Accelerated cascade melanoma therapy using enzyme-nanozyme-integrated dissolvable polymeric microneedles.

Dissolvable polymeric microneedles (DPMNs) have emerged as a powerful technology for the localized treatment of diseases, such as melanoma. Herein, we fabricated a DPMN patch containing a potent enzyme-nanozyme composite that transforms the upregulated glucose consumption of cancerous cells into lethal reactive oxygen species via a cascade reaction accelerated by endogenous chloride ions and external near-infrared (NIR) irradiation. This was accomplished by combining glucose oxidase (Gox) with a NIR-responsive chloroperoxidase-like copper sulfide (CuS) nanozyme. In contrast with subcutaneous injection, the microneedle system highly localizes the treatment, enhancing nanomedicine uptake by the tumor and reducing its systemic exposure to the kidneys and spleen. NIR irradiation further controls the potency and toxicity of the formulation by thermally disabling Gox. In a mouse melanoma model, this unique combination of photothermal, starvation, and chemodynamic therapies resulted in complete tumor eradication (99.2 ± 0.8 % reduction in tumor volume within 10 d) without producing signs of systemic toxicity. By comparison, other treatment combinations only resulted in a 42-76.5 % reduction in tumor growth. The microneedle patch design is therefore not only highly potent but also with regulated toxicity and improved safety.

Hypnosis and suggestion as interventions for functional neurological disorder: A systematic review.

OBJECTIVE: Functional neurological disorder (FND) involves the presence of neurological symptoms that cannot be explained by neurological disease. FND has long been linked to hypnosis and suggestion, both of which have been used as treatments. Given ongoing interest, this review examined evidence for the efficacy of hypnosis and suggestion as treatment interventions for FND. METHOD: A systematic search of bibliographic databases was conducted to identify group studies published over the last hundred years. No restrictions were placed on study design, language, or clinical setting. Two reviewers independently assessed papers for inclusion, extracted data, and rated study quality. RESULTS: The search identified 35 studies, including 5 randomised controlled trials, 2 non-randomised trials, and 28 pre-post studies. Of 1584 patients receiving either intervention, 1379 (87%) showed significant improvements, including many who demonstrated resolution of their symptoms in the short-term. Given the heterogeneity of interventions and limitations in study quality overall, more formal quantitative synthesis was not possible. CONCLUSIONS: The findings highlight longstanding and ongoing interest in using hypnosis and suggestion as interventions for FND. While the findings appear promising, limitations in the evidence base, reflecting limitations in FND research more broadly, prevent definitive recommendations. Further research seems warranted given these supportive findings.

Using fixed-potential electrodes to quantify iron and manganese redox cycling in upland soils.

Although metal redox reactions in soils can strongly affect carbon mineralization and other important soil processes, little is known about temporal variations in this redox cycling. Recently, potentiostatically poised electrodes (fixed-potential electrodes) have shown promise for measuring the rate of oxidation and reduction at a specific reduction potential in situ in riparian soils. Here for the first time, we used these electrodes in unsaturated soils to explore the fine-scale temporal redox fluctuations of both iron and manganese in response to environmental conditions. We used three-electrode systems with working electrodes fixed at 100 mV (vs. SHE) and 400 mV at 50 cm and 70 cm in the valley floor soil of a headwater watershed. Electrodes fixed at 100 mV to mimic iron oxides and at 400 mV to mimic manganese oxides allowed real-time reduction and oxidation rates to be calculated from temporal variations in the electric current. Electrode measurements were compared to soil porewater chemistry, pCO2, pO2, groundwater level, resistivity measurements, and precipitation. The fixed-potential electrodes recorded fluctuations over timescales from minutes to weeks. A consistently negative current was observed at 100 mV (interpreted as oxidation of Fe), while the 400-mV electrode fluctuated between negative and positive currents (Mn oxidation and reduction). When the water table rose above the electrodes, reduction was promoted, but above the water table, rainfall only stimulated oxidation. Precipitation frequency thus drove the multi-day reduction or oxidation events (return interval of 5-10 days). These measurements represent the first direct detections of frequency, period, and amplitude of oxidation and reduction events in unsaturated soils. Fixed-potential electrodes hold promise for accurately exploring the fast-changing biogeochemical impacts of metal redox cycling in soils and represent a significant advance for reactions that have been difficult to quantify.

Electrophysiological trajectories of concussion recovery: From acute to prolonged stages in late teenagers.

PURPOSE: Numerous studies have reported electrophysiological differences between concussed and non-concussed groups, but few studies have systematically explored recovery trajectories from acute concussion to symptom recovery and the transition from acute concussion to prolonged phases. Questions remain about recovery prognosis and the extent to which symptom resolution coincides with injury resolution. This study therefore investigated the electrophysiological differences in recoveries between simple and complex concussion. METHODS: Student athletes with acute concussion from a previous study (19(2) years old) were tracked from pre-injury baseline, 24-48 hours after concussion, and through in-season recovery. The electroencephalography (EEG) with P300 evoked response trajectories from this acute study were compared to an age-matched population of 71 patients (18(2) years old) with prolonged post-concussive symptoms (PPCS), 61 (SD 31) days after concussion. RESULTS: Acute, return-to-play, and PPCS groups all experienced a significant deficit in P300 amplitude compared to the pre-injury baseline group. The PPCS group, however, had significantly different EEG spectral and coherence patterns from every other group. CONCLUSION: These data suggest that while the evoked response potentials deficits of simple concussion may persist in more prolonged stages, there are certain EEG measures unique to PPCS. These metrics are readily accessible to clinicians and may provide useful parameters to help predict trajectories, characterize injury (phenotype), and track the course of injury.

Editing reality in the brain.

Recent information technologies such as virtual reality (VR) and augmented reality (AR) allow the creation of simulated sensory worlds with which we can interact. Using programming language, digital details can be overlaid onto displays of our environment, confounding what is real and what has been artificially engineered. Natural language, particularly the use of direct verbal suggestion (DVS) in everyday and hypnotic contexts, can also manipulate the meaning and significance of objects and events in ourselves and others. In this review, we focus on how socially rewarding language can construct and influence reality. Language is symbolic, automatic and flexible and can be used to augment bodily sensations e.g. feelings of heaviness in a limb or suggest a colour that is not there. We introduce the term 'suggested reality' (SR) to refer to the important role that language, specifically DVS, plays in constructing, maintaining and manipulating our shared reality. We also propose the term edited reality to encompass the wider influence of information technology and linguistic techniques that results in altered subjective experience and review its use in clinical settings, while acknowledging its limitations. We develop a cognitive model indicating how the brain's central executive structures use our personal and linguistic-based narrative in subjective awareness, arguing for a central role for language in DVS. A better understanding of the characteristics of VR, AR and SR and their applications in everyday life, research and clinical settings can help us to better understand our own reality and how it can be edited.

"You Forget to Apply It to Staff": A Compassion-Focused Group for Mental Health Inpatient Staff. An Exploration of the Barriers to Attendance.

This study explored the feasibility and acceptability of an experiential compassion-focused group intervention for mental health inpatient staff. Findings demonstrated that although participants found sessions enjoyable, and reported a number of benefits, the group attrition was high. Semi-structured interviews were conducted to explore issues related to group dropout. Thematic analysis highlighted overarching systemic challenges to attendance, and five key themes emerged: The Nature of the Ward; Slowing Down Is Not Allowed; It is Not in Our Nature; Guilt & Threat; We Are Not Important. Clinical implications, limitations and practice recommendations to support group attendance are also addressed.

Giving Up on Consciousness as the Ghost in the Machine.

Consciousness as used here, refers to the private, subjective experience of being aware of our perceptions, thoughts, feelings, actions, memories (psychological contents) including the intimate experience of a unified self with the capacity to generate and control actions and psychological contents. This compelling, intuitive consciousness-centric account has, and continues to shape folk and scientific accounts of psychology and human behavior. Over the last 30 years, research from the cognitive neurosciences has challenged this intuitive social construct account when providing a neurocognitive architecture for a human psychology. Growing evidence suggests that the executive functions typically attributed to the experience of consciousness are carried out competently, backstage and outside subjective awareness by a myriad of fast, efficient non-conscious brain systems. While it remains unclear how and where the experience of consciousness is generated in the brain, we suggested that the traditional intuitive explanation that consciousness is causally efficacious is wrong-headed when providing a cognitive neuroscientific account of human psychology. Notwithstanding the compelling 1st-person experience (inside view) that convinces us that subjective awareness is the mental curator of our actions and thoughts, we argue that the best framework for building a scientific account is to be consistent with the biophysical causal dependency of prior neural processes. From a 3rd person perspective, (outside view), we propose that subjective awareness lacking causal influence, is (no more) than our experience of being aware, our awareness of our psychological content, knowing that we are aware, and the belief that that such experiences are evidence of an agentive capacity shared by others. While the human mind can be described as comprising both conscious and nonconscious aspects, both ultimately depend on neural process in the brain. In arguing for the counter-intuitive epiphenomenal perspective, we suggest that a scientific approach considers all mental aspects of mind including consciousness in terms of their underlying, preceding (causal) biological changes, in the realization that most brain processes are not accompanied by any discernible change in subjective awareness.

The neurochemistry of hypnotic suggestion.

A diverse array of studies has been devoted to understanding the neurochemical systems supporting responsiveness to hypnotic suggestions, with implications for experimental and clinical applications of hypnosis. However, this body of research has only rarely been integrated and critically evaluated and the prospects for the reliable pharmacological manipulation of hypnotic suggestibility remain poorly understood. Here we draw on pharmacological, genotyping, neuroimaging, and electrophysiological research to synthesize current knowledge regarding the potential role of multiple widely-studied neurochemicals in response to suggestion. Although we reveal multiple limitations with this body of evidence, we identify converging results implicating different neurochemical systems in response to hypnotic suggestion. We conclude by assessing the extent to which different results align or diverge and outline multiple avenues for future research. Elucidating the neurochemical systems underlying response to suggestion has the potential to significantly advance our understanding of suggestion.

Direct verbal suggestibility: Measurement and significance.

Hypnotic suggestibility is part of the wider psychological trait of direct verbal suggestibility (DVS). Historically, DVS in hypnosis has informed theories of consciousness and of conversion disorder. More recently it has served as a research tool in cognitive science and in cognitive neuroscience in particular. Here we consider DVS as a general trait, its relation to other psychological characteristics and abilities, and to the origin and treatment of clinical conditions. We then outline the distribution of DVS in the population, its measurement, relationship to other forms of suggestibility, placebo responsiveness, personal characteristics, gender, neurological processes and other factors, such as expectancy. There is currently no scale specifically designed to measure DVS outside a hypnotic context. The most commonly used and well-researched of the hypnosis-based scales, the Harvard Group Scale, is described and identified as a basis for a more broadly based measure of DVS for use in psychological research.

Seismic refraction tracks porosity generation and possible CO2 production at depth under a headwater catchment.

In weathered bedrock aquifers, groundwater is stored in pores and fractures that open as rocks are exhumed and minerals interact with meteoric fluids. Little is known about this storage because geochemical and geophysical observations are limited to pits, boreholes, or outcrops or to inferences based on indirect measurements between these sites. We trained a rock physics model to borehole observations in a well-constrained ridge and valley landscape and then interpreted spatial variations in seismic refraction velocities. We discovered that P-wave velocities track where a porosity-generating reaction initiates in shale in three boreholes across the landscape. Specifically, velocities of 2.7 ± 0.2 km/s correspond with growth of porosity from dissolution of chlorite, the most reactive of the abundant minerals in the shale. In addition, sonic velocities are consistent with the presence of gas bubbles beneath the water table under valley and ridge. We attribute this gas largely to CO2 produced by 1) microbial respiration in soils as meteoric waters recharge into the subsurface and 2) the coupled carbonate dissolution and pyrite oxidation at depth in the rock. Bubbles may nucleate below the water table because waters depressurize as they flow from ridge to valley and because pores have dilated as the deep rock has been exhumed by erosion. Many of these observations are likely to also describe the weathering and flow path patterns in other headwater landscapes. Such combined geophysical and geochemical observations will help constrain models predicting flow, storage, and reaction of groundwater in bedrock systems.

Residential churn moderates the relationship between economic deprivation and psychiatric admission: evidence from Wales.

BACKGROUND: There is a well-established link between area-level socioeconomic deprivation and psychiatric admission rates. Social capital has been proposed as a possible protective factor that may buffer economically deprived communities, but it may be disrupted in areas with high population turnover. This study aims to test whether population turnover, hereafter called churn, moderates the social gradient of psychiatric admissions. METHODS: Population churn rates, low income rates and psychiatric admission rates for 1909 lower super output areas in Wales were analysed using Poisson generalised linear mixed-effects models. Additional analyses explored the impact of deprivation measured more generally and the potential confound of population density. RESULTS: Population churn moderated the association between socioeconomic deprivation and psychiatric admission rates, such that greater social gradients in admission rates were found in areas with greater churn. Economic deprivation and churn were also found to be independently positively associated with admission rates. These relationships remained significant when using a broader measure of deprivation and after adjusting for population density. CONCLUSION: High churn appears to exacerbate the detrimental effects of economic deprivation on mental health as well as being a risk factor in its own right. Residential stability rates should be considered when designing and implementing policies which aim to understand, prevent and treat mental health problems in at-risk communities.

In-clinic event related potentials after sports concussion: A 4-year study.

PURPOSE: Electrophysiological event-related potentials (ERP's) have been reported to change after concussion. The objective of this study is to use a simple 2-tone auditory P300 ERP in routine clinical settings to measure changes from baseline after concussion and to determine if these changes persist at return to play when other standard measures have normalized. METHODS: Three-hundred sixty-four (364) student athletes, aged 17-23 years, participating in contact sports were tracked over consecutive years. In this blinded study P300, plus physical reaction times and Trail Making tests, were collected alongside standard clinical evaluations. Changes in these measures after concussion were compared to clinical outcomes over various stages of post-injury recovery. RESULTS: Concussed players experienced significant reaction time and/or P300 amplitude changes compared to pre-concussion baseline measurements (p< 0.005). P300 changes persisted in 38% of the players after standard measures, including reaction times, had cleared. Many of those players slow to normalize were part of the sub-concussive symptom group and/or appeared more prone to repeat concussions. CONCLUSION: These data suggest significant P300 amplitude changes after concussion that are quantifiable and consistent. These changes often normalized slower than other standard assessments. More data are needed to determine if slow normalization relates to sub-concussive or repeated events.

UNITED KINGDOM NORMS FOR THE HARVARD GROUP SCALE OF HYPNOTIC SUSCEPTIBILITY, FORM A.

The Harvard Group Scale of Hypnotic Susceptibility, Form A (HGSHS:A), is widely used as a measure of suggestibility to screen participants for research purposes. To date, there have been a number of normative studies of the HGSHS:A, the majority of which originate from Western countries. The outcomes of these Western studies are summarized, and variations in methodologies are described and discussed. Also reported are the psychometric properties of the HGSHS:A in a large contemporary United Kingdom (UK) sample. Overall, these UK results are consistent with the earlier Western norms studies in terms of response distribution and item difficulty, with only minor differences. The continued use of HGSHS:A as a screening procedure is supported, particularly if corrected for response subjectivity/involuntariness and with revised amnesia scoring. The HGSHS:A is also important as a potential measure of the broader trait of direct verbal suggestibility.

Symbiotic simulation for the operational management of inpatient beds: model development and validation using Δ-method.

In many modern hospitals, resources are shared between patients who require immediate care, and must be dealt with as they arrive (emergency patients), and those whose care requirements are partly known to the hospital some time in advance (elective patients). Catering for these two types of patients is a challenging short-term operational decision-making problem, since some portion of each resource must be set aside for emergency patients when planning for the number and type of elective patients to admit. This paper shows how symbiotic simulation can help hospitals with important short-term operational decision making. We demonstrate how a symbiotic simulation model can be developed from an existing simulation model by adding the ability to load the state of the physical system at run-time and by making use of conditional length-of-stay distributions. The model is parameterised using 18 months of patient administrative data from an Anonymised General Hospital. Further, we propose a new Δ-Method that is suitable for validating a stochastic symbiotic simulation model. We demonstrate the benefit of our symbiotic simulation by showing how it can be used as an early warning system, and how additional patient-level information which might only become available after admission, can affect the predicted bed census.

Detecting and explaining why aquifers occasionally become degraded near hydraulically fractured shale gas wells.

Extensive development of shale gas has generated some concerns about environmental impacts such as the migration of natural gas into water resources. We studied high gas concentrations in waters at a site near Marcellus Shale gas wells to determine the geological explanations and geochemical implications. The local geology may explain why methane has discharged for 7 years into groundwater, a stream, and the atmosphere. Gas may migrate easily near the gas wells in this location where the Marcellus Shale dips significantly, is shallow (∼1 km), and is more fractured. Methane and ethane concentrations in local water wells increased after gas development compared with predrilling concentrations reported in the region. Noble gas and isotopic evidence are consistent with the upward migration of gas from the Marcellus Formation in a free-gas phase. This upflow results in microbially mediated oxidation near the surface. Iron concentrations also increased following the increase of natural gas concentrations in domestic water wells. After several months, both iron and SO42- concentrations dropped. These observations are attributed to iron and SO42- reduction associated with newly elevated concentrations of methane. These temporal trends, as well as data from other areas with reported leaks, document a way to distinguish newly migrated methane from preexisting sources of gas. This study thus documents both geologically risky areas and geochemical signatures of iron and SO42- that could distinguish newly leaked methane from older methane sources in aquifers.

Chasing the Rainbow: The Non-conscious Nature of Being.

Despite the compelling subjective experience of executive self-control, we argue that "consciousness" contains no top-down control processes and that "consciousness" involves no executive, causal, or controlling relationship with any of the familiar psychological processes conventionally attributed to it. In our view, psychological processing and psychological products are not under the control of consciousness. In particular, we argue that all "contents of consciousness" are generated by and within non-conscious brain systems in the form of a continuous self-referential personal narrative that is not directed or influenced in any way by the "experience of consciousness." This continuously updated personal narrative arises from selective "internal broadcasting" of outputs from non-conscious executive systems that have access to all forms of cognitive processing, sensory information, and motor control. The personal narrative provides information for storage in autobiographical memory and is underpinned by constructs of self and agency, also created in non-conscious systems. The experience of consciousness is a passive accompaniment to the non-conscious processes of internal broadcasting and the creation of the personal narrative. In this sense, personal awareness is analogous to the rainbow which accompanies physical processes in the atmosphere but exerts no influence over them. Though it is an end-product created by non-conscious executive systems, the personal narrative serves the powerful evolutionary function of enabling individuals to communicate (externally broadcast) the contents of internal broadcasting. This in turn allows recipients to generate potentially adaptive strategies, such as predicting the behavior of others and underlies the development of social and cultural structures, that promote species survival. Consequently, it is the capacity to communicate to others the contents of the personal narrative that confers an evolutionary advantage-not the experience of consciousness (personal awareness) itself.

Brain mechanisms for loss of awareness of thought and movement.

Loss or reduction of awareness is common in neuropsychiatric disorders and culturally influenced dissociative phenomena but the underlying brain mechanisms are poorly understood. fMRI was combined with suggestions for automatic writing in 18 healthy highly hypnotically suggestible individuals in a within-subjects design to determine whether clinical alterations in awareness of thought and movement can be experimentally modelled and studied independently of illness. Subjective ratings of control, ownership, and awareness of thought and movement, and fMRI data were collected following suggestions for thought insertion and alien control of writing movement, with and without loss of awareness. Subjective ratings confirmed that suggestions were effective. At the neural level, our main findings indicated that loss of awareness for both thought and movement during automatic writing was associated with reduced activation in a predominantly left-sided posterior cortical network including BA 7 (superior parietal lobule and precuneus), and posterior cingulate cortex, involved in self-related processing and awareness of the body in space. Reduced activity in posterior parietal cortices may underlie specific clinical and cultural alterations in awareness of thought and movement. Clinically, these findings may assist development of imaging assessments for loss of awareness of psychological origin, and interventions such as neurofeedback.

Suggestions to Reduce Clinical Fibromyalgia Pain and Experimentally Induced Pain Produce Parallel Effects on Perceived Pain but Divergent Functional MRI-Based Brain Activity.

OBJECTIVE: Hypnotic suggestion is an empirically validated form of pain control; however, the underlying mechanism remains unclear. METHODS: Thirteen fibromyalgia patients received suggestions to alter their clinical pain, and 15 healthy controls received suggestions to alter experimental heat pain. Suggestions were delivered before and after hypnotic induction with blood oxygen level-dependent (BOLD) activity measured concurrently. RESULTS: Across groups, suggestion produced substantial changes in pain report (main effect of suggestion, F2, 312 = 585.8; p < .0001), with marginally larger changes after induction (main effect of induction, F1, 312 = 3.6; p = .060). In patients, BOLD response increased with pain report in regions previously associated with pain, including thalamus and anterior cingulate cortex. In controls, BOLD response decreased with pain report. All changes were greater after induction. Region-of-interest analysis revealed largely linear patient responses with increasing pain report. Control responses, however, were higher after suggestion to increase or decrease pain from baseline. CONCLUSIONS: Based on behavioral report alone, the mechanism of suggestion could be interpreted as largely similar regardless of the induction or type of pain experience. The functional magnetic resonance imaging data, however, demonstrated larger changes in brain activity after induction and a radically different pattern of brain activity for clinical pain compared with experimental pain. These findings imply that induction has an important effect on underlying neural activity mediating the effects of suggestion, and the mechanism of suggestion in patients altering clinical pain differs from that in controls altering experimental pain. Patient responses imply that suggestions altered pain experience via corresponding changes in pain-related brain regions, whereas control responses imply suggestion engaged cognitive control.

The relationship between different types of dissociation and psychosis-like experiences in a non-clinical sample.

This study investigated whether detachment-type dissociation, compartmentalisation-type dissociation or absorption was most strongly associated with psychosis-like experiences in the general population. Healthy participants (N=215) were tested with the Dissociative Experiences Scale (DES, for detachment-related dissociative experiences); the Harvard Group Scale of Hypnotic Susceptibility (HGSHS: A, for dissociative compartmentalisation); the Tellegen Absorption Scale (TAS, for non-clinical 'functional' dissociative experience); and two measures of psychotic-like experiences, the 21-item Peters et al. Delusions Inventory (PDI-21) and the Cardiff Anomalous Perceptions Scale (CAPS). In multiple regression analyses, DES and TAS but not HGSHS: A scores were found to be significantly associated with PDI-21 and CAPS overall scores. A post hoc hierarchical cluster analysis checking for cluster overlap between DES and CAPS items, and the TAS and CAPS items showed no overlap between items on the DES and CAPS and minimal overlap between TAS and CAPS items, suggesting the scales measure statistically distinct phenomena. These results show that detachment-type dissociation and absorption, but not compartmentalisation-type dissociation are significantly associated with psychosis-like experiences in a non-clinical population.