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Objective: Prominent models postulate that alcohol-related attentional bias (AB), emerging from the overactivation of the reward system, plays a key role in severe alcohol use disorder (sAUD) and is independent from voluntary control. We determined whether AB is indeed compulsive or can be modulated by the control/inhibition system., Method: Patients with sAUD (17 women, 13 men, mean age of 47, White) and matched healthy controls (16 women, 14 men, mean age of 44, White) performed a visual probe task with behavioral (reaction time) and eye-tracking (first fixation location and duration, second fixation location, dwell time) measures. They also performed an avoidance task, requiring to focus on a target by voluntarily inhibiting eye movements toward alcohol/nonalcohol/nonappetitive distractors and measuring overt (break frequency) and covert (fixational eye movements) attentional processes., Results: Patients with sAUD exhibited an avoidance AB indexed by (a) reduced attentional resources dedicated to alcohol-related stimuli, namely, reduced dwell time ( p = .040) and second fixation ( p = .001) toward these stimuli; (b) increased inhibitory processes, namely, easier inhibition of saccades toward alcohol measured by lower break frequency ( p < .001); and (c) covert eye movements posited further away from alcohol., Conclusions: In contradiction with theoretical models, our two tasks did not show any AB toward alcohol in sAUD. Instead, patients exhibited an avoidance AB indexed by increased inhibitory processes as well as reduced overt and covert attentional resources dedicated to alcohol-related stimuli. These results question the theoretical and clinical role of AB, as measured through reliable eye-tracking tasks, in sAUD. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Ventricular backup leads may be considered in selected patients with His bundle pacing (HBP), but it remains unknown to what extent this is useful. A total of 184 HBP patients were studied. At last follow-up, 147 (79.9%) patients retained His bundle capture at programmed output. His bundle pacing lead revision was performed in 5/36 (13.9%) patients without a backup lead and in 3/148 (2.0%) patients with a backup lead (P = 0.008). One patient without a backup lead had syncope due to atrial oversensing. Thus, implantation of ventricular backup leads may avoid lead revision and adverse events in selected HBP patients., Competing Interests: Conflict of interest: H.B. has received speaker fees and institutional research grants from Abbott, Biotronik, Boston Scientific, Medtronic, and Microport. None of the other authors have any disclosures., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Oxygen homeostasis is maintained in plants and animals by O 2 -sensing enzymes initiating adaptive responses to low O 2 (hypoxia). Recently, the O 2 -sensitive enzyme ADO was shown to initiate degradation of target proteins RGS4/5 and IL32 via the Cysteine/Arginine N-degron pathway. ADO functions by catalysing oxidation of N-terminal cysteine residues, but despite multiple proteins in the human proteome having an N-terminal cysteine, other endogenous ADO substrates have not yet been identified. This could be because alternative modifications of N-terminal cysteine residues, including acetylation, prevent ADO-catalysed oxidation. Here we investigate the relationship between ADO-catalysed oxidation and NatA-catalysed acetylation of a broad range of protein sequences with N-terminal cysteines. We present evidence that human NatA catalyses N-terminal cysteine acetylation in vitro and in vivo. We then show that sequences downstream of the N-terminal cysteine dictate whether this residue is oxidised or acetylated, with ADO preferring basic and aromatic amino acids and NatA preferring acidic or polar residues. In vitro, the two modifications appear to be mutually exclusive, suggesting that distinct pools of N-terminal cysteine proteins may be acetylated or oxidised. These results reveal the sequence determinants that contribute to N-terminal cysteine protein modifications, with implications for O 2 -dependent protein stability and the hypoxic response., (© 2024. The Author(s).)

Defining the initial events in oncogenesis and the cellular responses they entrain, even in advance of morphologic abnormality, is a fundamental challenge in understanding cancer initiation. As a paradigm to address this, we longitudinally studied the changes induced by loss of the tumor suppressor gene von Hippel Lindau (VHL), which ultimately drives clear cell renal cell carcinoma. Vhl inactivation was directly coupled to expression of a tdTomato reporter within a single allele, allowing accurate visualization of affected cells in their native context and retrieval from the kidney for single-cell RNA sequencing. This strategy uncovered cell type-specific responses to Vhl inactivation, defined a proximal tubular cell class with oncogenic potential, and revealed longer term adaptive changes in the renal epithelium and the interstitium. Oncogenic cell tagging also revealed markedly heterogeneous cellular effects including time-limited proliferation and elimination of specific cell types. Overall, this study reports an experimental strategy for understanding oncogenic processes in which cells bearing genetic alterations can be generated in their native context, marked, and analyzed over time. The observed effects of loss of Vhl in kidney cells provide insights into VHL tumor suppressor action and development of renal cell carcinoma., Significance: Single-cell analysis of heterogeneous and dynamic responses to Vhl inactivation in the kidney suggests that early events shape the cell type specificity of oncogenesis, providing a focus for mechanistic understanding and therapeutic targeting., (©2024 The Authors; Published by the American Association for Cancer Research.)

Aims: Monitoring current of injury (COI) during left bundle branch area pacing (LBBAP) implantation is useful to evaluate lead depth. Technical aspects for recording COI amplitude have not been well studied. Our aims were to evaluate the impact of high-pass filter settings on electrogram recordings during LBBAP implantation., Methods and Results: Consecutive patients with successful LBBAP implantation had unipolar recordings of COI at final lead position at different high-pass filter settings (0.01-1 Hz) from the tip electrode during sensing and pacing, and from the ring electrode during sensing. Duration of saturation-induced signal loss was also measured at each filter setting. COI amplitudes were compared between lumenless and stylet-driven leads. A total of 156 patients (96 males, aged 81.4 ± 9.6 years) were included. Higher filter settings led to significantly lower COI amplitudes. In 50 patients with COI amplitude < 10 mV, the magnitude of the drop was on average 1-1.5 mV (and up to 4 mV) between 0.05 and 0.5 Hz, meaning that cut-offs may not be used interchangeably. Saturation-induced signal loss was on average 10 s at 0.05 Hz and only 2 s with 0.5 Hz. When pacing was interrupted, the sensed COI amplitude varied (either higher or lower) by up to 4 mV, implying that it is advisable to periodically interrupt pacing to evaluate the sensed COI when reaching levels of ∼10 mV. Lead type did not impact COI amplitude., Conclusion: High-pass filters have a significant impact on electrogram characteristics at LBBAP implantation, with the 0.5 Hz settings having the most favourable profile., Competing Interests: Conflict of interest: H.B. has received speaker fees and institutional research grants from Abbott, Biotronik, Boston Scientific, Medtronic, and Microport., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Adults shift their attention to the right or to the left along a spatial continuum when solving additions and subtractions, respectively. Studies suggest that these shifts not only support the exact computation of the results but also anticipatively narrow down the range of plausible answers when processing the operands. However, little is known on when and how these attentional shifts arise in childhood during the acquisition of arithmetic. Here, an eye-tracker with high spatio-temporal resolution was used to measure spontaneous eye movements, used as a proxy for attentional shifts, while children of 2nd (8 y-o; N = 50) and 4th (10 y-o; N = 48) Grade solved simple additions (e.g., 4+3) and subtractions (e.g., 3-2). Gaze patterns revealed horizontal and vertical attentional shifts in both groups. Critically, horizontal eye movements were observed in 4th Graders as soon as the first operand and the operator were presented and thus before the beginning of the exact computation. In 2nd Graders, attentional shifts were only observed after the presentation of the second operand just before the response was made. This demonstrates that spatial attention is recruited when children solve arithmetic problems, even in the early stages of learning mathematics. The time course of these attentional shifts suggests that with practice in arithmetic children start to use spatial attention to anticipatively guide the search for the answer and facilitate the implementation of solving procedures. RESEARCH HIGHLIGHTS: Additions and subtractions are associated to right and left attentional shifts in adults, but it is unknown when these mechanisms arise in childhood. Children of 8-10 years old solved single-digit additions and subtractions while looking at a blank screen. Eye movements showed that children of 8 years old already show spatial biases possibly to represent the response when knowing both operands. Children of 10 years old shift attention before knowing the second operand to anticipatively guide the search for plausible answers., (© 2023 The Authors. Developmental Science published by John Wiley & Sons Ltd.)

Background and Aims: Competing models disagree on three theoretical questions regarding alcohol-related attentional bias (AB), a key process in severe alcohol use disorder (SAUD): (1) is AB more of a trait (fixed, associated with alcohol use severity) or state (fluid, associated with momentary craving states) characteristic of SAUD; (2) does AB purely reflect the over-activation of the reflexive/reward system or is it also influenced by the activity of the reflective/control system and (3) does AB rely upon early or later processing stages? We addressed these issues by investigating the time-course of AB and its modulation by subjective craving and cognitive load in SAUD., Design: A free-viewing eye-tracking task, presenting pictures of alcoholic and non-alcoholic beverages, combined with a concurrent cognitive task with three difficulty levels., Setting: A laboratory setting in the detoxification units of three Belgian hospitals., Participants: We included 30 patients with SAUD self-reporting craving at testing time, 30 patients with SAUD reporting a total absence of craving and 30 controls matched on sex and age. All participants from SAUD groups met the DSM-5 criteria for SAUD., Measurements: We assessed AB through early and late eye-tracking indices. We evaluated the modulation of AB by craving (comparison between patients with/without craving) and cognitive load (variation of AB with the difficulty level of the concurrent task)., Findings: Dwell time measure indicated that SAUD patients with craving allocated more attention towards alcohol-related stimuli than patients without craving (P < 0.001, d = 1.093), resulting in opposite approach/avoidance AB according to craving presence/absence. SAUD patients without craving showed a stronger avoidance AB than controls (P = 0.003, d = 0.806). AB did not vary according to cognitive load (P = 0.962, η 2 p  = 0.004)., Conclusions: The direction of alcohol-related attentional bias (approach/avoidance) appears to be determined by patients' subjective craving at testing time and does not function as a stable trait of severe alcohol use disorder. Alcohol-related attentional bias appears to rely on later/controlled attentional stages but is not modulated by the saturation of the reflective/control system., (© 2023 Society for the Study of Addiction.)

Social cognition impairments, and notably emotional facial expression (EFE) recognition difficulties, as well as their functional and clinical correlates, are increasingly documented in severe alcohol use disorder (SAUD). However, insights into their underlying mechanisms are lacking. Here, we tested if SAUD was associated with alterations in the attentional processing of EFEs. In a preregistered study, 40 patients with SAUD and 40 healthy controls (HCs) had to identify the emotional expression conveyed by faces while having their gaze recorded by an eye-tracker. We assessed indices of initial (first fixation locations) and later (number of fixations and dwell-time) attention with reference to regions of interest corresponding to the eyes, mouth, and nose, which carry key information for EFE recognition. We centrally found that patients had less first fixations to key facial features in general, as well as less fixations and dwell time to the eyes specifically, relative to the rest of the face, compared to controls. These effects were invariant across emotional expressions. Additional exploratory analyses revealed that patients with SAUD had a less structured viewing pattern than controls. These results offer novel, direct, evidence that patients with SAUD's socioaffective difficulties already emerge at the facial attentional processing stage, along with precisions regarding the nature and generalizability of the effects. Potential implications for the mechanistic conceptualization and treatment of social cognition difficulties in SAUD are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objectives: CEACAM5 is a cell-surface glycoprotein expressed on epithelial cells of some solid tumors. Tusamitamab ravtansine (SAR408701), a humanized antibody-drug conjugate targeting CEACAM5, is in clinical development for nonsquamous non-small cell lung cancer (NSQ-NSCLC) with CEACAM5 high expression (HE), defined as membranous CEACAM5 immunohistochemistry staining at ≥ 2+ intensity in ≥ 50% of tumor cells., Materials and Methods: We investigated correlations between CEACAM5 expression by immunohistochemistry, CEACAM5 protein expression by ELISA, and CEACAM5 RNA expression by RNA-seq in NSQ-NSCLC patient-derived xenograft (PDX) models, and tumor responses to tusamitamab ravtansine in these models. We assessed prevalence of CEACAM5 HE, clinicopathologic characteristics and molecular markers in patients with NSQ-NSCLC in clinical cohorts., Results: In a lung PDX set of 10 NSQ-NSCLC specimens, correlations between CEACAM5 by IHC, ELISA and RNA-seq ranged from 0.72 to 0.88. In a larger lung PDX set, higher H-scores were present in NSQ- (n = 93) vs SQ-NSCLC (n = 128) models, and in 12 of these NSQ-NSCLC models, more tumor responses to tusamitamab ravtansine occurred in CEACAM5 HE (5/8; 62.5%) versus moderate or negative expression (1/4; 25%), including 3 with KRAS mutations among the 6 responders. In clinical NSQ-NSCLC samples, CEACAM5 HE prevalence was (52/214; 24.3%) in primary tumors and (6/17; 35.3%) in metastases. In NSQ-NSCLC primary tumors, CEACAM5 HE prevalence was significantly higher in KRAS-altered versus wild-type (35.0% vs 19.5%; P = 0.028) and in programmed cell death ligand 1 (PD-L1) negative (tumor cells 0%)/low (1-49%) versus high (≥50%) (33.3%, 26.1%, 5.0%; P = 0.031), but not significantly different in EGFR-mutated versus wild-type (20.0% vs 25.7%, P = 0.626)., Conclusions: In NSQ-NSCLC tumors, CEACAM5 HE prevalence was 24.3% overall and was higher with KRAS altered and with PD-L1 negative/low tumors but similar regardless of EGFR mutation status. These findings support targeting CEACAM5 and the clinical development of tusamitamab ravtansine for patients with NSQ-NSCLC with CEACAM5 HE., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: E. Angevin has served in a consulting or advisory role for Merck Sharp & Dohme, GlaxoSmithKline, Celgene Research, and MedImmune; and reports travel/accommodations/other expenses from AbbVie, Roche, Sanofi, Pfizer, and MedImmune. J.-C. Soria is an employee of Amgen; holds stock in Gritstone Bio and Relay Therapeutics; and has served in a consulting or advisory role for Hookipa Pharmaceuticals. A.-M. Lefebvre, C. Nicolazzi, C. Larois, F. Attenot, F. Falda-Buscaiot, C. Dib, N. Ternès, A.-L. Bauchet, B. Demers, M. Chadjaa, S. Sidhu, C. Combeau, S. Naimi, M. Chiron, and C. Henry are employees of and hold stock in Sanofi. N. Masson is an employee of IT&M Stats, which was subcontracted by Sanofi to provide statistical services for this investigation. J. Adam and J.-Y. Scoazec have no disclosures to report., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Left bundle branch area pacing (LBBAP) is most often delivered using lumenless leads (LLL), but may also be performed using stylet-driven leads (SDL). There are limited reports on comparison of these tools, mainly limited to reports describing initial operator experience or without detailed procedural data. Our aim was to perform an in-depth comparison of SDLs and LLLs for LBBAP at implantation and follow-up in a larger cohort of patients with experience that extends beyond that of the initial learning curve., Methods and Results: A total of 306 consecutive patients (age 77±11 years, 183 males) undergoing LBBAP implantation at a single centre were prospectively included. The population was split into two groups of 153 patients, based upon initial use of a SDL (from four manufacturers) or a LLL. After having discounted the initial learning curve of 50 patients, there was no difference in success rate between initial use of lead type (96.0% with SDL versus 94.3% with LLL, p = 0.56). There were no significant differences in success between lead models. ECG and electrical parameters were comparable between the groups. Post-operative macro-dislodgement occurred in 4.3% of patients (essentially within the first day following implantation) and presumed micro-dislodgement with loss of conduction system capture or rise in threshold (occurring mostly during the first month) was observed in 4.7% of patients, without differences between groups., Conclusions: LBBAP may be safely and effectively performed using either LLLs or SDLs, which provides implanters with alternatives for delivering this therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Tusamitamab ravtansine is an antibody-drug conjugate that targets carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivers a cytotoxic maytansinoid payload. In a phase I dose-escalation study, the maximum tolerated dose (MTD) was 100 mg/m 2 every 2 weeks (Q2W). Here we report results for two alternative schedules., Experimental Design: Adults ages ≥18 years (range, 34-73) with locally advanced/metastatic solid tumors ( N = 43; colon/rectum, 29; stomach, 7; pancreas, 4; other, 3) expressing/likely to express CEACAM5 received intravenous tusamitamab ravtansine 120-170 mg/m 2 [loading dose (LD)], then 100 mg/m 2 Q2W (Q2W-LD, n = 28), or 120-190 mg/m 2 fixed dose [every 3 weeks (Q3W), n = 15]. The primary endpoint was dose-limiting toxicities (DLTs) during cycles 1-2 (Q2W-LD) and cycle 1 (Q3W)., Results: Reversible DLTs were observed in 2 of 9 patients (grade 2 keratopathy; grade 2 keratitis) with 170 mg/m 2 in Q2W-LD and in 2 of 3 patients (grade 2 keratopathy; grade 3 transaminase elevation) with 190 mg/m 2 in Q3W. Nineteen (67.9%) patients in Q2W-LD and 13 (86.7%) patients in Q3W experienced treatment-related adverse events (AE); 3 of 43 patients discontinued treatment because of AEs. The most common AEs were asthenia, gastrointestinal complaints, keratopathy, keratitis, and peripheral sensory neuropathy. In this small, heavily pretreated population, no confirmed responses were observed; however, stable disease occurred in 35.7% of patients in Q2W-LD and 40.0% of patients in Q3W., Conclusions: Tusamitamab ravtansine had a favorable safety profile with both alternative administration schedules; MTDs were 170 mg/m 2 (LD) followed by 100 mg/m 2 Q2W, and 170 mg/m 2 Q3W as a fixed dose. (NCT02187848)., Significance: The collective results of this phase I dose-escalation study will inform further studies of tusamitamab ravtansine in patients with solid tumors with CEACAM5 expression, including patients with non-small cell lung cancer., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: Alcohol-related attentional bias (AB) is thought to play a key role in the emergence and maintenance of excessive alcohol use. Recent models suggest that AB, classically considered as a permanent feature in alcohol use disorders, is rather modulated by temporary motivational states., Aims: We explored the influence of current mood and craving on AB in binge drinking, through a mood induction procedure combined with eye-tracking measures of AB., Methods: In Experiment 1, we measured AB (visual probe task with eye-tracking measures) among binge drinkers ( n  = 48) and light drinkers ( n  = 32) following positive, negative and neutral mood inductions. Participants reported subjective craving and mood before/after induction. In Experiment 2, we measured AB among the same binge drinkers compared with 29 moderate drinkers following alcohol-related negative, non-alcohol-related negative and neutral mood inductions., Results: In Experiment 1, induced negative mood and group positively predicted subjective craving, which was positively associated with AB. We found no effect of induced positive mood nor a direct mood-AB association. In Experiment 2, the relationships AB presented with both induced negative mood and group were again mediated by craving. Inducing alcohol-related negative mood did not modify the mood-craving association., Conclusions: Alcohol-related AB is not a stable binge drinking characteristic but rather varies according to transient motivational (i.e., craving) and emotional (i.e., negative mood) states. This study provides important insights to better understand AB in subclinical populations and emphasizes the importance of considering motivational and affective states as intercorrelated, to offer multiple ways to reduce excessive alcohol use.

Solving subtraction and addition problems is accompanied by spontaneous leftward and rightward gaze shifts, respectively. These shifts have been related to attentional processes involved in mental arithmetic, but whether these processes induce overt attentional shifts mediated by the activation of the motor programs underlying lateral eye movements or covert shifts only is still unknown. Here, we used the abducted eye paradigm to selectively disrupt activation of the oculomotor system and prevent oculomotor preparation, which affects overt but not covert attentional shifts. Participants had to mentally solve addition and subtraction problems while fixating a screen positioned either in front of them or laterally to their left or right such that they were physically unable to programme and execute saccades further into their temporal field while they still could do so in their nasal field. In comparison to the frontal condition, rightward eye abduction impaired additions (with carrying), and leftward eye abduction impaired subtractions (with borrowing) showing that at least some arithmetic problems rely on processes dedicated to overt attentional shifts. We propose that when solving arithmetic problems requires procedures such as carrying and borrowing, oculomotor mechanisms operating on a mental space transiently built in working memory are recruited to represent one numerical magnitude in relation to another (e.g. the first operand and the result)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Social cognition impairments in severe alcohol use disorder (SAUD) are increasingly established. However, fundamental aspects of social cognition, and notably the attentional processing of socio-affective information, remain unexplored, limiting our understanding of underlying mechanisms. Here, we determined whether patients with SAUD show attentional biases to specific socio-affective cues, namely emotional faces., Method: In a modified dot-probe paradigm, 30 patients with SAUD and 30 demographically matched healthy controls (HC) were presented with pairs of neutral-emotional (angry, disgusted, happy, sad) faces while having their eye movements recorded. Indices of early/automatic (first fixations, latency to first fixations) and later/controlled (number of fixations, dwell-time) processes were computed., Results: Patients with SAUD did not differ from HC in their attention to angry/disgusted/sad vs. neutral faces. However, patients with SAUD fixated/dwelled less on happy vs. neutral faces in the first block of stimuli than HC, who presented an attentional bias to happy faces., Limitations: Sample-size was determined to detect medium-to-large effects and subtler ones may have been missed. Further, our cross-sectional design provides no explanation as to whether the evidenced biases precede or are a consequence of SAUD., Conclusions: These results extend the social cognition literature in SAUD to the attentional domain, by evidencing the absence of a controlled attentional bias toward positive social cues in SAUD. This may reflect reduced sensitivity to social reward and could contribute to higher order social cognition difficulties and social dysfunction., Competing Interests: Conflict of Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The pupil light response is more than a pure reflexive mechanism that reacts to the amount of light entering the eye. The pupil size may also react to the luminance of objects lying in the visual periphery, revealing the locus of covert attention. In the present study, we took advantage of this response to study the spatial coding of abstract concepts with no physical counterpart: numbers. The participants' gaze was maintained fixed in the middle of a screen whose left and right parts were dark or bright, and variations in pupil size were recorded during an auditory number comparison task. The results showed that small numbers accentuated pupil dilation when the darker part of the screen was on the left, while large numbers accentuated pupil dilation when the darker part of the screen was on the right. This finding provides direct evidence for covert attention shifts on a left-to-right oriented mental spatial representation of numbers. From a more general perspective, it shows that the pupillary response to light is subject to modulation from spatial attention mechanisms operating on mental contents., (© 2022. The Psychonomic Society, Inc.)

The Jumonji domain-containing protein JMJD6 is a 2-oxoglutarate-dependent dioxygenase associated with a broad range of biological functions. Cellular studies have implicated the enzyme in chromatin biology, transcription, DNA repair, mRNA splicing, and cotranscriptional processing. Although not all studies agree, JMJD6 has been reported to catalyze both hydroxylation of lysine residues and demethylation of arginine residues. However, despite extensive study and indirect evidence for JMJD6 catalysis in many cellular processes, direct assignment of JMJD6 catalytic substrates has been limited. Examination of a reported site of proline hydroxylation within a lysine-rich region of the tandem bromodomain protein BRD4 led us to conclude that hydroxylation was in fact on lysine and catalyzed by JMJD6. This prompted a wider search for JMJD6-catalyzed protein modifications deploying mass spectrometric methods designed to improve the analysis of such lysine-rich regions. Using lysine derivatization with propionic anhydride to improve the analysis of tryptic peptides and nontryptic proteolysis, we report 150 sites of JMJD6-catalyzed lysine hydroxylation on 48 protein substrates, including 19 sites of hydroxylation on BRD4. Most hydroxylations were within lysine-rich regions that are predicted to be unstructured; in some, multiple modifications were observed on adjacent lysine residues. Almost all of the JMJD6 substrates defined in these studies have been associated with membraneless organelle formation. Given the reported roles of lysine-rich regions in subcellular partitioning by liquid-liquid phase separation, our findings raise the possibility that JMJD6 may play a role in regulating such processes in response to stresses, including hypoxia.

Background: Acute aortic syndrome is associated with aortic medial degeneration. 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography (PET) detects microscopic tissue calcification as a marker of disease activity., Objectives: In a proof-of-concept study, this investigation aimed to establish whether 18 F-NaF PET combined with computed tomography (CT) angiography could identify aortic medial disease activity in patients with acute aortic syndrome., Methods: Patients with aortic dissection or intramural hematomas and control subjects underwent 18 F-NaF PET/CT angiography of the aorta. Aortic 18 F-NaF uptake was measured at the most diseased segment, and the maximum value was corrected for background blood pool activity (maximum tissue-to-background ratio [TBR max ]). Radiotracer uptake was compared with change in aortic size and major adverse aortic events (aortic rupture, aorta-related death, or aortic repair) over 45 ± 13 months., Results: Aortic 18 F-NaF uptake co-localized with histologically defined regions of microcalcification and elastin disruption. Compared with control subjects, patients with acute aortic syndrome had increased 18 F-NaF uptake (TBR max : 1.36 ± 0.39 [n = 20] vs 2.02 ± 0.42 [n = 47] respectively; P < 0.001) with enhanced uptake at the site of intimal disruption (+27.5%; P < 0.001). 18 F-NaF uptake in the false lumen was associated with aortic growth (+7.1 mm/year; P = 0.011), and uptake in the outer aortic wall was associated with major adverse aortic events (HR: 8.5 [95% CI: 1.4-50.4]; P = 0.019)., Conclusions: In patients with acute aortic syndrome, 18 F-NaF uptake was enhanced at sites of disease activity and was associated with aortic growth and clinical events. 18 F-NaF PET/CT holds promise as a noninvasive marker of disease severity and future risk in patients with acute aortic syndrome. ( 18 F Sodium Fluoride PET/CT in Acute Aortic Syndrome [FAASt]; NCT03647566)., Competing Interests: Funding Support and Author Disclosure All funding support is from the United Kingdom. Mr Syed and Drs Fletcher, Dweck, Shah, and Tavares, Mr Kaczynki, and Dr Newby were supported by the British Heart Foundation (FS/18/31/33676, FS/19/15/34155, FS/11/014, FS/14/78/31020, CH/09/002, RG/16/10/32375, RE/18/5/34216). Dr Dweck has received the Sir Jules Thorn Award for Biomedical Research 2015 (15/JTA). Dr Newby has received a Wellcome Trust Senior Investigator Award (WT103782AIA). Dr van Beek has been supported by the Scottish Imaging Network—a Platform of Scientific Excellence (SINAPSE). Edinburgh Clinical Research Facility and Edinburgh Imaging Facility are supported by NHS Research Scotland. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Behavioural studies have suggested that number manipulation involves shifting attention along a left-to-right oriented continuum. However, these studies provide little evidence about the time course of attention shifts during number processing. We used an eye-tracker with high spatio-temporal resolution to measure eye movements during the mental solving of addition (e.g., 43 + 4) and subtraction problems (e.g., 53 - 6), as a proxy for the rightward and leftward attention shifts that accompany these operations. A first difference in eye position was observed as soon as the operator was heard: the hearing of "plus" shifted the eye rightward compared to "minus". A second difference was observed later between problem offset and response onset: addition shifted the eye rightward and upward compared to subtraction, suggesting that the space used to represent the problem is bidimensional. Further analyses confirmed the fast deployment of spatial attention and evidenced its relationship with the carrying and borrowing procedures triggered by the problem presentation. The predictive role of horizontal eye movements, in particular, is essential to understand how attention contributes to narrow down the range of plausible answers. We propose that attention illuminates significant portions of the numerical continuum anticipatively to guide the search of the answer and facilitate the implementation of solving procedures in verbal working memory., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Providing ongoing care for a family member or loved one with special needs is challenging. It is estimated that about 21% of the adult population in the United States are providing unpaid care for loved ones at home. Of that group, 5.7% are caring for children with special needs. Special needs can range from developmental delay to the provision of complex medical treatments. Family caregivers take on numerous roles to coordinate activities of daily living, therapies, in-home services, school, and appointments. This is often a great source of stress on family caregivers. Providing the proper support for care to remain at home reduces the disruption to children and families' lives (Carter et al., 2012). A pilot project was developed for children with physical, cognitive, and/or developmental impairment. This project was coordinated by nursing and physical therapy faculty and their students. Parents as well as nursing and physical therapy students benefited mutually. Our preliminary responses from families indicated stress relief from caregiving and benefiting from the ability to talk to other parents in similar circumstances., (© 2021 Wiley Periodicals LLC.)

Attention allows pieces of information stored in visuospatial short-term memory (VSSTM) to be selectively processed. Previous studies showed that shifts of attention in VSSTM in response to a retro-cue are accompanied by eye movements in the direction of the position of the memorized item although there is nothing left to look at. This finding raises the possibility that shifts of attention in VSSTM are underpinned by mechanisms originally involved in the planning and control of eye movements. To explore this possibility, we investigated the ability of an individual with congenital horizontal gaze paralysis (HGP2) to shift her attention horizontally or vertically toward a memorized item within VSSTM using a retro-cue paradigm. As efficient oculomotor programming is not innate but requires some trial and error learning and adaptation to develop, congenital paralysis prevents this development. Consequently, if shifts of attention in VSSTM rely on the same mechanisms as those supporting the programming of eye movements, then horizontal congenital gaze paralysis should necessarily prevent typical retro-cueing effect in the paralyzed axis. At odds with this prediction, HGP2 showed a typical retro-cueing effect in her paralyzed axis. This original finding indicates that selecting an item within VSSTM does not depend on the ability to program a saccade., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Dominant theoretical models consider that attentional biases (AB) towards alcohol-related stimuli play a key role in the development and maintenance of alcohol use disorder (AUD). Their assessment has however showed high inconsistencies and has been mostly based on unreliable behavioral measures. This study evaluated the presence and extent of alcohol-related AB in recently detoxified inpatients with severe AUD by combining the visual probe task (VPT) paradigm with eye-tracking measures, known to improve the VPT reliability in subclinical populations., Methods: We recruited 24 patients and 27 matched healthy controls. They performed the VPT (measuring reaction time when processing visual targets preceded by alcoholic and matched non-alcoholic pictures) combined with eye-tracking measures (dwell time, first fixation direction/duration, second fixation direction) during two sessions. Estimates of internal consistency, split-half reliability, and test-retest reliability were measured., Results: Patients showed shorter dwell time for alcohol cues (p = .004, d=.853) and reduced number of fixations towards alcohol after a first fixation on non-alcohol cues (p = .012, d=.758) compared to controls. These findings suggest the presence of alcohol-related avoidance AB in detoxified patients with severe AUD. The VPT achieved excellent reliability for these eye-tracking measures. Reaction times and first fixation measures did not indicate any AB pattern and showed poor reliability., Conclusions: The VPT, when combined with dwell time and second fixation direction, constitutes a reliable method for assessing AB in detoxified patients. It showed the presence of an alcohol-related avoidance bias in this clinical population, in contradiction with the approach bias predicted by theoretical models., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Acute alcohol intoxication and alcohol use disorders are characterized by a wide range of psychological and cerebral impairments, which have been widely explored using neuropsychological and neuroscientific techniques. Eye tracking has recently emerged as an innovative tool to renew this exploration, as eye movements offer complementary information on the processes underlying perceptive, attentional, memory or executive abilities. Building on this, the present systematic and critical literature review provides a comprehensive overview of eye tracking studies exploring cognitive and affective processes among alcohol drinkers. Using PRISMA guidelines, 36 papers that measured eye movements among alcohol drinkers were extracted from three databases (PsycINFO, PubMed, Scopus). They were assessed for methodological quality using a standardized procedure, and categorized based on the main cognitive function measured, namely perceptive abilities, attentional bias, executive function, emotion and prevention/intervention. Eye tracking indexes showed that alcohol-related disorders are related to: (1) a stable pattern of basic eye movement impairments, particularly during alcohol intoxication; (2) a robust attentional bias, indexed by increased dwell times for alcohol-related stimuli; (3) a reduced inhibitory control on saccadic movements; (4) an increased pupillary reactivity to visual stimuli, regardless of their emotional content; (5) a limited visual attention to prevention messages. Perspectives for future research are proposed, notably encouraging the exploration of eye movements in severe alcohol use disorders and the establishment of methodological gold standards for eye tracking measures in this field.

Rationale: Severe alcohol use disorder (SAUD) is a psychiatric condition linked to cerebral and cognitive consequences. SAUD is notably characterized by an overactivation of the reflexive/reward system when confronted with alcohol-related cues. Such overreactivity generates a preferential allocation of attentional resources toward these cues, labeled as attentional biases (AB). Theoretical assumptions have been made regarding the characteristics of AB and their underlying processes. While often considered as granted, these assumptions remain to be experimentally validated., Aims: We first identify the theoretical assumptions made by previous studies exploring the nature and role of AB. We then discuss the current evidence available to establish their validity. We finally propose research avenues to experimentally test them., Methods: Capitalizing on a narrative review of studies exploring AB in SAUD, the current limits of the behavioral measures used for their evaluation are highlighted as well as the benefits derived from the use of eye-tracking measures to obtain a deeper understanding of their underlying processes. We describe the issues related to the theoretical proposals on AB and propose research avenues to test them. Four experimental axes are proposed, respectively, related to the determination of (a) the genuine nature of the mechanisms underlying AB; (b) their stability over the disease course; (c) their specificity to alcohol-related stimuli and (d) their reflexive or controlled nature., Conclusions: This in-depth exploration of the available knowledge related to AB in SAUD, and of its key limitations, highlights the theoretical and clinical interest of our innovative experimental perspectives capitalizing on eye-tracking measures., (© The Author(s) 2020. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

The widespread cognitive and cerebral consequences of prenatal alcohol exposure have been established during the last decades, through the exploration of fetal alcohol spectrum disorders (FASD) using neuropsychological and neuroscience tools. This research field has recently benefited from the emergence of innovative measures, among which eye tracking, allowing a precise measure of the eye movements indexing a large range of cognitive functions. We propose a comprehensive review, based on PRISMA guidelines, of the eye tracking studies performed in populations with FASD. Studies were selected from the PsycINFO, PubMed and Scopus databases, and were evaluated through a standardized methodological quality assessment. Studies were classified according to the eye tracking indexes recorded (saccade characteristics, initial fixation, number of fixations, dwell time, gaze pattern) and the process measured (perception, memory, executive functions). Eye tracking data showed that FASD are mostly associated with impaired ocular perceptive/motor abilities (i.e., altered eye movements, centrally for saccade initiation), lower accuracy as well as increased error rates in saccadic eye movements involving working memory abilities, and reduced inhibitory control on saccades. After identifying the main limitations presented by the reviewed studies, we propose guidelines for future research, underlining the need to increase the standardization of diagnosis and evaluation tools, and to improve the methodological quality of eye tracking measures., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Numerous studies have shown the impact of lung cancer disease on patient quality of life (QoL), but no research has yet examined the impact of illness representations (IR) in the assessment of QoL in lung cancer. Our goal is to explore the role of IR as adeterminant of QoL for lung cancer patients. Data were collected from 162 French patients who completed aself-administered questionnaire including ageneric measure of QoL. It also contains aspecific measure of psychological distress, mental adjustment to cancer, and socio-demographic and medical data. Regression analysis revealed that consequences, treatment control, identity and understanding predicted QoL and the activity dimension of QoL. Perceived consequences and identity seemed to have adeleterious impact on QoL, while treatment control predicted abetter QoL, related to the level of psychological distress and education level. The results suggest the importance of considering IR as adeterminant of QoL. They corroborate earlier findings on the relationship between IR and QoL associated with other pathologies. Psychosocial variables appeared to have more impact on QoL than socio-demographic and clinical variables, which shows the importance of considering IR in order to improve the QoL of patients.

The representation of numbers in human adults is linked to space. In Western cultures, small and large numbers are associated respectively with the left and right sides of space. An influential framework attributes the emergence of these spatial-numerical associations (SNAs) to cultural factors such as the direction of reading and writing, because SNAs were found to be reduced or inverted in right-to-left readers/writers (e.g., Arabic, Farsi, or Hebrew speakers). However, recent cross-cultural and animal studies cast doubt on the determining role of reading and writing directions on SNAs. In this study, we assessed this role in mental arithmetic, which requires explicit number manipulations and has revealed robust leftward or rightward biases in Western participants. We used a temporal order judgement task in French and Arabic speakers, two languages that have opposite reading/writing directions. Participants had to solve subtraction and addition problems presented auditorily while at the same time determining which of a left or right visual target appeared first on a screen. The results showed that the right target was favoured more often when solving additions than when solving subtractions both in the French- (n = 31) and Arabic-speaking (n = 25) groups. This was true even in Arabic-speaking participants whose preference for ordering of various series of numerical and non-numerical stimuli went from right to left (n = 10). These results indicate that SNAs in mental arithmetic cannot be explained by the direction of reading/writing habits and call for a reconsideration of current models to acknowledge the pervasive role of biological factors in SNAs in adults., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Attentional bias towards alcohol-related stimuli is a core characteristic of severe alcohol use disorders (AUD), directly linked to clinical variables (e.g. alcohol consumption, relapse). Nevertheless, the extent of this bias in subclinical populations remains poorly documented. This is particularly true for binge drinking, an alcohol consumption pattern highly prevalent in youth, characterised by an alternation between excessive intakes and withdrawal periods., Aims: We used eye-tracking to: (a) measure attentional bias in binge drinking, (b) determine its time course by dissociating early/late processing stages, (c) clarify its specificity for alcohol-related stimuli compared to other appetitive stimulations and (d) explore its modulation by current craving intensity., Methods: Binge drinkers ( n =42) and matched controls ( n =43) performed a visual probe task, requiring visual targets preceded by pairs of pictures to be processed, with three conditions (i.e. alcohol vs. soft drink, alcohol vs. high-calorie food, high-calorie food vs. low-calorie food)., Results: No group difference was observed for early processing (i.e. first area of interest visited). Dwell times highlighted a bias towards soft drinks and healthy food among controls, without any global bias towards alcohol in binge drinkers. Centrally, a comparison of binge drinkers with low versus high current craving intensity indicated that binge drinking was associated with a bias towards alcohol and high-calorie food only in the presence of a high craving towards these stimuli., Conclusion: Attentional bias towards alcohol reported in severe AUD is only found in binge drinkers in the presence of high craving and is generalised to other appetitive cues.

Spatial biases associated with subtraction or addition problem solving are generally considered as reflecting leftward or rightward attention shifts along a mental numerical continuum, but an alternative hypothesis not implying spatial attention proposes that the operator (plus or minus sign) may favour a response to one side of space (left or right) because of semantic associations. We tested these two accounts in a series of temporal order judgement experiments that consisted in the auditory presentation of addition or subtraction problems followed 200 ms (Experiments 1-2) or 800 ms (Experiment 3) later by the display of two lateralized targets in close temporal succession. To dissociate the side where the operation first brought their attention from the side they had to respond to, we asked participants to report which of the left or right target appeared first or last on screen. Under the attention-orienting account, addition should elicit more rightward responses than subtraction when participants have to focus on the first target, but more leftward responses when they have to focus on the last target, because the latter is opposite to the side where the operation first brought their attention. Under the semantic account, addition should elicit more rightward responses than subtraction, no matter the focus is on the first or last target, because participants should systematically favour the side conceptually linked to the operator. The results of the three experiments converge to indicate that, in lateralized target detection tasks, the spatial biases induced by arithmetic operations stem from semantic associations.

Objective: Transcranial direct current stimulation (tDCS) provides a way to modulate spatial attention by enhancing the ratio of neural activity between the left and right hemispheres, with a potential benefit for the rehabilitation of visual neglect., Methods: We tested the effect of bilateral tDCS in healthy individuals performing a visual detection task. This protocol consists in the positioning of the anode and cathode on mirror positions over the left and right parietal areas. The stimulation was repeated over three days to maximize the chance to observe a bias to the hemispace controlateral to the anode., Results: Compared to a sham treatment, left anodal - right cathodal stimulation enhanced attention across the full range of space, since the first day with no build-up effect on the next days, and modified the balance of left-right omissions when stimuli appeared at the same time., Conclusion: Bilateral tDCS improved detection in both visual fields, with no privileged processing of one side, except when concurrent stimuli were presented. The results provide partial support to the hemispheric rivalry hypothesis., Significance: The technique has the potential to boost attention in neglect patients but should be used as an adjuvant rather than as an alternative to functional rehabilitation., Competing Interests: Declaration of Competing Interest None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Eye tracking has emerged as a reliable neuroscience tool indexing the eye movements' correlates of impairments resulting from alcohol-use disorders, ranging from perceptive abilities to high-level cognitive functions. This systematic review, following PRISMA guidelines, encompasses all human studies using eye tracking in participants presenting acute alcohol consumption. A literature search was conducted in PsycINFO, PubMed and Scopus, and a standardized methodological quality assessment was performed. Eye tracking studies were classified according to the processes measured (perception, attentional bias, memory, executive functions, prevention message processing). Eye tracking data centrally showed a global visuo-motor impairment (related to reduced cerebellar functioning) following alcohol intoxication, together with reduced memory and inhibitory control of eye movements. Conversely, the impact of such intoxication on alcohol-related attentional bias is still debated. The limits of this literature have been identified, leading to the emergence of new research avenues to increase the understanding of eye movements during alcohol intoxication, and to the proposal of guidelines for future research., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Behavioral studies have reported interactions between number processing and spatial attention, suggesting that number processing involves shifting attention along a mental continuum on which numbers are represented in ascending order. However, direct evidence for attention shifts remains scarce, the respective contribution of the horizontal and vertical axes is unclear, and little is known about the time course of attention shifts during mental manipulation of numbers. In the present study, we used an eye-tracking device with a high spatiotemporal resolution to measure gaze patterns in a task that required participants to compare number words (20 to 70) to a fixed reference (45) while looking at a blank screen (Experiment 1) or at colorful pictures (Experiment 2). Experiment 1 revealed late attention shifts evoking an epiphenomenon rather than a functional process because they occurred after the response. Experiment 2 revealed horizontal and vertical attention shifts emerging during the first stages of the comparison process. A leftward and downward ocular drift was observed while participants were listening to numbers smaller than the reference compared to numbers larger than the reference. The results showed that earlier shifts were observed when numbers were far from the reference because the decade was sufficiently discriminating to allow a fast decision. In contrast, close numbers were associated with later attention shifts because their proximity with the reference required processing the unit. We conclude that number comparison is a dynamic process that exploits visual imagery mechanisms to magnify the position of numbers on a two-dimensional space representing their magnitude. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Insufficient analgesia affects around 50% of emergency department patients. The use of a protocol helps to reduce the risk of oligoanalgesia in this context. Our objective was to describe the feasibility and efficacy of a multimodal analgesia protocol (combining paracetamol, oxycodone, and inhaled methoxyflurane) initiated by triage nurse. We performed a prospective, observational study in an emergency department (Grenoble Alpes University Hospital, France) between December 2017 and April 2018. Adult non-severe trauma patients with a numerical pain rating scale (NRS) score ≥ 4 were included. The primary efficacy criterion was the proportion of patients with an NRS score ≤ 3 at 15 min. Pain intensity was measured for 60 min and during radiography. Data on adverse events and satisfaction were recorded. A total of 200 adult patients were included (median [interquartile range (IQR)] age: 32 [23-49] years; 126 men (63%)). Sixty-six patients (33%) reported an NRS score ≤ 3 at 15 min. The time required to achieve a decrease of at least 2 points in the NRS score was 10 (5-20) min. The median [IQR] pain intensity was 4 [2-5] before radiography and 4 [2-6] during radiography. Adverse events were frequent (n = 128, 64%). No serious adverse events were reported. The patients and caregivers reported good levels of satisfaction. The administration of a nurse-driven multimodal analgesia protocol (combining paracetamol, oxycodone, and methoxyflurane) was feasible on admission to the emergency department. It rapidly produced long-lasting analgesia in adult trauma patients.Trial registration: NCT03380247.

Organisms must respond to hypoxia to preserve oxygen homeostasis. We identify a thiol oxidase, previously assigned as cysteamine (2-aminoethanethiol) dioxygenase (ADO), as a low oxygen affinity (high- K m ) amino-terminal cysteine dioxygenase that transduces the oxygen-regulated stability of proteins by the N-degron pathway in human cells. ADO catalyzes the conversion of amino-terminal cysteine to cysteine sulfinic acid and is related to the plant cysteine oxidases that mediate responses to hypoxia by an identical posttranslational modification. We show in human cells that ADO regulates RGS4/5 (regulator of G protein signaling) N-degron substrates, modulates G protein-coupled calcium ion signals and mitogen-activated protein kinase activity, and that its activity extends to other N-cysteine proteins including the angiogenic cytokine interleukin-32. Identification of a conserved enzymatic oxygen sensor in multicellular eukaryotes opens routes to better understanding and therapeutic targeting of adaptive responses to hypoxia.2 ) amino-terminal cysteine dioxygenase that transduces the oxygen-regulated stability of proteins by the N-degron pathway in human cells. ADO catalyzes the conversion of amino-terminal cysteine to cysteine sulfinic acid and is related to the plant cysteine oxidases that mediate responses to hypoxia by an identical posttranslational modification. We show in human cells that ADO regulates RGS4/5 (regulator of G protein signaling) N-degron substrates, modulates G protein-coupled calcium ion signals and mitogen-activated protein kinase activity, and that its activity extends to other N-cysteine proteins including the angiogenic cytokine interleukin-32. Identification of a conserved enzymatic oxygen sensor in multicellular eukaryotes opens routes to better understanding and therapeutic targeting of adaptive responses to hypoxia., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: Neuropsychological studies suggest that the ability to compensate for the presence of spatial neglect highly depends on the attentional resources a patient can rely on. The present research aimed to study neglect in situations where attentional resources are limited due to multitasking., Method: We examined two patients more than 3 years after a right-hemispheric stroke. Both had received neuropsychological rehabilitation for left neglect and did not show any impairment in standard tests. We used a dual-task paradigm combining a peripheral target detection task with a central shape recognition task. Peripheral targets could appear in left/right positions but also in lower/upper positions., Results: In patient #1, dual-task condition exacerbated left neglect and extinction. Patient #2 did not show any sign of neglect along the horizontal axis, but omitted half of the lower targets when they were presented simultaneously with upper targets under dual-task condition. This behavior reflects altitudinal extinction as the detection of single targets appearing either in upper or lower position was preserved., Conclusion: The present findings show that dual-tasking is a sensitive tool for the quantitative and qualitative assessment of spatial attention deficits, which are often overlooked by standard methods, especially in chronic stage. (JINS, 2019, 25, 644-653).

Study Objective: To investigate the performance of a rapid RT-PCR assay to detect influenza A/B at emergency department admission., Methods: This single-center prospective study recruited adult patients attending the emergency department for influenza-like illness. Triage nurses performed nasopharyngeal swab samples and ran rapid RT-PCR assays using a dedicated device (cobas Liat, Roche Diagnostics, Meylan, France) located at triage. The same swab sample was also analyzed in the department of virology using conventional RT-PCR techniques. Patients were included 24 hours-a-day, 7 days-a-week. The primary outcome was the diagnostic accuracy of the rapid RT-PCR assay performed at triage., Results: A total of 187 patients were included over 11 days in January 2018. Median age was 70 years (interquartile range 44 to 84) and 95 (51%) were male. Nine (5%) assays had to be repeated due to failure of the first assay. The sensitivity of the rapid RT-PCR assay performed at triage was 0.98 (95% confidence interval (CI): 0.91-1.00) and the specificity was 0.99 (95% CI: 0.94-1.00). A total of 92 (49%) assays were performed at night-time or during the weekend. The median time from patient entry to rapid RT-PCR assay results was 46 [interquartile range 36-55] minutes., Conclusion: Rapid RT-PCR assay performed by nurses at triage to detect influenza A/B is feasible and highly accurate., Competing Interests: Roche Diagnostics had no role in the study design; collection, analysis, or interpretation of data; writing of the paper; and/or decision to submit for publication. None of the authors received direct funding from this company. MundiPharma and Purdue: These sister companies had no role in this study and are currently working outside the field of influenza diagnosis or treatment. MM and DV received a grant to conduct a trial on pain management in the ED (NCT03380247). MM also received consultant fees as a “pain management expert” from these companies. DV received a grant from AstraZenecca to conducted biological analysis in a subgroup of patients from a larger study investigating exacerbation of Chronic Obstructive Pulmonary Disease (NCT03474575). This company had no role in the present study. DV did not receive fee from this company. These competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

Hypoxia-inducible factor (HIF) is the major transcriptional regulator of cellular responses to hypoxia. The two principal HIF-α isoforms, HIF-1α and HIF-2α, are progressively stabilized in response to hypoxia and form heterodimers with HIF-1β to activate a broad range of transcriptional responses. Here, we report on the pan-genomic distribution of isoform-specific HIF binding in response to hypoxia of varying severity and duration, and in response to genetic ablation of each HIF-α isoform. Our findings reveal that, despite an identical consensus recognition sequence in DNA, each HIF heterodimer loads progressively at a distinct repertoire of cell-type-specific sites across the genome, with little evidence of redistribution under any of the conditions examined. Marked biases towards promoter-proximal binding of HIF-1 and promoter-distant binding of HIF-2 were observed under all conditions and were consistent in multiple cell type. The findings imply that each HIF isoform has an inherent property that determines its binding distribution across the genome, which might be exploited to therapeutically target the specific transcriptional output of each isoform independently., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

Fibrotic idiopathic interstitial pneumonia patients derived benefit from a pulmonary rehabilitation programme in terms of exercise tolerance, anxiety, depression and quality of life without increasing their daily life physical activity http://ow.ly/WV7U30kgNkU., Competing Interests: Conflict of interest: B. Wallaert reports personal fees, non-financial support and other (advisory board) from Boehringer Ingelheim, personal fees and non-financial support from Vitalaire, personal fees, non-financial support and other (advisory board) from Roche, outside the submitted work. Conflict of interest: O. Le Rouzic reports personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim, Chiesi, Lilly and Novartis; non-financial support from GlaxoSmithKline, MundiPharma, Pfizer, Teva, Santelys Association, Vertex and Vitalaire, all outside the submitted work. Conflict of interest: L. Wémeau-Stervinou reports personal fees, non-financial support and other (advisory board) from Boehringer-Ingelheim, personal fees and non-financial support from Roche, personal fees from Bristol-Myers-Squibb and Janssen-Cilag, outside the submitted work. Conflict of interest: Formaction Santé (J.M. Grosbois) received financial support from Adair, France Oxygène, Homeperf, LVL, Orkyn, Santélys, SOS Oxygène, Sysmed, VitalAire, and the ARS Hauts-de-France for home-based PR programmes.

Processing numbers induces shifts of spatial attention in probe detection tasks, with small numbers orienting attention to the left and large numbers to the right side of space. This has been interpreted as supporting the concept of a mental number line with number magnitudes ranging from left to right, from small to large numbers. Recently, the investigation of this spatial-numerical link has been extended to mental arithmetic with the hypothesis that solving addition or subtraction problems might induce attentional displacements, rightward or leftward, respectively. At the neurofunctional level, the activations elicited by the solving of additions have been shown to resemble those induced by rightward eye movements. However, the possible behavioural counterpart of these activations has not yet been observed. Here, we investigated overt attentional shifts with a target detection task primed by addition and subtraction problems (2-digit ± 1-digit operands) in participants whose gaze orientation was recorded during the presentation of the problems and while calculating. No evidence of early overt attentional shifts was observed while participants were hearing the first operand, the operator or the second operand, but they shifted their gaze towards the right during the solving step of addition problems. These results show that gaze shifts related to arithmetic problem solving are elicited during the solving procedure and suggest that their functional role is to access, from the first operand, the representation of the result.

Cells adapt to environmental changes, including fluctuations in oxygen levels, through the induction of specific gene expression programs. To identify genes regulated by hypoxia at the transcriptional level, we pulse-labeled HUVEC cells with 4-thiouridine and sequenced nascent transcripts. Then, we searched genome-wide binding profiles from the ENCODE project for factors that correlated with changes in transcription and identified binding of several components of the Sin3A co-repressor complex, including SIN3A, SAP30 and HDAC1/2, proximal to genes repressed by hypoxia. SIN3A interference revealed that it participates in the downregulation of 75% of the hypoxia-repressed genes in endothelial cells. Unexpectedly, it also blunted the induction of 47% of the upregulated genes, suggesting a role for this corepressor in gene induction. In agreement, ChIP-seq experiments showed that SIN3A preferentially localizes to the promoter region of actively transcribed genes and that SIN3A signal was enriched in hypoxia-repressed genes, prior exposure to the stimulus. Importantly, SINA3 occupancy was not altered by hypoxia in spite of changes in H3K27ac signal. In summary, our results reveal a prominent role for SIN3A in the transcriptional response to hypoxia and suggest a model where modulation of the associated histone deacetylase activity, rather than its recruitment, determines the transcriptional output., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objectives: Recent findings suggest that mental arithmetic involves shifting attention on a mental continuum in which numbers would be ordered from left to right, from small to large numbers, with addition and subtraction causing rightward or leftward shifts, respectively. Neuropsychological data showing that brain-damaged patients with left neglect experience difficulties in solving subtraction but not addition problems support this hypothesis. However, the reverse dissociation is needed to establish the causal role of spatial attention in mental arithmetic., Method: R.H., a 65-year-old left-brain-damaged patient exhibiting right unilateral visuospatial and representational neglect, was tested with various numerical tasks including numerical comparison, arithmetic problem-solving, and numerical interval bisection., Results: In numerical comparison, R.H. showed a selective response latency increase when judging numbers larger than the references whereas his performance was normal for numbers smaller than the references. In the arithmetic task, R.H. was impaired in solving addition but not subtraction problems. In contrast, performance in number bisection shows a deviation toward larger numbers., Conclusion: These results establish a double dissociation between subtraction and addition solving in patients with left versus right neglect and demonstrate clear evidence that attentional mechanisms are crucial for mental arithmetic. We suggest that attention shifts are involved whenever a number is represented relative to another on a mental continuum, be it during numerical comparison or arithmetic problem-solving. R.H.'s performance in numerical interval bisection indicates that this task involves processes that are distinct from those involved in number comparison and mental arithmetic. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Solving arithmetic problems has been shown to induce shifts of spatial attention, subtraction problems orienting attention to the left side, and addition problems to the right side of space. At the neurofunctional level, the activations elicited by the solving of arithmetical problems resemble those elicited by horizontal eye movements. Whether overt orientation of attention (i.e., eye movements) can be linked to the solving procedure is, however, still under debate. In the present study, we used optokinetic stimulation (OKS) to trigger automatic eye movements to orient participants' overt attention to the right or to the left of their visual field while they were solving addition or subtraction problems. The results show that, in comparison to leftward OKS and a control condition, rightward OKS facilitates the solving of addition problems that necessitate a carrying procedure. Subtraction solving was unaffected by leftward or rightward OKS. These results converge with previous findings to show that attentional shifts are functionally related to mental arithmetic processing.

Objective: Selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitors are among the most commonly prescribed drugs in patients admitted to the ICU. Our objective was to systematically review available literature for evidence of benefit or harm in ICU patients resulting from chronic effects, continued use, or withdrawal., Data Sources: Medline, Embase, and Cochrane Central Register of Controlled Trials (1990 to November 2014)., Study Selection: We searched for studies of ICU patients with recorded selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor prescription before or during admission, and reporting morbidity, mortality, adverse events, and resource measures like ICU length of stay. We considered all study designs. We excluded studies of deliberate overdose and depression in non-ICU settings. Two authors independently and in duplicate screened citations and reviewed text of studies to apply selection criteria., Data Extraction: Two authors abstracted data on patient characteristics in exposed and control groups; use of selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitors previously or during ICU; comparator intervention; and outcomes, and also assessed methodologic quality., Data Synthesis: The database search retrieved 4,172 unique citations, of which 289 were reviewed, and 13 studies representing a total of 20,048 patients met selection criteria. There were five cohort studies, one case series, and seven case reports. Only one case report suggested benefit from selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor use and 11 studies reported morbidity in patients using these medications at admission to ICU. However, due to inadequate drug administration reporting, it was generally unclear if outpatient selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitors were continued in ICU, complicating interpretation., Conclusions: There may be excess morbidity in critically ill selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor users, but uncertainty remains whether this is due to chronic effects, ongoing use, or drug withdrawal. Further research with improved standards of drug administration reporting is needed to help clinicians decide when to use selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitors in critically ill patients.

The JmjC histone lysine demethylases (KDMs) are epigenetic regulators involved in the removal of methyl groups from post-translationally modified lysyl residues within histone tails, modulating gene transcription. These enzymes require molecular oxygen for catalytic activity and, as 2-oxoglutarate (2OG)-dependent oxygenases, are related to the cellular oxygen sensing HIF hydroxylases PHD2 and FIH. Recent studies have indicated that the activity of some KDMs, including the pseudogene-encoded KDM4E, may be sensitive to changing oxygen concentrations. Here, we report detailed analysis of the effect of oxygen availability on the activity of the KDM4 subfamily member KDM4A, importantly demonstrating a high level of O 2 sensitivity both with isolated protein and in cells. Kinetic analysis of the recombinant enzyme revealed a high K M app (O 2 ) of 173 ± 23 μM, indicating that the activity of the enzyme is able to respond sensitively to a reduction in oxygen concentration. Furthermore, immunofluorescence experiments in U2OS cells conditionally overexpressing KDM4A showed that the cellular activity of KDM4A against its primary substrate, H3K9me3, displayed a graded response to depleting oxygen concentrations in line with the data obtained using isolated protein. These results suggest that KDM4A possesses the potential to act as an oxygen sensor in the context of chromatin modifications, with possible implications for epigenetic regulation in hypoxic disease states. Importantly, this correlation between the oxygen sensitivity of the catalytic activity of KDM4A in biochemical and cellular assays demonstrates the utility of biochemical studies in understanding the factors contributing to the diverse biological functions and varied activity of the 2OG oxygenases.

Background: Biases in beliefs about the self are associated with psychopathology and depressive and anxious mood, but it is not clear if both negative and positive beliefs are associated with depression or anxiety. We examined these relationships in people who present with a wide range of depressive and anxious mood across diagnostic categories., Methods: We probed positive and negative beliefs about the self with a task in which 74 female participants with either affective disorder (depression and/or anxiety), borderline personality disorder or no psychiatric history indicated the degree to which 60 self-related words was "like them" or "not like them". Depressive and anxious mood were assessed with the Beck Depression Inventory-II and the Beck Anxiety Inventory., Results: The participants with no psychiatric history (n=25) reported a positive bias in their beliefs about the self, the participants with affective disorder (n=23) reported no bias, and the participants with BPD (n=26) reported a negative bias. Two hierarchical multiple regressions demonstrated that the positive and negative beliefs contributed additively to the ratings of depression (corrected for anxiety), but did not contribute to the ratings of anxiety (corrected for depression)., Limitations: Despite the apparent small sample size, the regression analyses indicated adequate sampling. Anxiety is a much more heterogeneous condition than is depression, so it may be difficult to find relevant self-descriptors. Only measures of endorsement were used., Conclusions: Biases in beliefs about the self are associated with depressed, but not anxious mood, across diagnostic categories., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

Previous studies have shown that left neglect patients are impaired when they have to orient their attention leftward relative to a standard in numerical comparison tasks. This finding has been accounted for by the idea that numerical magnitudes are represented along a spatial continuum oriented from left to right with small magnitudes on the left and large magnitudes on the right. Similarly, it has been proposed that duration could be represented along a mental time line that shares the properties of the number continuum. By comparing directly duration and numerosity processing, this study investigates whether or not the performance of neglect patients supports the hypothesis of a mental time line. Twenty-two right brain-damaged patients (11 with and 11 without left neglect), as well as 11 age-matched healthy controls, had to judge whether a single dot presented visually lasted shorter or longer than 500 ms and whether a sequence of flashed dots was smaller or larger than 5. Digit spans were also assessed to measure verbal working memory capacities. In duration comparison, no spatial-duration bias was found in neglect patients. Moreover, a significant correlation between verbal working memory and duration performance was observed in right brain-damaged patients, irrespective of the presence or absence of neglect. In numerical comparison, only neglect patients showed an enhanced distance effect for numerical magnitude smaller than the standard. These results do not support the hypothesis of the existence of a mental continuum oriented from left to right for duration. We discuss an alternative account to explain the duration impairment observed in right brain-damaged patients., (© 2015 The British Psychological Society.)

Solving arithmetic problems has been shown to induce shifts of spatial attention in simple probe-detection tasks, subtractions orienting attention to the left side and additions to the right side of space. Whether these attentional shifts constitute epiphenomena or are critically linked to the calculation process is still unknown. In the present study, we investigate participants' performance on addition and subtraction solving while they have to detect central or lateralized targets. The results show that lateralized distractors presented in the hemifield congruent to the operation to be solved interfere with arithmetical solving: participants are slower to solve subtractions or additions when distractors are located on the left or on the right, respectively. These results converge with previous data to show that attentional shifts underlie not only number processing but also mental arithmetic. They extend them as they reveal the reverse effect of the one previously reported by showing that inducing attention shifts interferes with the solving of arithmetic problems. They also demonstrate that spatial attentional shifts are part of the calculation procedure of solving mentally arithmetic problems. Their functional role is to access, from the first operand, the representation of the result in a direction congruent to the operation.