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The neural process of contextual integration has been examined through the phenomenology of semantic incongruence of words. The present study investigated whether the effort of contextual integration would be heightened by the increased demand of selective attention and attention orientation to unfamiliar Chinese stroke style and sequence. It also examined whether visual imagery of unfamiliar stroke style and sequence would mitigate the effort of contextual integration of unfamiliar Chinese stroke. Nineteen participants take part in two cognitive tasks: (a) imagery of Chinese strokes and (b) detection of Chinese familiar and unfamiliar stroke style. An electroencephalogram was concurrently recorded for the analysis of event-related potential (ERP). Results revealed significant differences in attention orientation and effort of contextual integration between familiar and unfamiliar Chinese strokes, as indicated by larger amplitudes of N160 (100–200 ms) & P200 (260–380 ms) components. Furthermore, a larger amplitude of N400 (300–500 ms) component, signifying the neural process of integrating external from the context, was obtained when individuals viewed unfamiliar Chinese strokes. These findings suggest a cognitive effort was needed to process unfamiliar Chinese stimuli, followed by a greater mental effort required for contextual integration of the unfamiliar stimuli. Furthermore, top-down control of visual imagery would facilitate the process of contextual integration via generating internal representation. This finding provides a new insight that the effort expended in contextual integration may be associated with both attentional control and the generation of internal representation from long-term storage across visual stimuli with varying levels of stimulus familiarity. In summary, our study provided insights into the cognitive mechanisms underlying attentional control, contextual integration, and the role of visual imagery in the processing of stimuli with different levels of familiarity. Furthermore, it suggested the potential utility of the N400 component as a biomarker for assessing attention control and memory retrieval functions.

في هذا الكتاب المذهل سر الثراء الجزء الثالث قام كلا من سونيل تولسياني وبراين تريسي بجمع قادة اليوم القادمين من جميع أنحاء العالم للكشف عن إستراتيجياتهم المتطورة لمساعدتك على أن تصبح ثريا بشكل كبير. داخل هذه الصفحات، ستجد تقنيات وأدوات لتغيير الحياة لتحقيق أحلامك. سواء كنت تريد أن تصبح رائد أعمال ومليونير فائق الثروة، أو تشتري العقارات دون استخدام أموالك الخاصة، أو تتقاعد ثريا في سن أصغر، أو تقوم بجذب عملائك ذوي الدخل المرتفع، أو إعداد نفسك لتربح مبالغ ضخمة من الدخل السلبي، فهذا الكتاب مناسب لك تماما.

No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients. This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450. Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2–16·8). Median progression-free survival was 3·0 months (95% CI 2·8–4·1) in the nivolumab group versus 1·8 months (1·4–2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53–0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5–12·1) in the nivolumab group versus 6·9 months (5·0–8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52–0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group. Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy. Stand up to Cancer–Cancer Research UK and Bristol Myers Squibb.

Research has shown that people with chronic pain have difficulty directing their attention away from pain. A mental strategy that incorporates focused attention and distraction has been found to modulate the perception of pain intensity. That strategy involves placing attention on the nociceptive stimulus felt and shifting attention to a self-generated sub-nociceptive image and rehearsing it. Event-related potential was used to study the possible processes associated with the focus-then-orient strategy. Eighteen pain-free participants received different levels of 50-ms nociceptive stimulations elicited by electric shocks at the right lateral malleolus (ankle). In perception trials, participants maintained the perceived nociceptive stimulus in working memory for 3,000 ms. In imagery trials, participants mentally generated and maintained the corresponding sub-nociceptive image they had learned previously. After both types of trials, participants evaluated the pain intensity of the incoming stimulus by recalling the feeling of the nociceptive stimulation at the beginning of the trial. Shifting attention from the incoming nociceptive to a self-generated sub-nociceptive image elicited central P2 and centro-parietal P3 waves, which were found to correlate with proportional scores on the Stroop Test. They were followed by a frontal N400 and a parietal P600, denoting generation of sub-nociceptive images in working memory. The voltages elicited in these potentials correlated moderately with attenuation of the pain ratings of the recalled nociceptive stimulations. Focus-and-orient attention across nociceptive and sub-nociceptive images appears to be related to response inhibition. Mental rehearsal of the sub-nociceptive images was found to modulate the perception of the nociceptive sensation felt prior to the imagery. Such modulation seems to be mediated by generating and maintaining sub-nociceptive images in working memory. Future studies should explore the mental processes associated with orienting attention for pain modulation among people with pathological pain and frontal lobe dysfunction.

Background: The effectiveness of the Patient Empowerment Program (PEP) has been demonstrated in people with diabetes mellitus (DM); however, the underlying reasons for its effectiveness remain unclear. To improve effectiveness, we need to study the psychological mechanism(s) of PEP to understand why it is effective. This study hypothesized that the Theory of Planned Behavior (TPB), modified specifically for people with DM, could describe the mechanism explaining PEP effects. Methods: A longitudinal design was used. Patients with type 2 DM (n = 365; 151 males; mean age = 62.9 ± 9.6 years) received two education sessions (i.e. seminars delivered by registered nurses to provide disease-specific knowledge), and some (n = 210) further enrolled afterwards in five empowerment sessions (i.e. small-group interactive workshops conducted by social workers to practice action planning, problem solving, and experience sharing). Validated questionnaires were used to measure risk perception, health literacy, attitude, subjective norm, perceived behavioral control and behavioral intention on diabetes self-care behaviors, and four diabetes self-care behaviors (diet control, exercise, blood glucose monitoring, and foot care) at baseline. Three months later (i.e. at the end of PEP), all participants completed the behavioral intention and diabetes self-care behaviors measures again. Attitude, subjective norm, perceived behavioral control, behavioral intention, and diabetes self-care behaviors were assessed to represent the TPB constructs. Risk perception and health literacy elements relevant to people with DM were assessed and added to modify the TPB. Results: The behavioral intention was associated with three diabetes self-care behaviors: exercise, blood glucose monitoring, and foot care. The behavioral intention was found to be a significant mediator in the following relationships: empowerment session participation and exercise (β = 0.045, p = 0.04), and empowerment session participation and foot care (β = 0.099, p < 0.001). Conclusions: The effects of enrollment of empowerment sessions in PEP on exercise and foot care were likely to be mediated through behavioral intention.

BACKGROUND: Chronic discogenic pain includes degeneration-driven changes under the mechanical macroenvironment of an internal disc, which leads to the progressive changes of biochemical microenvironment that induce abnormal ingrowth of the nociceptor. The propriety of the animal model reflecting the pathologic natural history has not been assessed. OBJECTIVES: This study investigated the biochemical evidence of chronic discogenic pain by employing a discogenic pain animal model induced by shear force. STUDY DESIGN: Animal study utilizing rats in vivo model of a shear force device. METHODS: Fifteen rats were divided into 3 groups (n = 5/group) according to the period for which sustained dorsoventral shear force was applied (1 week or 2 weeks); the control group received the spinous attachment unit, without a spring. Pain data were collected using von Frey hairs on the hind paws. Growth factor and cytokine abundance was analyzed in the dorsal root ganglion (DRG) and plasma. RESULTS: After the shear force devices were installed, the significant variables were found to markedly increase in the DRG tissues of the 2-week group; however, they were not altered in the 1-week group. Specifically, interleukin (IL)-6, neurogrowth factor (NGF), transforming growth factor (TGF)-alpha, platelet-derived growth factor (PDGF)-beta, and vascular endothelial growth factor (VEGF) were increased. Meanwhile, the plasma levels of tumor necrosis factor-alpha, IL-1beta, IL-5, IL-6, IL-12, and NGF were increased in the 1-week group; whereas, TGF-alpha, PDGF-beta, and VEGF were increased in the 2-week group. LIMITATIONS: The limitations include the general limitations of quadrupedal animals, the poor precision and flexural deformation of shear force devices, inaccuracies regarding the evaluation of histological denaturation, and short intervention and observational periods. CONCLUSIONS: This animal model effectively generated biochemical responses to shear loading with evidence of neurological changes induced without direct macrodamage to the outer annulus fibrosus. Chemical internals were induced by mechanical externals among the contributing factors of chronic discogenic pain. KEY WORDS: Discogenic pain, dorsal root ganglion, intervertebral discs, low back pain, shear force, interleukin, growth factor, animal model

Leveraging adaptive tumour immunity to control mesothelioma via immune checkpoint blockade is now a standard therapeutic approach. However, the determinants of sensitivity remain elusive. Low non-synonymous mutation burden and programmed death-ligand 1 expression, an abundance of immunosuppressive immune cell infiltration, and 9p21 deletion should all mitigate responses to therapy. To address this knowledge gap, we conducted a double blind, placebo-controlled, randomized phase III trial of the PD1 inhibitor, nivolumab (ClinicalTrial.gov registration: NCT03063450). After 37.2 months of follow-up, the primary endpoint of progression free-survival, but not overall survival was met. The nivolumab response rate was 10.3%, and related grade 3 or above adverse events occurred in 20.4% versus 7.2% for placebo. Progression-free and overall survival were longer in nivolumab-treated responders versus non-responders. In an exploratory multiomic analysis, blinded whole exome, transcriptome and multiplex immune profiling were used to interrogate R- versus NR-subgroups. Non-synonymous and neoantigen mutation burden were no different between groups, however R-mesotheliomas were infiltrated with activated CD8 + T- and CD19 + B-lymphocytes, organised into tertiary lymphoid structures. B-cell infiltration correlated with pro-inflammatory chemokines including IL24 and CCL19. Conversely, epithelial-mesenchymal transition and mitosis were associated with resistance to nivolumab. These findings illuminate features which can be leveraged to advance precision immunotherapy in this rare cancer setting. The sensitivity of mesothelioma to the treatment of immune checkpoint blockade remains elusive. Here this group reports a double blind, placebo-controlled, randomized phase III trial of PD1 inhibitor (Nivolumab) on 332 patients with relapsed mesothelioma, and to uncover determinants of efficacy.

Shifting between one's external and internal environments involves orienting attention. Studies on differentiating subprocesses associated with external-to-internal orienting attention are limited. This study aimed to reveal the characteristics of the disengagement, shifting and reengagement subprocesses by using somatosensory external stimuli and internally generated images. Study participants were to perceive nociceptive external stimuli (External Low (E ) or External High (E )) induced by electrical stimulations (50 ms) followed by mentally rehearsing learned subnociceptive images (Internal Low (I ) and Internal High (I )). Behavioral responses and EEG signals of the participants were recorded. The three significant components elicited were: fronto-central negativity (FCN; 128-180 ms), fronto-central P2 (200-260 ms), and central P3 (320-380 ms), which reflected the three subprocesses, respectively. Differences in the FCN and P2 amplitudes during the orienting to the subnociceptive images revealed only in the E but not E stimulus condition that are new findings. The results indicated that modulations of the disengagement and shifting processes only happened if the external nociceptive stimuli were of high salience and the external-to-internal incongruence was large. The reengaging process reflected from the amplitude of P3 correlated significantly with attenuation of the pain intensity felt from the external nociceptive stimuli. These findings suggested that the subprocesses underlying external-to-internal orienting attention serve different roles. Disengagement subprocess tends to be stimulus dependent, which is bottom-up in nature. Shifting and reengagement tend to be top-down subprocesses, which taps on cognitive control. This subprocess may account for the attenuation effects on perceived pain intensity after orienting attention.

This paper presents a resolution-reconfigurable wide-range resistive sensor readout interface for wireless multi-gas monitoring applications that displays results on a smartphone. Three types of sensing resolutions were selected to minimize processing power consumption, and a dual-mode front-end structure was proposed to support the detection of a variety of hazardous gases with wide range of characteristic resistance. The readout integrated circuit (ROIC) was fabricated in a 0.18 μm CMOS process to provide three reconfigurable data conversions that correspond to a low-power resistance-to-digital converter (RDC), a 12-bit successive approximation register (SAR) analog-to-digital converter (ADC), and a 16-bit delta-sigma modulator. For functional feasibility, a wireless sensor system prototype that included in-house microelectromechanical (MEMS) sensing devices and commercial device products was manufactured and experimentally verified to detect a variety of hazardous gases.