The role of systematicity in early referent selection.

Previous studies showed that word learning is affected by children's existing knowledge. For instance, knowledge of semantic category aids word learning, whereas a dense phonological neighbourhood impedes learning of similar-sounding words. Here, we examined to what extent children associate similar-sounding words (e.g., rat and cat) with objects of the same semantic category (e.g., both are animals), that is, to what extent children assume meaning overlap given form overlap between two words. We tested this by first presenting children (N = 93, Mage = 22.4 months) with novel word-object associations. Then, we examined the extent to which children assume that a similar sounding novel label, that is, a phonological neighbour, refers to a similar looking object, that is, a likely semantic neighbour, as opposed to a dissimilar looking object. Were children to preferentially fixate the similar-looking novel object, it would suggest that systematic word form-meaning relations aid referent selection in young children. While we did not find any evidence for such word form-meaning systematicity, we demonstrated that children showed robust learning for the trained novel word-object associations, and were able to discriminate between similar-sounding labels and also similar-looking objects. Thus, we argue that unlike iconicity which appears early in vocabulary development, we find no evidence for systematicity in early referent selection.

Exploring older people's understanding of the QOL-ACC, a new preference-based quality-of-life measure, for quality assessment and economic evaluation in aged care: the impact of cognitive impairment and dementia.

BACKGROUND: Quality-of-life is an essential outcome for quality assessment and economic evaluation in health and social care. The-Quality-of-Life - Aged Care Consumers (QOL-ACC) is a new preference-based quality-of-life measure, psychometrically validated with older people in aged care. More evidence is needed to inform the self-report reliability of the QOL-ACC in older people with varying levels of cognitive impairment and dementia. METHODS: A think-aloud protocol was developed and applied with older residents. The Mini Mental State Examination (MMSE) was applied to assign participants to no cognitive impairment (NCI - MMSE score ≥ 27) and cognitive impairment (MMCI - MMSE score < 27) subgroups. Three independent raters utilised a Tourangeau survey response model-based framework to identify response issues. Data were compared across cognition subgroups and synthesized using a 'traffic light' grading to classify frequency and type of response issues. Gradings were utilised to assess self-report reliability according to different levels of cognitive impairment. RESULTS: Qualitative data from 44 participants (NCI = 20, MMCI = 24) were included for analysis. Response issues were more evident in the cognitive impairment subgroup than the no cognitive impairment subgroup. All participants who received a 'red' grade had an MMSE score of < 20 and 66% of 'amber' grades occurred in the cognitive impairment subgroup. CONCLUSIONS: The QOL-ACC is able to be completed reliably by older residents with an MMSE score > 17. Future research is needed to assess the generalisability of these findings to other preference-based quality of life instruments and for older people in other care settings including health systems.

Dopamine Measurement Using Engineered CNT-CQD-Polymer Coatings on Pt Microelectrodes.

This study aims to develop a microelectrode array-based neural probe that can record dopamine activity with high stability and sensitivity. To mimic the high stability of the gold standard method (carbon fiber electrodes), the microfabricated platinum microelectrode is coated with carbon-based nanomaterials. Carboxyl-functionalized multi-walled carbon nanotubes (COOH-MWCNTs) and carbon quantum dots (CQDs) were selected for this purpose, while a conductive polymer like poly (3-4-ethylene dioxythiophene) (PEDOT) or polypyrrole (PPy) serves as a stable interface between the platinum of the electrode and the carbon-based nanomaterials through a co-electrodeposition process. Based on our comparison between different conducting polymers and the addition of CQD, the CNT-CQD-PPy modified microelectrode outperforms its counterparts: CNT-CQD-PEDOT, CNT-PPy, CNT-PEDOT, and bare Pt microelectrode. The CNT-CQD-PPy modified microelectrode has a higher conductivity, stability, and sensitivity while achieving a remarkable limit of detection (LOD) of 35.20 ± 0.77 nM. Using fast-scan cyclic voltammetry (FSCV), these modified electrodes successfully measured dopamine's redox peaks while exhibiting consistent and reliable responses over extensive use. This electrode modification not only paves the way for real-time, precise dopamine sensing using microfabricated electrodes but also offers a novel electrochemical sensor for in vivo studies of neural network dynamics and neurological disorders.

How do older adults receiving aged care services understand and respond to the EQ-5D-5L? A think-aloud study in residential care.

PURPOSE: The EQ-5D-5L is a preference-based instrument for measuring and valuing health-related quality of life (HRQoL). The EQ-5D-5L has been used extensively in economic evaluation, including in aged care. However, older adults' understanding of the EQ-5D-5L has not been comprehensively investigated to date. This research aimed to assess older adults' understanding of the EQ-5D-5L using a think-aloud protocol with two cognition groups: no cognitive impairment and mild/moderate cognitive impairment. METHODS: Participants' cognition was assessed using the Standardised Mini-Mental State Examination (SMMSE). Face-to face interviews were conducted with concurrent and retrospective think-aloud encouraged through verbal probing. Audio recordings were transcribed, and qualitative analysis, informed by the Tourangeau four-stage Response Model (comprehension, retrieval, decision process, response process) was conducted in NVivo. RESULTS: In total, 46 older adults (age 65 +) were recruited from 10 residential care facilities across South Australia (n = 25 no cognitive impairment, n = 21 mild/moderate cognitive impairment). Comprehension, retrieval, judgement and response mapping issues were common across all cognition levels and EQ-5D-5L dimensions. The two dimensions resulting in the most response issues were usual activities and personal care. CONCLUSION: Older adults may bring a different understanding to the EQ-5D-5L descriptive system than that expected given testing with general population samples. Dimension descriptors that are more relevant to this population may facilitate responses that better align with the underlying EQ-5D-5L concept model.

Feasibility of self-reported health related quality of life assessment with older people in residential care: insights from the application of eye tracking technology.

PURPOSE: Increasingly there are calls to routinely assess the health-related quality of life (HRQoL) of older people receiving aged care services, however the high prevalence of dementia and cognitive impairment remains a challenge to implementation. Eye-tracking technology facilitates detailed assessment of engagement and comprehension of visual stimuli, and may be useful in flagging individuals and populations who cannot reliably self-complete HRQoL instruments. The aim of this study was to apply eye-tracking technology to provide insights into self-reporting of HRQoL among older people in residential care with and without cognitive impairment. METHODS: Residents (n = 41), recruited based on one of three cognition subgroups (no, mild, or moderate cognitive impairment), completed the EQ-5D-5L on a computer with eye tracking technology embedded. Number and length of fixations (i.e., eye gaze in seconds) for key components of the EQ-5D-5L descriptive system were calculated. RESULTS: For all dimensions, participants with no cognitive impairment fixated for longer on the Area of Interest (AOI) for the response option they finally chose, relative to those with mild or moderate cognitive impairment. Participants with cognitive impairment followed similar fixation patterns to those without. There was some evidence that participants with cognitive impairment took longer to complete and spent relatively less time attending to the relevant AOIs, but these differences did not reach statistical significance generally. CONCLUSIONS: This exploratory study applying eye tracking technology provides novel insights and evidence of the feasibility of self-reported HRQoL assessments in older people in aged care settings where cognitive impairment and dementia are highly prevalent.

Why are neurosurgeons sued? A single-center, half-decade review.

Purpose:The burden of medicolegal claims in neurosurgery is increasing in the UK. Trepidation associated with malpractice claims has the potential to negatively impact surgical practice and patient safety. What are the causes of these claims and can we address them? The aim of this study was to identify the incidence and total burden of litigation claims related to neurosurgery in a London tertiary center.Methods:We retrospectively reviewed all consecutive cases of claims in neurosurgery that were reported to NHSR between March 2013 and April 2018 by St George's Hospital legal department. This was an extension of previous study by Mukherjee et al., who studied the medicolegal claims in our institution in the preceding 9-year period (2004-2013).Results:There were 18 litigation claims against neurosurgery. Claims were reviewed for clinical event, cause, likelihood of pay-out and legal outcome. Eleven claims were settled in court and seven were settled without court proceeding. All claims were spinal cases, 56% emergency admissions. Causes included faulty surgical technique (39%), delayed treatment (33%), delayed diagnosis/misdiagnosis (17%), and lack of information (11%) with a likelihood of financial success of 43%, 67%, 33%, and 100%, respectively. The highest median pay-outs were for lack of information (£2.8 million) and faulty surgical technique (£1 million). When compared to the preceding 9-year period, there a modest reduction in claims per year, despite an increase in workload. Distribution of litigation causes remained similar but overall financial burden was higher.Conclusion:Spinal surgery has the highest malpractice claim risk in neurosurgical practice. Our review shows that faulty surgical technique is the leading cause of neurosurgical claims. Claims against lack of information, although less frequent, resulted in the highest median pay-out. This study reinforces previously published data that good surgical technique and thorough process of informed consent may reduce litigation in neurosurgery.

Splitting event-related potentials: Modeling latent components using regression-based waveform estimation.

Event-related potentials (ERPs) provide a multidimensional and real-time window into neurocognitive processing. The typical Waveform-based Component Structure (WCS) approach to ERPs assesses the modulation pattern of components-systematic, reoccurring voltage fluctuations reflecting specific computational operations-by looking at mean amplitude in predetermined time-windows. This WCS approach, however, often leads to inconsistent results within as well as across studies. It has been argued that at least some inconsistencies may be reconciled by considering spatiotemporal overlap between components; that is, components may overlap in both space and time, and given their additive nature, this means that the WCS may fail to accurately represent its underlying latent component structure (LCS). We employ regression-based ERP (rERP) estimation to extend traditional approaches with an additional layer of analysis, which enables the explicit modeling of the LCS underlying WCS. To demonstrate its utility, we incrementally derive an rERP analysis of a recent study on language comprehension with seemingly inconsistent WCS-derived results. Analysis of the resultant regression models allows one to derive an explanation for the WCS in terms of how relevant regression predictors combine in space and time, and crucially, how individual predictors may be mapped onto unique components in LCS, revealing how these spatiotemporally overlap in the WCS. We conclude that rERP estimation allows for investigating how scalp-recorded voltages derive from the spatiotemporal combination of experimentally manipulated factors. Moreover, when factors can be uniquely mapped onto components, rERPs may offer explanations for seemingly inconsistent ERP waveforms at the level of their underlying latent component structure.

Assessing the relative importance of key quality of life dimensions for people with and without a disability: an empirical ranking comparison study.

BACKGROUND: In economic evaluation, the quality of life of people with a disability has traditionally been assessed using preference-based instruments designed to measure and value quality of life. To provide robust measurement of the effectiveness of programs designed to improve the quality of life of people living with a disability, preference-based measures need to be sufficiently sensitive to detect incremental changes in the quality of life dimensions that are most important to people who have a disability. This study sought to explore whether there was a difference in the ranked order of importance of quality of life dimensions between people with a disability and people without a disability. METHODS: An online survey was developed and administered Australia wide. The first sample (n = 410) comprised adults (aged ≥ 18 years) with a disability (n = 208) and family carers of person/s with a disability who were asked to respond on behalf of the person with a disability (n = 202). The second sample included adults without disability (n = 443). Respondents were asked to rank the importance of 12 quality of life dimensions extracted from the content of established preference-based quality of life measures (EQ-5D, AQoL and ASCOT). RESULTS: People with a disability placed relatively higher importance on broader quality of life dimensions (e.g. Control, Independence, Self-care) relative to health status focused dimensions (e.g. Vision, Hearing, Physical mobility). This distinction was less differentiable for those 'without a disability'. The biggest differences in ranked importance of dimensions were in: Vision ('with disability' = 10th, 'without disability' = 4th), Self-care ('with disability' = 3rd, 'without disability' = 7th) and Mental well-being ('with disability' = 6th, 'without disability' = 2nd). CONCLUSIONS: The relative importance of quality of life dimensions for people with a disability differs to people without a disability. Quality of life is a key outcome for economic evaluation and for assessing the impact of disability care policy and practice in Australia and internationally. It is important that the effectiveness of interventions is measured and valued in ways which are fully reflective of the quality of life preferences of people with a disability.

Event-related potentials index lexical retrieval (N400) and integration (P600) during language comprehension.

The functional interpretation of two salient language-sensitive ERP components - the N400 and the P600 - remains a matter of debate. Prominent alternative accounts link the N400 to processes related to lexical retrieval, semantic integration, or both, while the P600 has been associated with syntactic reanalysis or, alternatively, to semantic integration. The often overlapping predictions of these competing accounts in extant experimental designs, however, has meant that previous findings have failed to clearly decide among them. Here, we present an experiment that directly tests the competing hypotheses using a design that clearly teases apart the retrieval versus integration view of the N400, while also dissociating a syntactic reanalysis/reprocessing account of the P600 from semantic integration. Our findings provide support for an integrated functional interpretation according to which the N400 reflects context-sensitive lexical retrieval - but not integration - processes. While the observed P600 effects were not predicted by any account, we argue that they can be reconciled with the integration view, if spatio-temporal overlap of ERP components is taken into consideration.

Influence of speakers' gaze on situated language comprehension: Evidence from Event-Related Potentials.

Behavioral studies have shown that speaker gaze to objects in a co-present scene can influence listeners' sentence comprehension. To gain deeper insight into the mechanisms involved in gaze processing and integration, we conducted two ERP experiments (N = 30, Age: [18, 32] and [19, 33] respectively). Participants watched a centrally positioned face performing gaze actions aligned to utterances comparing two out of three displayed objects. They were asked to judge whether the sentence was true given the provided scene. We manipulated the second gaze cue to be either Congruent (baseline), Incongruent or Averted (Exp1)/Mutual (Exp2). When speaker gaze is used to form lexical expectations about upcoming referents, we found an attenuated N200 when phonological information confirms these expectations (Congruent). Similarly, we observed attenuated N400 amplitudes when gaze-cued expectations (Congruent) facilitate lexical retrieval. Crucially, only a violation of gaze-cued lexical expectations (Incongruent) leads to a P600 effect, suggesting the necessity to revise the mental representation of the situation. Our results support the hypothesis that gaze is utilized above and beyond simply enhancing a cued object's prominence. Rather, gaze to objects leads to their integration into the mental representation of the situation before they are mentioned.

On the predictability of event boundaries in discourse: An ERP investigation.

When reading a text describing an everyday activity, comprehenders build a model of the situation described that includes prior knowledge of the entities, locations, and sequences of actions that typically occur within the event. Previous work has demonstrated that such knowledge guides the processing of incoming information by making event boundaries more or less expected. In the present ERP study, we investigated whether comprehenders' expectations about event boundaries are influenced by how elaborately common events are described in the context. Participants read short stories in which a common activity (e.g., washing the dishes) was described either in brief or in an elaborate manner. The final sentence contained a target word referring to a more predictable action marking a fine event boundary (e.g., drying) or a less predictable action, marking a coarse event boundary (e.g., jogging). The results revealed a larger N400 effect for coarse event boundaries compared to fine event boundaries, but no interaction with description length. Between 600 and 1000 ms, however, elaborate contexts elicited a larger frontal positivity compared to brief contexts. This effect was largely driven by less predictable targets, marking coarse event boundaries. We interpret the P600 effect as indexing the updating of the situation model at event boundaries, consistent with Event Segmentation Theory (EST). The updating process is more demanding with coarse event boundaries, which presumably require the construction of a new situation model.

Decompressive craniectomy for the treatment of malignant middle cerebral artery infarction.

INTRODUCTION: Malignant middle cerebral artery (MCA) infarction is associated with up to 80% mortality in the first week, despite maximal medical therapy. Decompressive craniectomy (DC) has been shown to improve survival rates in these patients. However, there are concerns that DC prolongs poor quality of life by increasing the number of survivors with major disability. This review will assess if DC in patients with malignant MCA infarction improves functional outcomes compared to maximal medical therapy. It will estimate the optimal time for surgery following stroke onset and ask if DC is effective in older patients (>60 years). METHODS: A literature search was conducted using Medline, Embase, PubMed and the Cochrane Library. Randomised controlled trials and meta-analysis that fulfilled the inclusion criteria and answered the clinical question were evaluated. RESULTS: Twelve papers were identified and considered appropriate to answer the clinical question. These included 8 prospective randomised controlled trials and 4 meta-analysis. A critical review of these papers was conducted. CONCLUSIONS: In patients 60 years of age or younger, DC within 48 hours of stroke onset significantly reduced risk of death and major disability (mRS >3) compared to maximal medical therapy only. In older patients (>60 years) DC also significantly improved survival but the majority of survivors were left with major disability (mRS 4-5). DC performed more than 48 hours after symptom onset does not appear to be superior to best medical management. The decision to perform decompressive surgery needs to be made on a case-by-case basis, taking into account the degree of disability patients and their carers are willing to accept.

Examining interrater agreement between self-report and proxy-report responses for the quality of life-aged care consumers (QOL-ACC) instrument.

BACKGROUND: Quality of life is an important quality indicator for health and aged care sectors. However, self-reporting of quality of life is not always possible given the relatively high prevalence of cognitive impairment amongst older people, hence proxy reporting is often utilised as the default option. Internationally, there is little evidence on the impact of proxy perspective on interrater agreement between self and proxy report. OBJECTIVES: To assess the impacts of (i) cognition level and (ii) proxy perspective on interrater agreement using a utility instrument, the Quality of Life-Aged Care Consumers (QOL-ACC). METHODS: A cross-sectional study was undertaken with aged care residents and family member proxies. Residents completed the self-report QOL-ACC, while proxies completed two proxy versions: proxy-proxy perspective (their own opinion), and proxy-person perspective (how they believe the resident would respond). Interrater agreement was assessed using quadratic weighted kappas for dimension-level data and concordance correlation coefficients and Bland-Altman plots for utility scores. RESULTS: Sixty-three residents (22, no cognitive impairment; 41, mild-to-moderate cognitive impairment) and proxies participated. In the full sample and in the mild-to-moderate impairment group, the mean self-reported QOL-ACC utility score was significantly higher than the means reported by proxies, regardless of perspective (p < 0.01). Agreement with self-reported QOL-ACC utility scores was higher when proxies adopted a proxy-person perspective. CONCLUSION: Regardless of cognition level and proxy perspective, proxies tend to rate quality of life lower than residents. Further research is needed to explore the impact of such divergences for quality assessment and economic evaluation in aged care.

Unravelling the Self-Report Versus Proxy-Report Conundrum for Older Aged Care Residents: Findings from a Mixed-Methods Study.

OBJECTIVES: No guidance currently exists as to the cognition threshold beyond which self-reported quality of life for older people with cognitive impairment and dementia is unreliable. METHODS: Older aged care residents (≥ 65 years) were randomly assigned to complete the EQ-5D-5L in computer-based (eye movements were tracked) or hard copy (participants were encouraged to 'think aloud') format. Cognition was assessed using the Mini-Mental State Examination (MMSE). Think aloud and eye tracking data were analysed by two raters, blinded to MMSE scores. At the participant level, predefined criteria were used to assign traffic light grades (green, amber, red). These grades indicate the extent to which extracted data elements provided evidence of self-report reliability. The MMSE-defined cognition threshold was determined following review of the distributions of assigned traffic light grades. RESULTS: Eighty-one residents participated and provided complete data (38 eye tracking, 43 think aloud). In the think aloud cohort, all participants with an MMSE score ≤ 23 (n = 10) received an amber or red grade, while 64% of participants with an MMSE score ≥ 24 (21 of 33) received green grades. In the eye tracking cohort, 68% of participants with an MMSE score ≥ 24 (15 of 22) received green grades. Of the 16 eye tracking participants with an MMSE score ≤ 23, 14 (88%) received an amber or red grade. CONCLUSIONS: Most older residents with an MMSE score ≥ 24 have sufficient cognitive capacity to self-complete the EQ-5D-5L. More research is needed to better understand self-completion reliability for other quality-of-life instruments in cognitively impaired populations.

The P600 as a continuous index of integration effort.

The integration of word meaning into an unfolding utterance representation is a core operation of incremental language comprehension. There is considerable debate, however, as to which component of the ERP signal-the N400 or the P600-directly reflects integrative processes, with far reaching consequences for the temporal organization and architecture of the comprehension system. Multi-stream models maintaining the N400 as integration crucially rely on the presence of a semantically attractive plausible alternative interpretation to account for the absence of an N400 effect in response to certain semantic anomalies, as reported in previous studies. The single-stream Retrieval-Integration account posits the P600 as an index of integration, further predicting that its amplitude varies continuously with integrative effort. Here, we directly test these competing hypotheses using a context manipulation design in which a semantically attractive alternative is either available or not, and target word plausibility is varied across three levels. An initial self-paced reading study revealed graded reading times for plausibility, suggesting differential integration effort. A subsequent ERP study showed no N400 differences across conditions, and that P600 amplitude is graded for plausibility. These findings are inconsistent with the interpretation of the N400 as an index of integration, as no N400 effect emerged even in the absence of a semantically attractive alternative. By contrast, the link between plausibility, reading times, and P600 amplitude supports the view that the P600 is a continuous index of integration effort. More generally, our results support a single-stream architecture and eschew the need for multi-stream accounts.

A 512-Ch Dual-Mode Microchip for Simultaneous Measurements of Electrophysiological and Neurochemical Activities.

In the study of the brain, large and high-density microelectrode arrays have been widely used to study the behavior of neurotransmission. CMOS technology has facilitated these devices by enabling the integration of high-performance amplifiers directly on-chip. Usually, these large arrays measure only the voltage spikes resulting from action potentials traveling along firing neuronal cells. However, at synapses, communication between neurons occurs by the release of neurotransmitters, which cannot be measured on typical CMOS electrophysiology devices. Development of electrochemical amplifiers has resulted in the measurement of neurotransmitter exocytosis down to the level of a single vesicle. To effectively monitor the complete picture of neurotransmission, measurement of both action potentials and neurotransmitter activity is needed. Current efforts have not resulted in a device that is capable of the simultaneous measurement of action potential and neurotransmitter release at the same spatiotemporal resolution needed for a comprehensive study of neurotransmission. In this paper, we present a true dual-mode CMOS device that fully integrates 256-ch electrophysiology amplifiers and 256-ch electrochemical amplifiers, along with an on-chip 512 electrode microelectrode array capable of simultaneous measurement from all 512 channels.

When a look is enough: Neurophysiological correlates of referential speaker gaze in situated comprehension.

Behavioral studies have shown that speaker gaze to objects in a co-present scene can influence listeners' expectations about how the utterance will unfold. These findings have recently been supported by ERP studies that linked the underlying mechanisms of the integration of speaker gaze with an utterance meaning representation to multiple ERP components. This leads to the question, however, as to whether speaker gaze should be considered part of the communicative signal itself, such that the referential information conveyed by gaze can help listeners not only form expectations but also to confirm referential expectations induced by the prior linguistic context. In the current study, we investigated this question by conducting an ERP experiment (N=24, Age:[19,31]), in which referential expectations were established by linguistic context together with several depicted objects in the scene. Those expectations then could be confirmed by subsequent speaker gaze that preceded the referential expression. Participants were presented with a centrally positioned face performing gaze actions aligned to utterances comparing two out of three displayed objects, with the task to judge whether the sentence was true given the provided scene. We manipulated the gaze cue to be either Present (toward the subsequently named object) or Absent preceding contextually Expected or Unexpected referring nouns. The results provided strong evidence for gaze as being treated as an integral part of the communicative signal: While in the absence of gaze, effects of phonological verification (PMN), word meaning retrieval (N400) and sentence meaning integration/evaluation (P600) were found on the unexpected noun, in the presence of gaze effects of retrieval (N400) and integration/evaluation (P300) were solely found in response to the pre-referent gaze cue when it was directed toward the unexpected referent with attenuated effects on the following referring noun.

Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC. METHODS: Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality. RESULTS: In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+ T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+ B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1-) eomesodermin (EOMES+)) CD8+ T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+ EOMES+) CD8+ T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation. CONCLUSION: Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors. TRIAL REGISTRATION NUMBER: NCT02562898.

Preoperative skin marking and perioperative checks require careful thought: a report of a near miss.

A patient marked preoperatively for ulnar nerve decompression under general anaesthesia was found to have symmetrical operative site markings. The correct skin mark was transferred to the other side by her sleeping position the night before surgery. Skin marking is an adjunct to safe surgery but is not failsafe.

On the nature of semantic constraints on lexical access.

We present two eye-tracking experiments that investigate lexical frequency and semantic context constraints in spoken-word recognition in German. In both experiments, the pivotal words were pairs of nouns overlapping at onset but varying in lexical frequency. In Experiment 1, German listeners showed an expected frequency bias towards high-frequency competitors (e.g., Blume, 'flower') when instructed to click on low-frequency targets (e.g., Bluse, 'blouse'). In Experiment 2, semantically constraining context increased the availability of appropriate low-frequency target words prior to word onset, but did not influence the availability of semantically inappropriate high-frequency competitors at the same time. Immediately after target word onset, however, the activation of high-frequency competitors was reduced in semantically constraining sentences, but still exceeded that of unrelated distractor words significantly. The results suggest that (1) semantic context acts to downgrade activation of inappropriate competitors rather than to exclude them from competition, and (2) semantic context influences spoken-word recognition, over and above anticipation of upcoming referents.