Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis.

INTRODUCTION: Recent advances in understanding the biology of ankylosing spondylitis (AS) using innovative genomic and proteomic approaches offer the opportunity to address current challenges in AS diagnosis and management. Altered expression of genes, microRNAs (miRNAs) or proteins may contribute to immune dysregulation and may play a significant role in the onset and persistence of inflammation in AS. The ability of exosomes to transport miRNAs across cells and alter the phenotype of recipient cells has implicated exosomes in perpetuating inflammation in AS. This study reports the first proteomic and miRNA profiling of plasma-derived exosomes in AS using comprehensive computational biology analysis. METHODS: Plasma samples from patients with AS and healthy controls (HC) were isolated via ultracentrifugation and subjected to extracellular vesicle flow cytometry analysis to characterise exosome surface markers by a multiplex immunocapture assay. Cytokine profiling of plasma-derived exosomes and cell culture supernatants was performed. Next-generation sequencing was used to identify miRNA populations in exosomes enriched from plasma fractions. CD4+ T cells were sorted, and the frequency and proliferation of CD4+ T-cell subsets were analysed after treatment with AS-exosomes using flow cytometry. RESULTS: The expression of exosome marker proteins CD63 and CD81 was elevated in the patients with AS compared with HC (q<0.05). Cytokine profiling in plasma-derived AS-exosomes demonstrated downregulation of interleukin (IL)-8 and IL-10 (q<0.05). AS-exosomes cocultured with HC CD4+ T cells induced significant upregulation of IFNα2 and IL-33 (q<0.05). Exosomes from patients with AS inhibited the proliferation of regulatory T cells (Treg), suggesting a mechanism for chronically activated T cells in this disease. Culture of CD4+ T cells from healthy individuals in the presence of AS-exosomes reduced the proliferation of FOXP3+ Treg cells and decreased the frequency of FOXP3+IRF4+ Treg cells. miRNA sequencing identified 24 differentially expressed miRNAs found in circulating exosomes of patients with AS compared with HC; 22 of which were upregulated and 2 were downregulated. CONCLUSIONS: Individuals with AS have different immunological and genetic profiles, as determined by evaluating the exosomes of these patients. The inhibitory effect of exosomes on Treg in AS suggests a mechanism contributing to chronically activated T cells in this disease.

First-in-human clinical trial of allogeneic, platelet-derived extracellular vesicles as a potential therapeutic for delayed wound healing.

The release of growth factors, cytokines and extracellular matrix modifiers by activated platelets is an important step in the process of healthy wound healing. Extracellular vesicles (EVs) released by activated platelets carry this bioactive cargo in an enriched form, and may therefore represent a potential therapeutic for the treatment of delayed wound healing, such as chronic wounds. While EVs show great promise in regenerative medicine, their production at clinical scale remains a critical challenge and their tolerability in humans is still to be fully established. In this work, we demonstrate that Ligand-based Exosome Affinity Purification (LEAP) chromatography can successfully isolate platelet EVs (pEVs) of clinical grade from activated platelets, which retain the regenerative properties of the parent cell. LEAP-isolated pEVs display the expected biophysical features of EV populations and transport essential proteins in wound healing processes, including insulin growth factor (IGF) and transforming growth factor beta (TGF-ß). In vitro studies show that pEVs induce proliferation and migration of dermal fibroblasts and increase dermal endothelial cells' angiogenic potential, demonstrating their wound healing potential. pEV treatment activates the ERK and Akt signalling pathways within recipient cells. In a first-in-human, double-blind, placebo-controlled, phase I clinical trial of healthy volunteer adults, designed primarily to assess safety in the context of wound healing, we demonstrate that injections of LEAP-purified pEVs in formulation buffer are safe and well tolerated (Plexoval II study, ACTRN12620000944932). As a secondary objective, biological activity in the context of wound healing rate was assessed. In this cohort of healthy participants, in which the wound bed would not be expected to be deficient in the bioactive cargo that pEVs carry, all wounds healed rapidly and completely and no difference in time to wound closure of the treated and untreated wounds was observed at the single dose tested. The outcomes of this study evidence that pEVs manufactured through the LEAP process can be injected safely in humans as a potential wound healing treatment, and warrant further study in clinical trials designed expressly to assess therapeutic efficacy in patients with delayed or disrupted wound healing.

Acceptability and Usability of a Wearable Device for Sleep Health Among English- and Spanish-Speaking Patients in a Safety Net Clinic: Qualitative Analysis.

BACKGROUND: Sleep disorders are common and disproportionately affect marginalized populations. Technology, such as wearable devices, holds the potential to improve sleep quality and reduce sleep disparities, but most devices have not been designed or tested with racially, ethnically, and socioeconomically diverse patients. Inclusion and engagement of diverse patients throughout digital health development and implementation are critical to achieving health equity. OBJECTIVE: This study aims to evaluate the usability and acceptability of a wearable sleep monitoring device-SomnoRing-and its accompanying mobile app among patients treated in a safety net clinic. METHODS: The study team recruited English- and Spanish-speaking patients from a mid-sized pulmonary and sleep medicine practice serving publicly insured patients. Eligibility criteria included initial evaluation of obstructed sleep apnea, which is most appropriate for limited cardiopulmonary testing. Patients with primary insomnia or other suspected sleep disorders were not included. Patients tested the SomnoRing over a 7-night period and participated in a 1-hour semistructured web-based qualitative interview covering perceptions of the device, motivators and barriers to use, and general experiences with digital health tools. The study team used inductive or deductive processes to code interview transcripts, guided by the Technology Acceptance Model. RESULTS: A total of 21 individuals participated in the study. All participants owned a smartphone, almost all (19/21) felt comfortable using their phone, and few already owned a wearable (6/21). Almost all participants wore the SomnoRing for 7 nights and found it comfortable. The following four themes emerged from qualitative data: (1) the SomnoRing was easy to use compared to other wearable devices or traditional home sleep testing alternatives, such as the standard polysomnogram technology for sleep studies; (2) the patient's context and environment, such as family and peer influence, housing status, access to insurance, and device cost affected the overall acceptance of the SomnoRing; (3) clinical champions motivated use in supporting effective onboarding, interpretation of data, and, ongoing technical support; and (4) participants desired more assistance and information to best interpret their own sleep data summarized in the companion app. CONCLUSIONS: Racially, ethnically, and socioeconomically diverse patients with sleep disorders perceived a wearable as useful and acceptable for sleep health. Participants also uncovered external barriers related to the perceived usefulness of the technology, such as housing status, insurance coverage, and clinical support. Future studies should further examine how to best address these barriers so that wearables, such as the SomnoRing, can be successfully implemented in the safety net health setting.

A portfolio analysis of autism research funding in Aotearoa New Zealand 2007-2021.

LAY ABSTRACT: We aimed to document the areas of autism research that have previously been funded in Aotearoa New Zealand. We searched for research grants awarded to autism research in Aotearoa New Zealand between 2007 and 2021. We compared the funding distribution in Aotearoa New Zealand to other countries. We asked people from the autistic community and broader autism community whether they were satisfied with this funding pattern, and whether it aligned with what is important to them and to autistic people. We found that the majority of funding for autism research was awarded to biology research (67%). Members of the autistic and autism communities were dissatisfied with the funding distribution, and expressed a lack of alignment with what is important to them. People from the community indicated that the funding distribution did not address the priorities of autistic people, and that it indicated a lack of engagement with autistic people. Autism research funding needs to reflect the priorities of the autistic and autism communities. Autistic people need to be included in autism research and related funding decisions.

Ensuring Global Access to Cancer Medicines: A Generational Call to Action.

SUMMARY: Essential cancer treatments are not accessible, affordable, or available to patients who need them in many parts of the world. A new Access to Oncology Medicines (ATOM) Coalition, using public-private partnerships, aims to bring essential cancer medicines and diagnostics to patients in low- and lower middle-income countries.

The impact of mobility scooter on occupational participation among older adults in Singapore: an exploratory study.

PURPOSE: With an ageing population, the use of mobility scooters by community-dwelling older adults with mobility limitations has been increasingly prevalent in Singapore. Their experiences in using mobility scooters remain unclear. This study aimed to explore the impact of mobility scooters on occupational performance and engagement among elderly Singaporeans. MATERIALS AND METHODS: Mobility scooter users were recruited via purposive and snowballing sampling. Semi-structured interviews were conducted in English or Mandarin via phone call or face-to-face and audio-recorded with permission. Interviews were transcribed verbatim in their original language and translated to English (when applicable) for thematic analysis. RESULTS: Twelve eligible participants (mean age: 75 years) completed the interviews. They were predominantly female Chinese with 7 receiving training from occupational therapists (OT). Four main themes emerged from the interviews describing their experiences of using mobility scooters: factors of decision-making in getting a mobility scooter, enhanced occupational participation with the use of the mobility scooter, enablers for community participation and barriers to community participation. Despite having barriers, older adults with mobility limitations generally still had positive experiences to continue using mobility scooters to perform occupations in the community. CONCLUSIONS: This study highlights the benefits of mobility scooters in supporting users' occupational performance and engagement in the community. Continual efforts are required from all stakeholders to provide an accessible environment and improve societal attitudes to further support the mobility scooter users.IMPLICATIONS FOR REHABILITATIONMobility scooter users can be deterred from performing their preferred occupations if they had a prior negative encounter and they mainly rely on self-developed coping strategies to overcome possible barriers in the community.Occupational therapists should identify and address the potential barriers when prescribing mobility scooters to older adult users.Occupational therapists should work collaboratively with other key stakeholders, such as external vendors and government agencies, to co-create a universal guideline to support and safeguard mobility scooter users.

Tankyrase represses autoinflammation through the attenuation of TLR2 signaling.

Dysregulation of Toll-like receptor (TLR) signaling contributes to the pathogenesis of autoimmune diseases. Here, we provide genetic evidence that tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, negatively regulates TLR2 signaling. We show that mice lacking tankyrase in myeloid cells developed severe systemic inflammation with high serum inflammatory cytokine levels. We provide mechanistic evidence that tankyrase deficiency resulted in tyrosine phosphorylation and activation of TLR2 and show that phosphorylation of tyrosine 647 within the TIR domain by SRC and SYK kinases was critical for TLR2 stabilization and signaling. Last, we show that the elevated cytokine production and inflammation observed in mice lacking tankyrase in myeloid cells were dependent on the adaptor protein 3BP2, which is required for SRC and SYK activation. These data demonstrate that tankyrase provides a checkpoint on the TLR-mediated innate immune response.

Catalysis-Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D2 Metabolite Methyl Ester.

A concise and stereoselective total synthesis of the clinically relevant tricyclic prostaglandin D2 metabolite (tricyclic-PGDM) methyl ester in racemic form was accomplished in eight steps from a readily available known cyclopentene-diol derivative. The synthesis features a nickel-catalyzed Ueno-Stork-type dicarbofunctionalization to generate two consecutive stereocenters, a palladium-catalyzed carbonylative spirolactonization to build the core oxaspirolactone, and a Z-selective cross-metathesis to introduce the (Z)-3-butenoate side chain, a group challenging to introduce through traditional Wittig protocols and troublesome for the two previous total syntheses. A general Z-selective cross-metathesis protocol to construct (Z)-ß,γ-unsaturated esters was also developed that has broad functional group tolerance and high stereoselectivity. Additionally, our synthesis already accumulated 75 mg of valuable material for an 18 O-tricyclic-PGDM-based assay used in clinical settings for inflammation.

Macrophage migration inhibitory factor drives pathology in a mouse model of spondyloarthritis and is associated with human disease.

Spondyloarthritis (SpA), a type 3 immunity-mediated inflammatory arthritis, is a systemic rheumatic disease that primarily affects the joints, spine, gut, skin, and eyes. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine, yet MIF's pathological role in SpA is unknown. Here, we observed that the expression of MIF and its receptor CD74 is increased in blood and tissues of curdlan (ß-glucan)­treated SKG mice, a mouse model of SpA. We found that neutrophils substantially expanded and produced MIF in curdlan-treated SKG mice and that human neutrophils from SpA patients secreted higher concentrations of MIF compared to healthy individuals. Although genetic deletion of Mif (Mif−/−) substantially suppressed the severity of SpA features, adoptive transfer of inflammatory neutrophils induced SpA pathology in curdlan-treated Mif−/− SKG mice; in contrast, blocking the function of neutrophils with anti­Gr-1 antibody suppressed the curdlan-induced SpA-like phenotype. We also determined that systemic MIF overexpression was sufficient to induce SpA-like clinical features in SKG mice with enhanced type 3 immunity, whereas SKG mice treated with a MIF antagonist prevented or attenuated curdlan-induced SpA manifestations. Mechanistically, we identified that MIF intensifies type 3 immunity by boosting human and mouse T regulatory cell (Treg) acquisition of a TH17 cell­like phenotype, including the up-regulation of interleukin-17 (IL-17) and IL-22 in vitro. Tregs in blood and synovial fluids from SpA patients have a pathologic TH17 phenotype. These results indicate that MIF is a crucial regulator and a potential therapeutic target in type 3 immunity-mediated arthritis.

A Novel 89Zr-labeled DDS Device Utilizing Human IgG Variant (scFv): "Lactosome" Nanoparticle-Based Theranostics for PET Imaging and Targeted Therapy.

"Theranostics," a new concept of medical advances featuring a fusion of therapeutic and diagnostic systems, provides promising prospects in personalized medicine, especially cancer. The theranostics system comprises a novel 89Zr-labeled drug delivery system (DDS), derived from the novel biodegradable polymeric micelle, "Lactosome" nanoparticles conjugated with specific shortened IgG variant, and aims to successfully deliver therapeutically effective molecules, such as the apoptosis-inducing small interfering RNA (siRNA) intracellularly while offering simultaneous tumor visualization via PET imaging. A 27 kDa-human single chain variable fragment (scFv) of IgG to establish clinically applicable PET imaging and theranostics in cancer medicine was fabricated to target mesothelin (MSLN), a 40 kDa-differentiation-related cell surface glycoprotein antigen, which is frequently and highly expressed by malignant tumors. This system coupled with the cell penetrating peptide (CPP)-modified and photosensitizer (e.g., 5, 10, 15, 20-tetrakis (4-aminophenyl) porphyrin (TPP))-loaded Lactosome particles for photochemical internalized (PCI) driven intracellular siRNA delivery and the combination of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) offers a promising nano-theranostic-based cancer therapy via its targeted apoptosis-inducing feature. This review focuses on the combined advances in nanotechnology and material sciences utilizing the "89Zr-labeled CPP and TPP-loaded Lactosome particles" and future directions based on important milestones and recent developments in this platform.

The gut-joint axis in spondyloarthritis: immunological, microbial, and clinical insights.

The strong genetic and clinical overlaps between spondyloarthritis (SpA) and inflammatory bowel disease (IBD) have placed much needed focus on the gut-joint axis of inflammation in SpA, leading to three key hypotheses that attempt to unravel this complex relationship. The arthritogenic peptide hypothesis and the aberrant cellular trafficking hypothesis have been put forth to rationalize the manner by which the innate and adaptive immune systems cooperate and converge during SpA pathogenesis. The bacterial dysbiosis hypothesis discusses how changes in the microbiome lead to architectural and immunological consequences in SpA. These theories are not mutually exclusive, but can provide an explanation as to why subclinical gut inflammation may sometimes precede joint inflammation in SpA patients, thereby implying a causal relationship. Such investigations will be important in informing therapeutic decisions which may be common to both SpA and IBD. However, these hypotheses can also offer insights for a coincident inflammatory relationship between the gut and the joint, particularly when assessing the immunological players involved. Insights from understanding how these systems might affect the gut and joint differently will be equally imperative to address where the therapeutic differences lie between the two diseases. Collectively, this knowledge has practical implications in predicting the likelihood of IBD development in SpA or presence of coincident SpA-IBD, uncovering novel therapeutic targets, and redesigning currently approved treatments. It is evident that a multidisciplinary approach between the rheumatology and gastroenterology fields cannot be ignored, when it comes to the care of SpA patients at risk of IBD or vice versa.

Lactosome-Conjugated siRNA Nanoparticles for Photo-Enhanced Gene Silencing in Cancer Cells.

The A3B-type Lactosome comprised of poly(sarcosine)3-block-poly(l-lactic acid), a biocompatible and biodegradable polymeric nanomicelle, was reported to accumulate in tumors in vivo via the enhanced permeability and retention (EPR) effect. Recently, the cellular uptake of Lactosome particles was enhanced through the incorporation of a cell-penetrating peptide (CPP), L7EB1. However, the ability of Lactosome as a drug delivery carrier has not been established. Herein, we have developed a method to conjugate the A3B-type Lactosome with ATP-binding cassette transporter G2 (ABCG2) siRNA for inducing in vitro apoptosis in the cancer cell lines PANC-1 and NCI-H226. The L7EB1 peptide facilitates the cellular uptake efficiency of Lactosome but does not deliver siRNA into cytosol. To establish the photoinduced cytosolic dispersion of siRNA, a photosensitizer loaded L7EB1-Lactosome was prepared, and the photosensitizer 5,10,15,20-tetra-kis(pentafluorophenyl)porphyrin (TPFPP) showed superiority in photoinduced cytosolic dispersion. We exploited the combined effects of enhanced cellular uptake by L7EB1 and photoinduced endosomal escape by TPFPP to efficiently deliver ABCG2 siRNA into the cytosol for gene silencing. Moreover, the silencing of ABCG2, a protoporphyrin IX (PpIX) transporter, also mediated photoinduced cell death via 5-aminolevulinic acid (ALA)-mediated PpIX accumulated photodynamic therapy (PDT). The synergistic capability of the L7EB1/TPFPP/siRNA-Lactosome complex enabled both gene silencing and PDT.

TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis.

Spondyloarthritis (SpA) represents a family of inflammatory diseases of the spine and peripheral joints. Ankylosing spondylitis (AS) is the prototypic form of SpA in which progressive disease can lead to fusion of the spine. Therapeutically, knowledge of type 3 immunity has translated into the development of IL-23- and IL-17A-blocking antibodies for the treatment of SpA. Despite being able to provide symptomatic control, the current biologics do not prevent the fusion of joints in AS patients. Thus, there is an unmet need for disease-modifying drugs. Genetic studies have linked the Janus kinase TYK2 to AS. TYK2 is a mediator of type 3 immunity through intracellular signaling of IL-23. Here, we describe and characterize a potentially novel small-molecule inhibitor of TYK2 that blocked IL-23 signaling in vitro and inhibited disease progression in animal models of SpA. The effect of the inhibitor appears to be TYK2 specific, using TYK2-inactive mice, which further revealed a duality in the induction of IL-17A and IL-22 by IL-23. Specifically, IL-22 production was TYK2/JAK2/STAT3 dependent, while IL-17A was mostly JAK2 dependent. Finally, we examined the effects of AS-associated TYK2 SNPs on TYK2 expression and function and correlated them with AS disease progression. This work provides evidence that TYK2 inhibitors have great potential as an orally delivered therapeutic for SpA.

Altered Cytotoxicity Profile of CD8+ T Cells in Ankylosing Spondylitis.

OBJECTIVE: Ankylosing spondylitis (AS) is an inflammatory arthritis in which men have a higher risk of developing progressive axial disease than women. Transcriptomic studies have shown reduced expression of cytotoxic cell genes in the blood of AS patients. HLA-B27 contributes the greatest risk for AS, suggesting a role for CD8+ T cells. This study was undertaken to profile AS patient cytotoxic cells with the hypothesis that an alteration in CD8+ T cells might explain the aberrant cytotoxic profile observed in patients. METHODS: Whole blood was examined for GZM and PRF1 gene expression by quantitative polymerase chain reaction. Serum and synovial fluid (SF) were examined for granzyme and perforin 1 expression by bead array, and blood and SF mononuclear cells were examined for granzyme and perforin 1 expression by fluorescence-activated cell sorting (FACS). RESULTS: GZM and PRF1 gene expression were both reduced in AS patients compared to healthy controls, especially in men. Perforin 1, but not granzyme, protein levels were reduced in AS patient serum. Granzymes were elevated in AS SF, but not in rheumatoid arthritis or osteoarthritis SF. FACS revealed a reduction in granzyme-positive and perforin 1-positive lymphocytes, but not an intrinsic defect in CD8+ T cell granzyme or perforin 1 production. CD8+ T cell frequency was reduced in the blood and increased in the SF of AS patients. CONCLUSION: Our findings indicate that AS patients have an altered cytotoxic T cell profile. These data suggest that CD8+ T cells with a cytotoxic phenotype are recruited to the joints, where they exhibit an activated phenotype. Thus, a central role for CD8+ T cells in AS may have been overlooked and deserves further study.

A Multidisciplinary Evaluation of Barriers to Enrolling Cancer Patients into Early Phase Clinical Trials: Challenges and Patient-centric Recommendations.

Introduction: Early phase clinical trials are the first clinical research step to bringing new cancer therapeutics to patients. At this stage, a new drug's safety, dosing, and scheduling profiles are established as the main endpoints. However, excellent responses due to biomarker-guided and immune checkpoint trials in early phase have resulted in direct approvals of new anti-cancer drugs. Despite doubling of the success rate of new drug approvals, many barriers exist to expeditiously bring active new drugs to the clinic. Areas covered: This review covers roles of members of the early phase program and the challenges they face in enrolling advanced cancer patients to trials. Practical solutions are provided from the perspective of the investigators, regulatory, investigational pharmacy, research nurses, clinical research coordinators, budgets, contracts, and data management. Expert opinion: We are witnessing a burgeoning era in drug development with rapid approval of efficacious drugs. This is achieved by a strong collaboration between investigators, academic institutions, pharmaceutical sponsors, scientists, Food and Drug Administration (FDA), and community practices. Herein, we discuss some of the challenges faced by early phase clinical trials programs and discuss methods of improvement.

Use of respiratory rates and heart rate variability in the assessment and treatment of children and adolescents with functional somatic symptoms.

Functional somatic symptoms (FSS) emerge when the stress system is activated in response to physical or emotional stress that is either chronic or especially intense. In such cases, the heightened state of physiological arousal and motor activation can be measured through biological markers. Our team have integrated the use of biological markers of body state - respiratory rate, heart rate (HR) and heart rate variability (HRV) measurements - as a way of helping families to understand how physical symptoms can signal activation of the body's stress systems. This study measured respiratory rates, HR and HRV in children and adolescents with FSS (and healthy controls) during baseline assessment to determine whether these biological markers were effective at differentiating patients with FSS. The study also implemented a biofeedback intervention during the assessment to determine whether patients with FSS were able to slow their respiratory rates and increase HRV. Patients with FSS had faster respiratory rates, faster HR, and lower HRV, suggesting activation of the autonomic nervous system coupled with activation of the respiratory motor system. Like controls, patients were able to slow their respiratory rates, but in contrast to controls, they were unable to increase their HRV. Our findings suggest that patients with FSS present in a state of physiological activation and struggle to regulate their body state. Patients with FSS are likely to need ongoing training and practice to regulate body state coupled with interventions that target regulatory capacity across multiple systems.

Psychogenic non-epileptic seizures in children and adolescents: Part I - Diagnostic formulations.

Psychogenic non-epileptic seizures (PNES) are a nonspecific, umbrella category that is used to collect together a range of atypical neurophysiological responses to emotional distress, physiological stressors and danger. Because PNES mimic epileptic seizures, children and adolescents with PNES usually present to neurologists or to epilepsy monitoring units. After a comprehensive neurological evaluation and a diagnosis of PNES, the patient is referred to mental health services for treatment. This study documents the diagnostic formulations - the clinical formulations about the probable neurophysiological mechanisms - that were constructed for 60 consecutive children and adolescents with PNES who were referred to our Mind-Body Rehabilitation Programme for treatment. As a heuristic framework, we used a contemporary reworking of Janet's dissociation model: PNES occur in the context of a destabilized neural system and reflect a release of prewired motor programmes following a functional failure in cognitive-emotional executive control circuitry. Using this framework, we clustered the 60 patients into six different subgroups: (1) dissociative PNES (23/60; 38%), (2) dissociative PNES triggered by hyperventilation (32/60; 53%), (3) innate defence responses presenting as PNES (6/60; 10%), (4) PNES triggered by vocal cord adduction (1/60; 2%), (5) PNES triggered by activation of the valsalva manoeuvre (1/60; 1.5%) and (6) PNES triggered by reflex activation of the vagus (2/60; 3%). As described in the companion article, these diagnostic formulations were used, in turn, both to inform the explanations of PNES that we gave to families and to design clinical interventions for helping the children and adolescents gain control of their PNES.

Psychogenic non-epileptic seizures in children and adolescents: Part II - explanations to families, treatment, and group outcomes.

Psychogenic non-epileptic seizures (PNES) - time-limited disturbances of consciousness and motor-sensory control, not accompanied by ictal activity on electroencephalogram (EEG) - are best conceptualized as atypical neurophysiological responses to emotional distress, physiological stressors and danger. Patients and families find the diagnosis of PNES difficult to understand; the transition from neurology (where the diagnosis is made) to mental health services (to which patients are referred for treatment) can be a bumpy one. This study reports how diagnostic formulations constructed for 60 consecutive children and adolescents with PNES were used to inform both the explanations about PNES that were given to them and their families and the clinical interventions that were used to help patients gain control over PNES. Families were able to accept the diagnosis of PNES and engage in treatment when it was explained how emotional distress, illness and states of high arousal could activate atypical defence responses in the body and brain - with PNES being an unwanted by-product of this process. Patients and their families made good use of therapeutic interventions. A total of 75% of children/adolescents (45/60) regained normal function and attained full-time return to school. Global Assessment of Functioning scores increased from 41 to 67 ( t(54) = 10.09; p < .001). Outcomes were less favourable in children/adolescents who presented with chronic PNES and in those with a chronic, comorbid mental health disorder that failed to resolve with treatment. The study highlights that prompt diagnosis, followed by prompt multidisciplinary assessment, engagement, and treatment, achieves improved outcomes in children/adolescents with PNES.