and those who had undergone PN after sunitinib (no-neoadjuvant vs. neoadjuvant). The change in tumor size and R.E.N.A.L. score were assessed. The primary outcome was the change in the estimated glomerular filtration rate (ΔeGFR) from preoperatively to the last postoperative follow-up visit., Results: The data from 125 consecutive patients were analyzed (47 neoadjuvant and 78 no-neoadjuvant; median follow-up, 21 months). The neoadjuvant plus PN patients had had a greater median tumor size preoperatively (7.2 vs. 6 cm; P = .045). Sunitinib caused a significant decrease in the median tumor size (from 7.2 to 5.8 cm [19.4%]; P = .012) and R.E.N.A.L. score (from 11 to 9; P = .001). No significant differences were found between the neoadjuvant and no-neoadjuvant groups in the ischemia time (P = .413) or incidence of complications (P = .728). The median ΔeGFR was similar (neoadjuvant, 6.4; no-neoadjuvant, 6.1; P = .534). Linear regression analysis for factors associated with an increasing ΔeGFR demonstrated increasing age (estimate, -0.074; P = .009) increasing body mass index (estimate, -0.087; P = .043), and decreasing baseline eGFR (estimate, -0.104; P = .02) as significant factors., Conclusion: The use of neoadjuvant sunitinib might facilitate complex PN and result in renal functional outcomes similar to those of patients with a complex renal mass who had not required neoadjuvant sunitinib., (Published by Elsevier Inc.)

A new solid-state nuclear magnetic resonance (NMR) thermometry sample is proposed. The 207 Pb NMR chemical shift of a lead halide perovskite, methylammonium lead chloride (MAPbCl 3 ) is very sensitive to temperature, 0.905±0.010ppmK -1 . The response to temperature is linear over a wide temperature range, from its tetragonal to cubic phase transition at 178K to >410K, making it an ideal standard for temperature calibrations in this range. Because the 207 Pb NMR lineshape for MAPbCl 3 appears symmetric, the sample is ideal for calibration of variable temperature NMR data acquired for spinning or non-spinning samples. A frequency-ratio method is proposed for referencing 207 Pb chemical shifts, based on the 1 H and 13 C frequencies of the methylammonium cation, which are used asan internal standard. Finally, this new NMR thermometer has been used to measure the degree of frictional heating asa function of spinning frequency for a series of MAS rotors ranging in outer diameter from 1.3 to 7.0mm. As expected, the largest diameter rotors are more susceptible to frictional heating, but lower diameter rotors are subjected to higher frictional heating temperatures as they are typically spun at much higher spinning frequencies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Vermiculite ore containing Libby amphibole asbestos (LAA) was mined in Libby, MT, from the 1920s-1990. Recreational and residential areas in Libby were contaminated with LAA. This objective of this study was to characterize childhood exposure to LAA and investigate its association with respiratory health during young adulthood., Methods: Young adults who resided in Libby prior to age 18 completed a health and activity questionnaire, pulmonary function testing, chest x-ray and HRCT scan. LAA exposure was estimated based on participant report of engaging in activities with potential LAA exposure. Quantitative LAA estimates for activities were derived from sampling data and literature reports., Results: A total of 312 participants (mean age 25.1 years) were enrolled and reported respiratory symptoms in the past 12 months including pleuritic chest pain (23%), regular cough (17%), shortness of breath (18%), and wheezing or whistling in the chest (18%). Cumulative LAA exposure was significantly associated with shortness of breath (aOR = 1.12, 95% CI 1.01-1.25 per doubling of exposure). Engaging in recreational activities near Rainy Creek Road (near the former mine site) and the number of instances heating vermiculite ore to make it expand or pop were also significantly associated with respiratory symptoms. LAA exposure was not associated with pulmonary function or pleural or interstitial changes on either chest x-ray or HRCT., Conclusions: Pleural or interstitial changes on x-ray or HRCT were not observed among this cohort of young adults. However, childhood exposure to LAA was significantly associated with respiratory symptoms during young adulthood. Pleuritic chest pain, in particular, has been identified as an early symptom associated with LAA exposure and therefore warrants continued follow-up given findings of progressive disease in other LAA exposed populations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Objectives: It has been proposed that delusional beliefs are attempts to explain anomalous experiences. Why, then, do anomalous experiences induce delusions in some people but not in others? One possibility is that people with delusions have reasoning biases that result in them failing to reject implausible candidate explanations for anomalous experiences. We examine this hypothesis by studying paranormal interpretations of anomalous experiences., Methods: We examined whether analytic cognitive style (i.e. the willingness or disposition to critically evaluate outputs from intuitive processing and engage in effortful analytic processing) predicted anomalous experiences and paranormal explanations for these experiences after controlling for demographic variables and cognitive ability., Results: Analytic cognitive style predicted paranormal explanations for anomalous experiences, but not the anomalous experiences themselves., Limitations: We did not study clinical delusions. Our attempts to control for cognitive ability may have been inadequate. Our sample was predominantly students., Conclusions: Limited analytic cognitive style might contribute to the interpretation of anomalous experiences in terms of delusional beliefs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Proton nuclear magnetic resonance ( 1 H NMR, or NMR) spectroscopy and inductively coupled plasma-mass spectrometry (ICP-MS) are commonly used for metabolomics and metal analysis in urine samples. However, creatinine quantification by NMR for the purpose of normalization of urinary metals has not been validated. We assessed the validity of using NMR analysis for creatinine quantification in human urine samples in order to allow normalization of urinary metal concentrations., Methods: NMR and ICP-MS techniques were used to measure metabolite and metal concentrations in urine samples from 10 healthy subjects. For metabolite analysis, two magnetic field strengths (600 and 700MHz) were utilized. In addition, creatinine concentrations were determined by using the Jaffe method., Results: Creatinine levels were strongly correlated (R 2 =0.99) between NMR and Jaffe methods. The NMR spectra were deconvoluted with a target database containing 151 metabolites that are present in urine. A total of 50 metabolites showed good correlation (R 2 =0.7-1.0) at 600 and 700MHz. Metal concentrations determined after NMR-measured creatinine normalization were comparable to previous reports., Conclusions: NMR analysis provided robust urinary creatinine quantification, and was sufficient for normalization of urinary metal concentrations. We found that NMR-measured creatinine-normalized urinary metal concentrations in our control subjects were similar to general population levels in Canada and the United Kingdom., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: To assess tasks completed by intensive care medical emergency team nurses., Research Design: Prospective observational study., Setting: Australian teaching hospital., Main Outcome Measures: Nursing-related technical and non-technical tasks and level of self-reported confidence and competence., Results: Amongst 400 calls, triggers and nursing tasks were captured in 93.5% and 77.3% of cases, respectively. The median patient age was 73 years. The four most common triggers were hypotension (22.0%), tachycardia (21.1%), low SpO2 (17.4%), and altered conscious state (10.1%). Non-technical skills included investigation review (33.7%), history acquisition (18.4%), contribution to the management plan (40.5%) and explanation to bedside nurses (78.3%), doctors (13.6%), allied health (3.9%) or patient/relative (39.5%). Technical tasks included examining the circulation (32%), conscious state (29.4%), and chest (26.5%). Additional tasks included adjusting oxygen (23.9%), humidification (8.4%), non-invasive ventilation (6.5%), performing an ECG (22%), and administrating fluid as a bolus (17.5%) or maintenance (16, 5.2%), or medication as a statim dose (16.8%) or infusion (5.2%). Self-reported competence and confidence appeared to be high overall amongst our MET nurses., Conclusion: Our findings provide important information on the tasks completed by Medical Emergency Team nurses and will guide future training., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The pathophysiological underpinnings of bipolar disorder are not fully understood. However, they may be due in part to changes in the phosphatidylinositol second messenger system (PI-cycle) generally, or changes in myo-inositol concentrations more specifically. Dextro-amphetamine has been used as a model for mania in several human studies as it causes similar subjective and physiological symptoms. We wanted to determine if dextro-amphetamine altered myo-inositol concentrations in vivo as it would clearly define a mechanism linking putative changes in the PI-cycle to the subjective psychological changes seen with dextro-amphetamine administration. Fifteen healthy human volunteers received a baseline scan, followed by second scan 75 min after receiving a 25 mg oral dose of dextro-amphetamine. Stimulated echo proton magnetic resonance spectroscopy (MRS) scans were preformed at 3.0 Tesla (T) in the dorsal medial prefrontal cortex (DMPFC). Metabolite data were adjusted for tissue composition and analyzed using LCModel. Twelve adult male rats were treated acutely with a 5-mg/kg intraperitoneal dose of dextro-amphetamine. After 1 h rats were decapitated and the brains were rapidly removed and frozen until dissection. Rat brains were dissected into frontal, temporal, and occipital cortical areas, as well as hippocampus. Tissue was analyzed using a Varian 18.8 T spectrometer. Metabolites were identified and quantified using Chenomx Profiler software. The main finding in the present study was that myo-inositol concentrations in the DMPFC of human volunteers and in the four rat brain regions were not altered by acute dextro-amphetamine. While it remains possible that the PI-cycle may be involved in the pathophysiology of bipolar disorder, it is not likely that the subjective and physiological of dextro-amphetamine are mediated, directly or indirectly, via alternations in myo-inositol concentrations.

In order to optimize the Fontan circulation, a technique for direct superior and inferior cavopulmonary connections was devised. Such pathways retain growth potential, obviate suture lines within the right atrium, and avoid prosthetic implants. They thus enable definitive, single-stage ventricular unloading, regardless of patient size or great artery position.

Assessing the student with intractable epilepsy requires skill not only in evaluating cognitive problems, but also detecting seizures and discovering how to adapt instruction to minimize their negative impact on learning. Ironically, assessment efforts are seen as compromised by the occurrence of seizures during testing, when determining how seizure events may interfere with learning and the instructional modifications that are necessary to cope with them, should be a key part of assessment. A dual approach to assessment is recommended that combines the identification of cognitive deficits with an evaluation of how recurring seizures may prevent the student from engaging in instruction. Without also evaluating the student's response to instruction, teaching to specific cognitive needs is limited by insufficient knowledge about how to keep the student involved in instruction when seizures occur. Static assessment evaluates cognitive functioning at the time of testing, without changing the way that the student learns and responds. By engaging the student in teaching/learning sessions, dynamic assessment explores how the student best learns despite cognitive deficits and the disruptive effect of seizures. This paper includes a description of the authors'experience in using dynamic assessment as an adjunct to static assessment in evaluating a student with intractable epilepsy., (Copyright 2001 BEA Trading Ltd.)

Objectives: To establish the prevalence and characteristics of self-reported diabetes in a representative sample of Victorian residents aged 40 years and older, and to compare the vision between people with and without self-reported diabetes., Design: Cross-sectional survey., Setting: Nine randomly selected suburban Melbourne clusters and four randomly selected rural Victorian clusters., Participants: 4,744 subjects (86% participation rate) aged > or = 40 years., Main Outcome Measures: Subjects answered a detailed questionnaire which provided demographic details, body mass index, and the duration and treatment of any diagnosis of diabetes. Refraction was performed and best-corrected visual acuity was measured., Results: The prevalence of self-reported diabetes was 5.1%. In a multivariate analysis, self-reported diabetes was positively associated with age (p < 0.01), male sex (p = 0.01), higher body mass index (p = 0.01), Mediterranean ethnicity (p = 0.01), unemployment (p = 0.05) and lack of private health insurance (p < 0.05). People with self-reported diabetes were more likely to have mild or moderate levels of visual impairment than people who reported no previous diagnosis of diabetes (p < 0.01)., Conclusions: Diabetes in Victoria is more prevalent among men and among people of Mediterranean origin. When planning educational programs and health service delivery, it is also important to consider that, compared with the general population, people with diabetes are less likely to be employed or to have private health insurance, and are more likely to have impaired vision.