Visuospatial Processing Deficits Linked to Posterior Brain Regions in Premanifest and Early Stage Huntington's Disease.

OBJECTIVES: Visuospatial processing deficits have been reported in Huntington's disease (HD). To date, no study has examined associations between visuospatial cognition and posterior brain findings in HD. METHODS: We compared 119 premanifest (55> and 64<10.8 years to expected disease onset) and 104 early symptomatic (59 stage-1 and 45 stage-2) gene carriers, with 110 controls on visual search and mental rotation performance at baseline and 12 months. In the disease groups, we also examined associations between task performance and disease severity, functional capacity and structural brain measures. RESULTS: Cross-sectionally, there were strong differences between all disease groups and controls on visual search, and between diagnosed groups and controls on mental rotation accuracy. Only the premanifest participants close to onset took longer than controls to respond correctly to mental rotation. Visual search negatively correlated with disease burden and motor symptoms in diagnosed individuals, and positively correlated with functional capacity. Mental rotation ("same") was negatively correlated with motor symptoms in stage-2 individuals, and positively correlated with functional capacity. Visual search and mental rotation were associated with parieto-occipital (pre-/cuneus, calcarine, lingual) and temporal (posterior fusiform) volume and cortical thickness. Longitudinally, visual search deteriorated over 12 months in stage-2 individuals, with no evidence of declines in mental rotation. CONCLUSIONS: Our findings provide evidence linking early visuospatial deficits to functioning and posterior cortical dysfunction in HD. The findings are important since large research efforts have focused on fronto-striatal mediated cognitive changes, with little attention given to aspects of cognition outside of these areas. (JINS, 2016, 22, 595-608).

Factors Associated with Greater Adherence to and Satisfaction with Transdermal Rivastigmine in Patients with Alzheimer's Disease and Their Caregivers.

BACKGROUND/AIMS: Adherence to cholinesterase inhibitors is important in order to maximise treatment efficacy. This study aimed to investigate patient and caregiver factors associated with adherence to and satisfaction with transdermal rivastigmine treatment. METHODS: Sociodemographic, clinical and psychosocial data were collected from 127 patients and their caregivers during the first follow-up visit after prescription. At the second follow-up, data were collected on 110 of the dyads. Adherence to and satisfaction with the treatment were assessed using the Medication Adherence Report Scale and an adapted version of the Alzheimer's Disease Caregiver Preference Questionnaire. RESULTS: 66.2% of the caregivers reported being adherent to, and 77.0% were satisfied with, the patch at the second follow-up. Factors predicting higher adherence at the second follow-up were caregivers' greater frequency of contact with patients, greater satisfaction with the information received about the patch, better tolerability of the patch and living at home with their caregivers. Greater concerns of the caregivers about the patch and the patients' belief in 'other' causes of their Alzheimer's disease predicted a lower adherence at the second follow-up. CONCLUSIONS: Assessing and addressing caregivers' concerns about transdermal rivastigmine, improving doctor-patient/caregiver communication to increase caregiver satisfaction with information about the patch as well as providing education and support around patients' beliefs and tolerability of the patch could improve adherence to transdermal rivastigmine.

Design and rationale of the Post-Intensive Care Syndrome - paediatrics (PICS-p) Longitudinal Cohort Study.

INTRODUCTION: As paediatric intensive care unit (PICU) mortality declines, there is growing recognition of the morbidity experienced by children surviving critical illness and their families. A comprehensive understanding of the adverse physical, cognitive, emotional and social sequelae common to PICU survivors is limited, however, and the trajectory of recovery and risk factors for morbidity remain unknown. METHODS AND ANALYSIS: The Post-Intensive Care Syndrome - paediatrics Longitudinal Cohort Study will evaluate child and family outcomes over 2 years following PICU discharge and identify child and clinical factors associated with impaired outcomes. We will enrol 750 children from 30 US PICUs during their first PICU hospitalisation, including 500 case participants experiencing ≥3 days of intensive care that include critical care therapies (eg, mechanical ventilation, vasoactive infusions) and 250 age-matched, sex-matched and medical complexity-matched control participants experiencing a single night in the PICU with no intensive care therapies. Children, parents and siblings will complete surveys about health-related quality of life, physical function, cognitive status, emotional health and peer and family relationships at multiple time points from baseline recall through 2 years post-PICU discharge. We will compare outcomes and recovery trajectories of case participants to control participants, identify risk factors associated with poor outcomes and determine the emotional and social health consequences of paediatric critical illness on parents and siblings. ETHICS AND DISSEMINATION: This study has received ethical approval from the University of Pennsylvania Institutional Review Board (protocol #843844). Our overall objective is to characterise the ongoing impact of paediatric critical illness to guide development of interventions that optimise outcomes among children surviving critical illness and their families. Findings will be presented at key disciplinary meetings and in peer-reviewed publications at fixed data points. Published manuscripts will be added to our public study website to ensure findings are available to families, clinicians and researchers. TRIALS REGISTRATION NUMBER: NCT04967365.

Condom use with serious and casual heterosexual partners: findings from a community venue-based survey of young adults.

Given the racial/ethnic disparities that characterize STI trends and recent increases in heterosexually transmitted HIV infection in the US, an understanding of factors underlying condom use among young adults in minority communities is vitally important. To this end, this paper presents findings from a community venue-based survey examining the influence of motivations, heuristics, and relationship factors on condom behaviors with serious and casual heterosexual partners in a sample of urban African American and Puerto Rican males and females ages 18-25 (n = 380). Condom use rates at time of last sex were considerably higher with casual partners (n = 87) than with serious (n = 313) partners, 77.9% vs. 38.7%. While dual pregnancy/STI prevention was the most frequently cited reason for use at last sex with casual partners, pregnancy prevention was the most frequently cited reason for use with serious partners. Bivariate conditional logistic regression analyses found two factors to be associated with condom use at last sex with casual partners: use at first sex with the partner and belief that neighborhood peers worried some/a lot about HIV. In contrast, such factors as condom heuristics (e.g., nonuse symbolizes trust), contraceptive status, and markers of emotional intimacy were associated with condom use with serious partners in both bivariate and multivariable analyses.

Utility of VestAid to Detect Eye-Gaze Accuracy in a Participant Exposed to Directed Energy.

INTRODUCTION: The VestAid is a tablet-based application that provides feedback about a patient's eye/head movements during exercise after concussion. The goal of this case series was to determine if VestAid could be used to detect eye-gaze accuracy in a participant exposed to directed energy (DE). MATERIALS AND METHODS: The VestAid results of a participant with DE were compared to an age- and gender-matched healthy control, a participant post-concussion, and a participant with vestibular neuritis. A tablet with VestAid software was utilized to record eye-gaze accuracy and head speed during VORx1 exercises using eye and facial recognition as participants were exposed to 12 visual scenes. RESULTS: The participant with DE consistently had difficulty with eye-gaze accuracy when the head was rotated towards the right for all trials. The participant with DE had poor eye-gaze accuracy during all phases of the head turn cycle compared to the control participant (mean 47.91%, [SD = 7.32%] for the DE participant versus mean 94.28%, [SD = 5.87%] for the control participant). Post-exercise dizziness and perceived difficulty in the 12 exercises completed by the participant with DE were strongly related (Spearman's rho = 0.7372, P = .0062). The participant with DE had the lowest scores on 10 of the 12 head movement trials. CONCLUSIONS: VestAid provided unique information about eye-gaze accuracy that detected eye movement abnormalities in the participants with DE exposure, concussion, and vestibular neuritis. The objective metrics of eye-gaze stability correlate with participants' symptoms and perceived difficulty of the eye/head movements.

Generalized thermalization in an integrable lattice system.

After a quench, observables in an integrable system may not relax to the standard thermal values, but can relax to the ones predicted by the generalized Gibbs ensemble (GGE) [M. Rigol et al., Phys. Rev. Lett. 98, 050405 (2007)]. The GGE has been shown to accurately describe observables in various one-dimensional integrable systems, but the origin of its success is not fully understood. Here we introduce a microcanonical version of the GGE and provide a justification of the GGE based on a generalized interpretation of the eigenstate thermalization hypothesis, which was previously introduced to explain thermalization of nonintegrable systems. We study relaxation after a quench of one-dimensional hard-core bosons in an optical lattice. Exact numerical calculations for up to 10 particles on 50 lattice sites (≈10(10) eigenstates) validate our approach.

Design and rationale of the "Sedation strategy and cognitive outcome after critical illness in early childhood" study.

There is increasing concern that sedatives commonly used during critical illness may be neurotoxic during the period of early brain development. The Sedation strategy and cognitive outcome after critical illness in early childhood (RESTORE-cognition) study is a prospective cohort study designed to examine the relationships between sedative exposure during pediatric critical illness and long-term neurocognitive outcomes. We assess multiple domains of neurocognitive function 2.5-5 years post-hospital discharge, at a single time point and depending on participant and clinician availability, in up to 500 subjects who had normal baseline cognitive function, were aged 2 weeks to 8 years at pediatric intensive care unit admission, and were enrolled in a cluster randomized controlled trial of a sedation protocol (the RESTORE trial; U01 HL086622 and HL086649). In addition, to provide comparable data on an unexposed group with similar baseline biological characteristics and environment, we are studying matched, healthy siblings of RESTORE patients. Our goal is to increase understanding of the relationships between sedative exposure, critical illness, and long-term neurocognitive outcomes in infants and young children by studying these subjects 2.5 to 5 years after their index hospitalization. This paper highlights the design challenges in conducting comprehensive neurocognitive assessment procedures across a broad age span at multiple testing centers across the United States. Our approach, which includes building interprofessional teams and novel cohort retention strategies, may be of help in future longitudinal trials.

BMP2/BMPR1A is linked to tumour progression in dedifferentiated liposarcomas.

Bone Morphogenic Protein 2 (BMP2) is a multipurpose cytokine, important in the development of bone and cartilage, and with a role in tumour initiation and progression. BMP2 signal transduction is dependent on two distinct classes of serine/threonine kinase known as the type I and type II receptors. Although the type I receptors (BMPR1A and BMPR1B) are largely thought to have overlapping functions, we find tissue and cellular compartment specific patterns of expression, suggesting potential for distinct BMP2 signalling outcomes dependent on tissue type. Herein, we utilise large publicly available datasets from The Cancer Genome Atlas (TCGA) and Protein Atlas to define a novel role for BMP2 in the progression of dedifferentiated liposarcomas. Using disease free survival as our primary endpoint, we find that BMP2 confers poor prognosis only within the context of high BMPR1A expression. Through further annotation of the TCGA sarcoma dataset, we localise this effect to dedifferentiated liposarcomas but find overall BMP2/BMP receptor expression is equal across subsets. Finally, through gene set enrichment analysis we link the BMP2/BMPR1A axis to increased transcriptional activity of the matrisome and general extracellular matrix remodelling. Our study highlights the importance of continued research into the tumorigenic properties of BMP2 and the potential disadvantages of recombinant human BMP2 (rhBMP2) use in orthopaedic surgery. For the first time, we identify high BMP2 expression within the context of high BMPR1A expression as a biomarker of disease relapse in dedifferentiated liposarcomas.

Profiling lung adenocarcinoma by liquid biopsy: can one size fit all?

BACKGROUND: Cancer is first and foremost a disease of the genome. Specific genetic signatures within a tumour are prognostic of disease outcome, reflect subclonal architecture and intratumour heterogeneity, inform treatment choices and predict the emergence of resistance to targeted therapies. Minimally invasive liquid biopsies can give temporal resolution to a tumour's genetic profile and allow the monitoring of treatment response through levels of circulating tumour DNA (ctDNA). However, the detection of ctDNA in repeated liquid biopsies is currently limited by economic and time constraints associated with targeted sequencing. METHODS: Here we bioinformatically profile the mutational and copy number spectrum of The Cancer Genome Network's lung adenocarcinoma dataset to uncover recurrently mutated genomic loci. RESULTS: We build a panel of 400 hotspot mutations and show that the coverage extends to more than 80% of the dataset at a median depth of 8 mutations per patient. Additionally, we uncover several novel single-nucleotide variants present in more than 5% of patients, often in genes not commonly associated with lung adenocarcinoma. CONCLUSION: With further optimisation, this hotspot panel could allow molecular diagnostics laboratories to build curated primer banks for 'off-the-shelf' monitoring of ctDNA by droplet-based digital PCR or similar techniques, in a time- and cost-effective manner.

Mendelian Randomisation study of the influence of eGFR on coronary heart disease.

Impaired kidney function, as measured by reduced estimated glomerular filtration rate (eGFR), has been associated with increased risk of coronary heart disease (CHD) in observational studies, but it is unclear whether this association is causal or the result of confounding or reverse causation. In this study we applied Mendelian randomisation analysis using 17 genetic variants previously associated with eGFR to investigate the causal role of kidney function on CHD. We used 13,145 participants from the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium and 194,427 participants from the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease (CARDIoGRAMplusC4D) consortium. We observed significant association of an unweighted gene score with CHD risk (odds ratio = 0.983 per additional eGFR-increasing allele, 95% CI = 0.970-0.996, p = 0.008). However, using weights calculated from UCLEB, the gene score was not associated with disease risk (p = 0.11). These conflicting results could be explained by a single SNP, rs653178, which was not associated with eGFR in the UCLEB sample, but has known pleiotropic effects that prevent us from drawing a causal conclusion. The observational association between low eGFR and increased CHD risk was not explained by potential confounders, and there was no evidence of reverse causation, therefore leaving the remaining unexplained association as an open question.

Disrupted anatomic networks in the 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22q11DS) is an uncommon genetic disorder with an increased risk of psychosis. Although the neural substrates of psychosis and schizophrenia are not well understood, aberrations in cortical networks represent intriguing potential mechanisms. Investigations of anatomic networks within 22q11DS are sparse. We investigated group differences in anatomic network structure in 48 individuals with 22q11DS and 370 typically developing controls by analyzing covariance patterns in cortical thickness among 68 regions of interest using graph theoretical models. Subjects with 22q11DS had less robust geographic organization relative to the control group, particularly in the occipital and parietal lobes. Multiple global graph theoretical statistics were decreased in 22q11DS. These results are consistent with prior studies demonstrating decreased connectivity in 22q11DS using other neuroimaging methodologies.

Improved survival in a cohort of trial participants with metastatic castration-resistant prostate cancer demonstrates the need for updated prognostic nomograms.

BACKGROUND: Median overall survival (OS) in men with metastatic castration-resistant prostate cancer (CRPC) was 13-16 mo in the predocetaxel era. Prognostic nomograms for survival estimation in CRPC were constructed prior to the introduction of docetaxel and other novel treatments. OBJECTIVE: To examine whether prognostic models still accurately reflect survival in a large cohort of trial participants. DESIGN, SETTING, AND PARTICIPANTS: Survival analysis of 442 men with CRPC sequentially treated in clinical trials at our institution from June 2003 to December 2011. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Predicted survival by Halabi and Smaletz nomograms was compared to observed survival. Cox model multivariate analysis (MVA) used variables at referral, including performance status (PS); levels of prostate-specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), haemoglobin (Hb), and albumin; presence of visceral disease, and metastatic disease at diagnosis. RESULTS AND LIMITATIONS: From point of referral, chemotherapy-naïve patients had a median OS of 30.6 mo (95% confidence interval [CI], 27.6-36.5 mo). In contrast, predicted survival using the Halabi and Smaletz models was 21 and 18 mo, respectively. In these patients, poor PS, lower Hb level, and increasing LDH level were the strongest predictors in the MVA. In patients referred after chemotherapy, survival from referral was 17.5 mo (95% CI, 16.0-19.5 mo) and increasing LDH level and presence of visceral metastases were the strongest predictors of survival. Median OS from diagnosis of CRPC was 40.7 mo in the overall cohort (95% CI, 36.8-44.0 mo). Clinical trial participation was safe, with low mortality rate. This cohort of men participated in phase 1, 2 and 3 trials and expanded access programs; their data may not reflect survival in all CRPC patients. CONCLUSIONS: Due to the impact of highly effective novel therapies on survival, prognostic nomograms in current use require revalidation regarding their ability to predict survival in CRPC.

Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer.

CONTEXT: Abiraterone acetate is a small-molecule cytochrome P450 17A1 (CYP17A1) inhibitor that is active in castration-resistant prostate cancer. OBJECTIVE: Our objective was to determine the impact of abiraterone with and without dexamethasone treatment on in vivo steroidogenesis. DESIGN AND METHODS: We treated 42 castrate, castration-resistant prostate cancer patients with continuous, daily abiraterone acetate and prospectively collected blood and urine before and during abiraterone treatment and after addition of dexamethasone 0.5 mg daily. RESULTS: Treatment with single-agent abiraterone acetate was associated with accumulation of steroids with mineralocorticoid properties upstream of CYP17A1. This resulted in side effects, including hypertension, hypokalemia, and fluid overload, in 38 of 42 patients that were generally treated effectively with eplerenone. Importantly, serum and urinary androgens were suppressed by more than 90% from baseline. Urinary metabolites of 17-hydroxypregnenolone and 17-hydroxyprogesterone downstream of 17α-hydroxylase remained unchanged. However, 3α5α-17-hydroxypregnanolone, which can be converted via the backdoor pathway toward 5α-dihydrotestosterone, increased significantly and correlated with levels of the major 5α-dihydrotestosterone metabolite androsterone. In contrast, urinary metabolites of 11-deoxycortisol and active glucocorticoids declined significantly. Addition of dexamethasone to abiraterone acetate significantly suppressed ACTH and endogenous steroids, including 3α5α-17-hydroxypregnanolone. CONCLUSION: CYP17A1 inhibition with abiraterone acetate is characterized by significant suppression of androgen and cortisol synthesis. The latter is associated with a rise in ACTH that causes raised mineralocorticoids, leading to side effects and incomplete 17α-hydroxylase inhibition. Concomitant inhibition of 17,20-lyase results in diversion of 17-hydroxyprogesterone metabolites toward androgen synthesis via the backdoor pathway. Addition of dexamethasone reverses toxicity and could further suppress androgens by preventing a rise in substrates of backdoor androgen synthesis.

Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers.

Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5-1600); this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS) hazard ratio of 2.4 (95% CI 1.4, 4.2) for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical 'hot-spot' mutations (KRAS, BRAF, PIK3CA) in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic acid biomarker studies have clinically important multi-purpose utility in advanced cancer patients and further studies to pursue their incorporation into the standard of care are warranted.

Unbiased and automated identification of a circulating tumour cell definition that associates with overall survival.

Circulating tumour cells (CTC) in patients with metastatic carcinomas are associated with poor survival and can be used to guide therapy. Classification of CTC however remains subjective, as they are morphologically heterogeneous. We acquired digital images, using the CellSearch™ system, from blood of 185 castration resistant prostate cancer (CRPC) patients and 68 healthy subjects to define CTC by computer algorithms. Patient survival data was used as the training parameter for the computer to define CTC. The computer-generated CTC definition was validated on a separate CRPC dataset comprising 100 patients. The optimal definition of the computer defined CTC (aCTC) was stricter as compared to the manual CellSearch CTC (mCTC) definition and as a consequence aCTC were less frequent. The computer-generated CTC definition resulted in hazard ratios (HRs) of 2.8 for baseline and 3.9 for follow-up samples, which is comparable to the mCTC definition (baseline HR 2.9, follow-up HR 4.5). Validation resulted in HRs at baseline/follow-up of 3.9/5.4 for computer and 4.8/5.8 for manual definitions. In conclusion, we have defined and validated CTC by clinical outcome using a perfectly reproducing automated algorithm.

A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma.

Metastatic renal cell carcinoma (RCC) is a molecularly heterogeneous disease that is intrinsically resistant to chemotherapy and radiotherapy. Although therapies targeted to the molecules vascular endothelial growth factor and mammalian target of rapamycin have shown clinical effectiveness, their effects are variable and short-lived, underscoring the need for improved treatment strategies for RCC. Here, we used quantitative phosphoproteomics and immunohistochemical profiling of 346 RCC specimens and determined that Src kinase signaling is elevated in RCC cells that retain wild-type von Hippel-Lindau (VHL) protein expression. RCC cell lines and xenografts with wild-type VHL exhibited sensitivity to the Src inhibitor dasatinib, in contrast to cell lines that lacked the VHL protein, which were resistant. Forced expression of hypoxia-inducible factor (HIF) in RCC cells with wild-type VHL diminished Src signaling output by repressing transcription of the Src activator protein tyrosine phosphatase 1B (PTP1B), conferring resistance to dasatinib. Our results suggest that a HIF-regulated VHL-PTP1B-Src signaling pathway determines the sensitivity of RCC to Src inhibitors and that stratification of RCC patients with antibody-based profiling may identify patients likely to respond to Src inhibitors in RCC clinical trials.

Threshold for chaos and thermalization in the one-dimensional mean-field bose-hubbard model.

We study the threshold for chaos and its relation to thermalization in the 1D mean-field Bose-Hubbard model, which, in particular, describes atoms in optical lattices. We identify the threshold for chaos, which is finite in the thermodynamic limit, and show that it is indeed a precursor of thermalization. Far above the threshold, the state of the system after relaxation is governed by the usual laws of statistical mechanics.