Group-based parent training programme for children with neurological conditions: a feasibility study.

OBJECTIVE AND DESIGN: This study aimed to determine the feasibility and effectiveness of a parent training programme for parents of children with neurological conditions and behaviours that challenge. SETTING: Child and adolescent mental health service within a specialist children's hospital. PARTICIPANTS: Parents of 31 children with neurological conditions and behaviours that challenge. INTERVENTIONS: Parents attended a 6-week evidence-based behavioural parenting programme delivered in a group format, either face-to-face or remote. MAIN OUTCOME MEASURES: Feasibility was determined by attendance rates. Effectiveness was analysed primarily using parent-reported measures of child behaviour (Strengths and Difficulties Questionnaire, Paediatric Quality of Life and Goal-Based Outcomes). Secondary measures of parental well-being were also reported (Brief Parental Self-Efficacy Scale, Depression Anxiety Stress Scale Short Form and Parental Sense of Competence). Paired t-tests or Wilcoxon rank-sum tests were conducted to analyse differences preintervention and postintervention. RESULTS: The attendance rates for the face-to-face and remote groups were 80% and 79%, respectively. Medium to large effect sizes were reported for most measures of child behaviour and parental well-being. There were statistically significant improvements found postintervention in children's behaviour (p=0.014), quality of life (p<0.001), goal-based outcomes (p<0.001), parental self-efficacy (p<0.001) and parental anxiety (p=0.030). Anecdotal feedback showed that parents indicated the group format was acceptable. CONCLUSIONS: The group parenting intervention for parents of children with heterogeneous neurological conditions and behaviours that challenge appears feasible and effective in improving child behaviour and parental well-being.

Applying an Established Exposure Response Prevention Protocol for Young People With Tourette Syndrome in an Intensive, Group Format: A Feasibility Study.

BACKGROUND: The motor and vocal tics that characterise Tourette syndrome are stigmatizing and impact on quality of life. Behavioural interventions such as Exposure Response Prevention or Comprehensive Behavioural Interventions for Tics are first line treatment for Tourette syndrome, but availability is limited. This study is the first to explore the impact of an established manualised Exposure Response Prevention treatment protocol, developed for individual therapy, but here uniquely delivered intensively, to a group. METHODS: A naturalistic study comprised of a consecutive series of children (N = 20), aged 8-16 years (M = 12, SD = 2.17) were offered Exposure Response Prevention in one of two groups, delivered in series within a specialist clinic. Young people received the equivalent of 12 sessions (matching the manualised individual protocol). RESULTS: The YGTSS and Giles de la Tourette Syndrome Quality of Life Scale for Children and Adolescents (Satisfaction Scale) showed significant improvement following treatment with moderate to large effect sizes. Thirty-five percent of children demonstrated a reliable improvement on the YGTSS Global Tic Severity score. CONCLUSIONS: These data suggest an established Exposure Response Prevention protocol can be delivered in an intensive, group setting with a positive clinical outcome. Replication in a randomized controlled trial is an important next step.

Devising a framework of optogenetic coding in the auditory pathway: Insights from auditory midbrain recordings.

Cochlear implants (CIs) restore activity in the deafened auditory system via electrical stimulation of the auditory nerve. As the spread of electric current in biological tissues is rather broad, the spectral information provided by electrical CIs is limited. Optogenetic stimulation of the auditory nerve has been suggested for artificial sound coding with improved spectral selectivity, as light can be conveniently confined in space. Yet, the foundations for optogenetic sound coding strategies remain to be established. Here, we parametrized stimulus-response-relationships of the auditory pathway in gerbils for optogenetic stimulation. Upon activation of the auditory pathway by waveguide-based optogenetic stimulation of the spiral ganglion, we recorded neuronal activity of the auditory midbrain, in which neural representations of spectral, temporal, and intensity information can be found. Screening a wide range of optical stimuli and taking the properties of optical CI emitters into account, we aimed to optimize stimulus paradigms for potent and energy-efficient activation of the auditory pathway. We report that efficient optogenetic coding builds on neural integration of millisecond stimuli built from microsecond light pulses, which optimally accommodate power-efficient laser diode operation. Moreover, we performed an activity-level-dependent comparison of optogenetic and acoustic stimulation in order to estimate the dynamic range and the maximal stimulation intensity amenable to single channel optogenetic sound encoding, and indicate that it complies well with speech comprehension in a typical conversation (65 dB). Our results provide a first framework for the development of coding strategies for future optogenetic hearing restoration.

Monoclonal Antibody Therapy for COVID-19: A Retrospective Observational Study at a Regional Hospital.

BACKGROUND: Monoclonal antibodies represent one option for treatment of COVID-19 early after infection. Although large clinical trials have been successfully conducted, real world data are needed to obtain a realistic assessment of the assumed effect on hospitalization rates. METHODS: For this retrospective, observational study, clinical data were collected in 2021 from outpatients (402) as well as hospitalized patients (350) receiving monoclonal antibodies Bamlanivimab, Casirivimab/Imdevimab or Etesevimab/Bamlanivimab. These data were compared with data from a control group of patients not receiving antibodies because admission to the hospital was too late for this therapy. RESULTS: Both groups showed a comparable spectrum of risk factors. Due to the late hospitalization of control patients, a higher frequency of severe symptoms, such as fever, dyspnea, syncope and lower viral load, were observed. CRP and leukocytes counts were also higher in the untreated group. Most importantly, hospitalization time was significantly shorter and the number of deaths was also lower in the treated group. CONCLUSIONS: Apparently, the application of anti-SARS-CoV-2 antibodies reduced the work load of our hospital as shown by the shorter hospitalization time and lower number of COVID-19-related deaths.

Improved understanding of non-epileptic seizures and reduced emergency health care usage following a single psychoeducational group for children and their parents.

RATIONALE: The aim of this study was to evaluate the effectiveness of a three-hour psychoeducation group in improving understanding of non-epileptic seizures (NES), health outcomes and quality of life in young people with NES. BACKGROUND: Multi-session psychoeducational groups for adults with NES have reported improved psychosocial functioning and reduced NES compared to those who do not receive psychoeducational interventions. To date there have been no studies in young people examining the effects of a single session of psychoeducation. METHOD: 15 young people with NES and their families attended a psychoeducation group within a specialist hospital following a multidisciplinary assessment. The group's effectiveness was evaluated in terms of perceptions of seizure controllability, seizure severity, the management of the condition and health-related quality of life measures. RESULTS: A significant decrease in accident and emergency (A&E) visits and ambulance call outs was observed following the psychoeducation group. Young people additionally reported increased knowledge of NES and ability to cope with the condition which was maintained at 6-week follow-up. Significant reduction in NES occurrence or quality of life was not observed. CONCLUSION: Significant reduction in A&E attendance and ambulance use was found following group psychoeducation and improvements in psychosocial functioning and knowledge about NES. Group psychoeducation has the potential to increase child and parental understanding of NES and reduce inappropriate healthcare usage.

Impact assessment of COVID-19 non-pharmaceutical interventions in long term care facilities in Cyprus: Safety improvement strategy.

The current COVID-19 crisis has changed our everyday lives almost in every aspect. Many people worldwide have died or hospitalised due to the severe impact of COVID-19 on the vulnerable population, and in particular to the elderly residents of long term care facilities (LTCF). The problem is amplified due to the fact that many of those occupants also suffer from comorbidities (e.g. respiratory and cardiovascular diseases, hypertension, etc.) and are therefore regarded as a susceptible host to severe COVID-19 disease. Impacts can be felt in the wider societal safety level. The aim of the present study is, therefore, to present the first National multimodal quality and safety improvement strategy plan for the LTCF in the Republic of Cyprus. The current program focused on the intensification of COVID-19 epidemiological surveillance, the promotion of educational training on best practises in infection control and prevention, and the implementation of additional non-pharmaceutical interventions (NPIs), according to the recommendations of ECDC (European Centre for Disease Prevention and Control) and WHO (World Health Organization). This innovative program fostered the interconnectivity and collaboration among the local authorities, academia and the local leaders of the LTCF. In addition, this program reinforced the importance of volunteerism and active participation of medical students in the National initiatives against the COVID-19 pandemic. The effectiveness of the adopted multimodal advanced care-safety planning program is appraised based on the reported new confirmed COVID-19 cases among LTCF healthcare workers and occupants, after the introducing and implementation of the selected NPIs. This multimodal strategy plan seems to be capable of reducing significantly the number of new cases of COVID-19 infections in LTCF and as a result, to also affect the residents' death number.

Biomechanical analysis of anterior pelvic ring fractures with intact peripelvic soft tissues: a cadaveric study.

PURPOSE: Biomechanical studies of the pelvis are usually performed using dissected pelvic specimens or synthetic bones. Thereby the stabilising effect of the surrounding soft tissues is analysed insufficiently. Biomechanical data for isolated anterior pelvic ring fractures are currently missing. Therefore, the purpose of this study was to develop a novel testing device for biomechanical analyses of the pelvis and to investigate two different anterior pelvic ring fractures in a cadaveric model with intact peripelvic soft tissues. METHODS: A new biomechanical table construction which enables the fixation and testing of complete cadaveric specimens was developed. It was used to investigate the relative motion and stiffness changes due to unilateral osteotomy of the superior and inferior pubic ramus. Five cadavers with a mean age of 55.6 years (± 15.53 years) were included and loaded with a sinusoidal, cyclic (1 Hz), compressive force of up to 365 N over ten cycles for each condition. RESULTS: Biomechanical testing of the pelvis with complete appended soft tissues was feasible. Native stiffness without a pelvic fracture was 64.31 N/mm (± 8.33 N/mm). A standardised unilateral osteotomy of the superior pubic ramus reduced the stiffness under isolated axial load by 2% (63.05 N/mm ± 7.45 N/mm, p = 0.690). Additional osteotomy of the inferior pubic ramus caused a further, statistically not significant, decrease by 5% (59.57 N/mm ± 6.84 N/mm, p = 0.310). CONCLUSIONS: The developed test device was successfully used for biomechanical analyses of the pelvis with intact peripelvic soft tissues. In a first study, isolated unilateral fractures of the anterior pelvic ring showed no relevant biomechanical variation compared to the intact situation under isolated axial load. Only 7% of the measured stiffness was created by both unilateral pubic rami. Therefore, the clinical practice to treat unilateral anterior pelvic ring fractures conservatively is supported by the results of this study.

Autism spectrum disorder in children and young people with non-epileptic seizures.

PURPOSE: Non-epileptic seizures are paroxysmal events which to an observer resemble epileptic seizures. Proposed risk factors incorporate biopsychosocial aspects including factors in the affected individual. Unexpectedly high rates of autism spectrum disorder (ASD) occurred in the clinical population reported here. Although elevated levels of psychiatric co-morbidity are known to be present in patients with NES, ASD has only been previously described in a single case report. METHODS: This case series captures rates of ASD in 59 children and young people who were referred to a specialist paediatric mental health service at Great Ormond Street Hospital, London, UK for assessment and treatment of non-epileptic seizures between 2012 and 2016. RESULTS: 10/59 (16.9%) of the children and young people with non-epileptic seizures also had ASD, with 5/10 (50%) of these undiagnosed with ASD before referral. Children and young people with ASD were significantly more likely to have tics or attention-deficit hyperactivity disorder than those without ASD. CONCLUSION: ASD may be a common co-morbidity in non-epileptic seizures. Careful clinical assessment with consideration of ASD traits is therefore important in the non-epileptic seizures population. It is beneficial to diagnose ASD early as its presence is likely to require a modified approach to assessment and treatment of non-epileptic seizures. Study of the development of non-epileptic seizures in ASD may suggest hypotheses for the pathogenesis of non-epileptic seizures in the wider population.

Alexithymia in children with medically unexplained symptoms: a systematic review.

OBJECTIVE: Adult research investigating the link between alexithymia and medically unexplained symptoms (MUS) has found a significant relationship between increased alexithymia and MUS. This difficulty in expressing emotions is likely to begin in childhood so the objective of this paper is to present a quantitative review of studies focussing on the association between MUS and alexithymia in children. METHODS: Databases were searched with predefined terms relating to alexithymia and MUS in children (0-17 years). Two reviewers independently assessed abstracts, extracted data and undertook quality analyses. Systematic review methods were used in accordance with Cochrane guidelines. RESULTS: Ten studies met the criteria for inclusion in the review. Seven of the eight studies which focused on a comparison between children with MUS and healthy controls, found higher levels of self-reported alexithymia in the children with MUS. However, in the two studies where children were asked to complete tasks that objectively measure alexithymia, significant differences were not found. Results of studies comparing alexithymia in children with MUS and children with medical/psychiatric controls were inconsistent; there was some evidence of increased anxiety and depression in young people with alexithymia and MUS but inconsistency of measures across studies makes drawing conclusions difficult. CONCLUSION: There is preliminary evidence that children with MUS have significantly higher levels of alexithymia than controls based on self-report measures; however, this finding was not replicated in objective tasks of alexithymia. Future studies should include validated tasks that objectively measure emotion recognition abilities and focus on possible mediating factors such as neurodevelopmental and mental health difficulties.

Cognitive-behavioural treatment of functional neurological symptoms (conversion disorder) in children and adolescents: A case series.

AIM: To describe a cognitive-behavioural treatment and clinical outcomes in a series of children with functional neurological symptoms (FNS). METHOD: Thirty-six children with FNS were assessed and of these twenty-two (13 male, 9 female) with a mean age 14.5 years (SD = 2.6, range 6-17 years) completed treatment with cognitive behaviour therapy embedded in routine child and adolescent clinical/systemic practice. Treatment outcomes were measured at baseline and post-intervention on the Child Global Assessment Scale (CGAS), Strengths and Difficulties Questionnaire (SDQ), Goal Based Outcomes (GBO) and Revised Child Anxiety and Depression Scale (RCADS). RESULTS: Scores on the CGAS improved significantly post-intervention (p < 0.001) with 82% of participants showing reliable change. Individualised goals (GBO) also showed clinically meaningful gains. Standard measures of emotional and behavioural symptoms (SDQ and RCADS) did not correlate well with clinical diagnoses, were usually subthreshold at baseline, and did not show significant improvement post-intervention. INTERPRETATION: The outcome of this pilot study suggests that CBT can be effective in the rehabilitation of young patients with FNS. Detection of common comorbid psychiatric disorders was not assisted by use of standardised measures, although most participants were clinically anxious or depressed. More research is needed to understand why children with FNS and their parents may not endorse mental health symptoms on questionnaires, and to further evaluate interventions within randomised controlled trials.

Liraglutide restores chronic ER stress, autophagy impairments and apoptotic signalling in SH-SY5Y cells.

Growing evidence suggests that agonists of glucagon-like peptide (GLP-1) receptor exert neuroprotective and neurorestorative effects across a range of experimental models of neuronal degeneration, and, recently, a pilot clinical trial of Liraglutide in Alzheimer's disease patients showed improvements in cerebral glucose consumption that signifies disease progression. However, the exact underlying mechanism of action remains unclear. Chronic endoplasmic reticulum (ER) stress has recently emerged as a mechanism for neuronal injury, rendering it a potent therapeutic target for acute and chronic neurodegenerative disorders. Here, we investigate the neuroprotective effects of Liraglutide along with the signalling network against prolong ER stress and autophagy impairments induced by the non-competitive inhibitor of sarco/ER Ca2+-ATPase, thapsigargin. We show that Liraglutide modulates the ER stress response and elicits ER proteostasis and autophagy machinery homeostasis in human SH-SY5Y neuroblastoma cell line. These effects correlate with resolution of hyper-activity of the antioxidant Nrf2 factor and restoration of the impaired cell viability and proliferation. Mechanistically, Liraglutide engages Akt and signal transducer and activator of transcription 3 (STAT3) signalling to favour adaptive responses and shift cell fate from apoptosis to survival under chronic stress conditions in SH-SY5Y cells.

Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer's Aß peptide.

Aggregation of amyloid-ß peptide (Aß) is a key event in the pathogenesis of Alzheimer's disease (AD). We investigated the effects of nanoliposomes decorated with the retro-inverso peptide RI-OR2-TAT (Ac-rGffvlkGrrrrqrrkkrGy-NH2) on the aggregation and toxicity of Aß. Remarkably low concentrations of these peptide inhibitor nanoparticles (PINPs) were required to inhibit the formation of Aß oligomers and fibrils in vitro, with 50% inhibition occurring at a molar ratio of ~1:2000 of liposome-bound RI-OR2-TAT to Aß. PINPs also bound to Aß with high affinity (Kd=13.2-50 nM), rescued SHSY-5Y cells from the toxic effect of pre-aggregated Aß, crossed an in vitro blood-brain barrier model (hCMEC/D3 cell monolayer), entered the brains of C57 BL/6 mice, and protected against memory loss in APPSWE transgenic mice in a novel object recognition test. As the most potent aggregation inhibitor that we have tested so far, we propose to develop PINPs as a potential disease-modifying treatment for AD.

Investigation of the absorption of resveratrol oligomers in the Caco-2 cellular model of intestinal absorption.

Resveratrol oligomers are biologically active polyphenols found in wine. No information about the bioavailability of these polyphenols is available. In order to discover if the resveratrol oligomers can pass the intestinal barrier, transport of the dimer ε-viniferin and the tetramer hopeaphenol was studied in the Caco-2 transwell system. A flux through the cell monolayer could neither be observed for ε-viniferin nor for hopeaphenol (apparent permeability coefficient (Papp)<1×10(-6)cms(-1)). In contrast, resveratrol showed a Papp of 11.9×10(-6)cms(-1). Nevertheless, about 16-30% of the oligomers were found in the lysed cellular fraction. This leads to the conclusion that the intestinal absorption rate of the two resveratrol oligomers, ε-viniferin and hopeaphenol, is low and negligible when compared to resveratrol. Therefore, it is unlikely that the oligomers could elicit a systemic biological effect after dietary intake. However, the compounds may act locally on the intestinal epithelium.

Regulatory T cells in allogeneic stem cell transplantation.

Growing evidence suggests that cellular adoptive immunotherapy is becoming an attractive though challenging approach in regulating tumor immunity and alloresponses in clinical transplantation. Naturally arising CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a key component in this regard. Over the last decade, a large body of evidence from preclinical models has demonstrated their crucial role in auto- and tumor immunity and has opened the door to their "first-in-man" clinical application. Initial studies in clinical allogeneic stem cell transplantation are very encouraging and may pave the way for other applications. Further improvements in Treg ex vivo or in vivo expansion technologies will simplify their global clinical application. In this review, we discuss the current knowledge of Treg biology and their potential for cell-based immunotherapy in allogeneic stem cell transplantation.

Recent compounds for immunosuppression and experimental therapies for acute graft-versus-host disease.

Acute graft-versus-host disease (GVHD) is a major source of morbidity and mortality after allogeneic stem cell transplantation. Therapy of established acute GVHD depends heavily on corticosteroids, which have limited efficacy and are considerably toxic. It is still a matter of debate whether there is an alternative therapy to corticosteroids. Second-line treatment for acute GVHD after failure of steroidsis not well substantiated due to the lack of controlled studie This review examines the current treatment for acute GVHD, as well as novel therapeutics, such as cellular approlaches (e.g., adoptive transfer of mesenchymal stem cellt) and , enhancement of regulatory T cells (e.g., photopheresis). These approaches avoid the toxicity of generalized immunosuppression and are likely to play a prominent futurer ole in acute GVHD therapy.

Novel immunosuppression compounds and experimental therapies for chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is a severe complication of allogeneic stem cell transplantation, with a substantial impact on the quality of life and survival, still lacking with regard to an optimal therapeutic strategy. Corticosteroids are considered the standard of care for first-line treatment of chronic GVHD, but only a minority of the patients responds to them durably. Management of steroid-refractory chronic GVHD is not well defined. This review surveys novel treatment strategies, such as therapies that expand regulatory T cells, target B cells or target the processes implicated in fibrosis that may allow more effective control of chronic GVHD in the future. Most therapies are based solely on phase II trials or on retrospective analyses with a wide range of overall responses. Large, well-designed prospective studies are eagerly needed to establish better treatments, as well as valid biomarkers to identify the likelihood of the response to a drug in advance.

The effects of the dopamine agonist rotigotine on hemispatial neglect following stroke.

Hemispatial neglect following right-hemisphere stroke is a common and disabling disorder, for which there is currently no effective pharmacological treatment. Dopamine agonists have been shown to play a role in selective attention and working memory, two core cognitive components of neglect. Here, we investigated whether the dopamine agonist rotigotine would have a beneficial effect on hemispatial neglect in stroke patients. A double-blind, randomized, placebo-controlled ABA design was used, in which each patient was assessed for 20 testing sessions, in three phases: pretreatment (Phase A1), on transdermal rotigotine for 7-11 days (Phase B) and post-treatment (Phase A2), with the exact duration of each phase randomized within limits. Outcome measures included performance on cancellation (visual search), line bisection, visual working memory, selective attention and sustained attention tasks, as well as measures of motor control. Sixteen right-hemisphere stroke patients were recruited, all of whom completed the trial. Performance on the Mesulam shape cancellation task improved significantly while on rotigotine, with the number of targets found on the left side increasing by 12.8% (P = 0.012) on treatment and spatial bias reducing by 8.1% (P = 0.016). This improvement in visual search was associated with an enhancement in selective attention but not on our measures of working memory or sustained attention. The positive effect of rotigotine on visual search was not associated with the degree of preservation of prefrontal cortex and occurred even in patients with significant prefrontal involvement. Rotigotine was not associated with any significant improvement in motor performance. This proof-of-concept study suggests a beneficial role of dopaminergic modulation on visual search and selective attention in patients with hemispatial neglect following stroke.

JAK2V617F allele burden is associated with transformation to myelofibrosis.

The JAK2V617F mutation has emerged in recent years as a diagnostic as well as treatment target in patients with polycythemia vera (PV). We analyzed JAK2V617F allele burden (JAK2(V617F)) in a Jewish population with PV. Results were correlated with disease symptoms and complications. Median JAK2(V617F) was 48% and 54% in patients of Ashkenazi and non-Ashkenazi origin, respectively (p =0.75). Higher JAK2(V617F) was seen in patients with imaging-proven splenomegaly (p =0.01). A correlation between JAK2(V617F) and the weekly hydoxyurea dose needed for disease control was found (p =0.043). In addition, a trend for higher allele burden in patients with longer disease duration (p =0.064) and those treated with cytoreductive drugs other than hydroxyurea (p =0.056) was noted. Higher JAK2(V617F) was seen in patients with transformation to myelofibosis (p =0.0001), but not in patients with vascular complications. JAK2(V617F) may assist in prognostic stratification of patients with PV.

Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations.

Myelodysplastic syndromes (MDS) are often accompanied by autoimmune phenomena. The underlying mechanisms for these associations remain uncertain, although T cell activation seems to be important. Human T-lymphotropic virus (HTLV-1) has been detected in patients with myelodysplastic syndromes, mostly in regions of the world which are endemic for the virus, and where association of HTLV-1 with rheumatological manifestation is not rare. We present here the case of a 58 year old man who presented with cytopenias, leukocytoclastic vasculitis of the skin and glomerulopathy, and was diagnosed as MDS (refractory anemia with excess blasts - RAEB 1). The patient also tested positive for HTLV-1 by PCR. After 8 monthly cycles of 5-azacytidine he achieved a complete hematologic remission. Following treatment, a second PCR for HTLV-1 was carried out and found to be negative. This is the first report in the literature of a HTLV-1-positive MDS with severe autoimmune manifestations, which was treated with the hypomethylating factor 5-azacitidine, achieving cytogenetic remission with concomitant resolution of the autoimmune manifestations, as well as HTLV-1-PCR negativity. HTLV-1-PCR negativity may be due to either immune mediated clearance of the virus, or a potential antiretroviral effect of 5-azacytidine. 5-azacytidine is known for its antiretroviral effects, although there is no proof of its activity against HTLV-1 infection in vivo.