A rapid spread of different strains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented pandemic. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the medical body has encountered major obstacles concerning disease management at different levels. Even though patients infected with this virus mainly present with respiratory symptoms, it has been associated with a plethora of well-documented cutaneous manifestations in the literature. However, little investigations have been conducted concerning COVID-19 and its impact on skin disorders mediated by type 2 inflammation leaving multiple dermatologists and other specialists perplexed by the lack of clinical guidelines or pathways. This review focuses on the effects of this pandemic in patients with skin disorders mediated by type 2 inflammation, specifically atopic dermatitis and chronic spontaneous urticaria. In addition, it will provide clinicians a guide on treatment and vaccination considerations for this stated set of patients. Given the rapid spread of the SARS-CoV-2 worldwide, multiple nations adopted a lockdown policy limiting all types of activities including healthcare services. Therefore, this incurred alternative approaches to maintain continuity of care including increasing use of teledermatology and home-based treatments . This waThe aim of this review is to highlight the impact of COVID-19 on patients with atopic dermatitis and chronic urticaria as well as provide clinicians with a guide on navigating these patients regarding treatment and vaccinations throughout the pandemic.Atopic dermatitis (AD) is a complex disease caused by the interplay of genes, immune system and the environment. It typically develops during infancy or childhood and is characterized by intense pruritus and a chronic or chronically relapsing dermatosis. Management of AD may be quite challenging and requires adequate continuity of care, especially in the older age group , 5.Literature and real-world experience have indicated that COVID-19 poses a great risk on patients with comorbidities including patients with atopic dermatitis . This isThe exaggerated immune innate and impaired adaptive immune inflammatory responses causing a cytokine storm have been postulated as a potential mechanism/s by which SARS-CoV-2 causes severe illness . Given tThe lockdown measures put in place during this critical COVID-19 pandemic has markedly decreased clinical activities in dermatology clinics and limited access to care by patients. However, it also gave health care professionals a window of opportunity in the field of teledermatology (web- and phone- counseling) which has significantly surged during the pandemic , 15. ThiTo minimize AD flares, the American Academy of Dermatology (AAD) and the European Task Force on Atopic Dermatitis (ETFAD) advocated reinforcing proper skin care regimens. These include the use of fragrance-free soap with warm water for hand washing followed directly by the application of moisturizer. If soap is unavailable, patients with AD should be instructed to use hand sanitizers devoid of sensitizing ingredients to minimize the risk of developing allergic contact dermatitis. Concerning face masks, cotton-woven face cloths are preferred over other potentially irritating face masks. Frequent laundering of these face cloths is recommended though studies on the optimal frequency of washing and the precise make of the fabric are currently lacking and will require additional studies , 3.Treatment of AD may be complex and necessitate the employment of immune-modulating therapies. Such therapies may be of concern if initiated in the setting of SARS-CoV-2 given the dysfunctional and/or exaggerated immune response seen with this infection . Additiovia SECURE-AD (Surveillance Epidemiology of Coronavirus Under Research Exclusion—Atopic Dermatitis) (www.covidderm.org). It is a web-based registry for clinicians to report COVID-19 outcomes in atopic dermatitis patients  is an autoimmune/autoallergic condition with a fluctuating course and may be difficult to control. It is characterized by the appearance of recurrent evanescent wheals lasting for more than 6 weeks and variable degree of pruritus. During the COVID-19 pandemic, several case reports, and series have been published on acute urticaria as a cutaneous manifestation of the SARS-CoV-2 infection . A thirdvia training at the second dose which includes an action plan in the event of anaphylaxis (Similar to patient with AD, patients with CSU reported great satisfaction with teledermatology , 25. Thephylaxis , 36. AddThe literature is scarce regarding SARS-CoV-2 vaccination in patients with CSU. On one hand, a small case series reported flares of CSU induced by the mRNA vaccine . Most ofmodus operandi. Current evidence indicates that patients with underlying skin allergies may be treated nearly like the general population. Special considerations should however be applied. These include modifying immune-modulating therapies and vaccination considerations. This sanitary emergency has also permitted the implementations of teledermatology on a large scale. Such a consultative platform is now widely accepted by patients with AD or CSU and provides continuity of care to these patients. The general recommendations published thus far and reviewed in this paper are largely derived from expert opinions and lack robust evidence for final recommendations. A collective worldwide effort is mandatory and is underway to obtain data from web-registries and design the appropriate management strategies needed in patients with skin allergies during this unabating pandemic.The COVID-19 pandemic has largely affected clinicians' and patients' daily practices forcing both groups to quickly adapt to a new model of


Users can also provide novel sequences (unavailable in public databases) for analysis. MSALigMap is written in Python. There are several tools and servers available for comparing and mapping active-site amino-acid residues among protein structures. However, there has not previously been a tool for mapping ligand binding amino-acid residues onto protein sequences of interest. Using MSALigMap, users can compare multiple protein sequences, such as those from different organisms or clinical strains, with sequences of proteins with crystal structures in PDB that are bound with the ligand/drug and DNA of interest. This allows users to easily map the binding residues and to predict the consequences of different mutations observed in the binding site. The MSALigMap server can be accessed at  Recently, genome and mRNA sequencing revealed the possibility to identify a large number of genes and transcripts ,2. As seTranscription factors are important for genetic regulation in all organisms and recognize sequence-specific regions in DNA called transcription factor binding sites (TFBSs). Through this type of interaction, transcription factors regulate (induce or repress) the expression of their target genes . AnnotatIdentifying binding sites is essential to achieving an understanding of catalytic reactions and to the classification of enzyme proteins involved in various biological processes. The number of 3D protein structures deposited in RCSB Protein Data Bank (PDB) ,13 has gMany excellent tools have been developed for this purpose; however, they have the limitations that they can be only used for comparing individual sequences against structural data. FeatureMap3D, a web-based tool, allows protein features to be mapped onto protein structures separately for each sequence submitted . Many sthttps://albiorix.bioenv.gu.se/MSALigMap/HomePage.py.As protein sequences provide insights into protein function, the mapping of functionally important amino acids from three-dimensional complexes onto proteins with unknown function can assist in protein evolutionary analyses and protein design. This demands for tools that can be used to transfer annotated features from characterized protein sequences to novel sequences. Given the necessity of transferring binding-site information about ligands such as drugs, DNA, substrates, or cofactors for large uncharacterized sequences from homologous PDB 3D protein structures, we developed MSALigMap, a user-friendly Python-based tool that requires only two input files. This tool can be used to assist the user in mapping the binding residues onto homologous non-structure protein sequences based on the sequences of PDB 3D protein structures provided by the user. However, this tool can be used particularly when the sequence identity for the selected sequences with similar function is above the twilight zone, i.e., above 30% identity. The MSALigMap server can be accessed at https://albiorix.bioenv.gu.se/MSALigMap/HomePage.py) developed in Python (>3.0) for protein sequence alignment and the mapping of functionally important amino acids onto known and novel unannotated homologous sequences with similar function. The web interface was developed in HTML on the XAMPP server running on a Linux system. Python CGI programming was used for developing MSALigMap. This tool was not designed to generate alignment of its own; rather, the current version uses MAFFT [MSALigMap is a web-based tool  of the structure is used for extracting 2D details from the 3D protein structures. PDBsum is used for extracting the ligand-binding- and DNA-binding-site information. The command line version of ClustalO is used for performing the multiple sequence alignment of the user-specified protein sequences.The basic workflow is illustrated in The identified PDB codes are searched in the PDB database and downloaded A. The prThe protein sequences are extracted from the PDB atom file, and the non-structure protein sequences are aligned using the ClustalO tool, which is installed locally C. There The DSSP protein secondary structure annotations of the PDB 3D protein structures are extracted from the MRS server  using thFor protein–ligand and protein–peptide complexes, the ligand and peptide binding amino-acid residues whose interactions are classified as hydrogen-bonded or non-bonded are extracted using the LigPlot  output aThe mapping of functionally important amino acids is then performed with MSALigMap F. MSALighttps://albiorix.bioenv.gu.se/MSALigMap/HomePage.py. The input sequences are submitted through the URL. The current version of the server has options for separately analyzing protein–ligand, protein–DNA, and protein–peptide complexes  and substituted (blue) across all sequences.Arabidopsis thaliana (Arabidopsis) [The main features of MSALigMap are the color-coded secondary structure alignment of the PDB structure and the mapping of ligand binding amino-acid residues onto non-PDB sequences A. Next, idopsis)  ; hydrogen-bonded amino acids are designated in bold, and non-bonded interacting amino acids are underlined. Secondary structure information about the PDB 3D crystal structures is provided to facilitate a comparison of the conservation of secondary structure elements across the sequences of protein crystal structures. The results of the sequence alignment of both bonded and non-bonded amino-acid residues are shown below to illustrate the level of conservation of active-site amino acids among the proteins of interest. The alignment of amino acids of the binding site alone is provided, where identical and mutated/substituted amino acids are color-shaded in red and blue, respectively. In the current analysis, of the 13 amino acids that formed a hydrogen bond between the ligand NDP and the protein, 4 were highly conserved across the sequences used in the study. However, of the 33 amino acids that were identified as forming non-bonded interactions, 9 amino acids were identified to be highly conserved.Triticum aestivum (wheat) using the BLASTP program  extension proteins (LRXs) represent an example of proteins that bind to redundant signaling RALF peptides. The protein sequence of the LRX crystal structure of the LRX protein in complex with the RALF peptide in Arabidopsis (PDB code: 6QWN)  was used program B. Two ho program . The secTriticum aestivum (wheat) genome   Table 2C. A prev) genome . In Figu) genome A. The DN) genome B. Compar) genome  that binIt is not possible to use the tools presented here to distinguish whether mapped protein–ligand interactions are within the protein backbone or sidechain; for that purpose, the recently launched LiBiSco program can be used . The ligAn important application of functional annotation is the mapping of ligand and DNA binding amino-acid residues from characterized proteins onto novel protein sequences that are generated in genome sequencing projects. In this context, MSALigMap is presented as a tool for mapping the active-site amino-acid residues that bind to either ligand or DNA onto the sequences of proteins with unknown functions by transferring information extracted from structural data of protein structural complexes. These mapped residues can be then used by users to carry out further experimental studies for exploring the efficiency of these mapped amino acids; alternatively, any in silico tools, such as Variant Effect Predictor (VEP) , or avai


According to the Institute of Medicine, immediate steps must be taken to educate and train both the current and future health care workforce to work collaboratively in addressing the diverse needs of the growing older adult population.1 Most healthcare professionals had very little education or clinical training in the care of older adults nor the most effective ways to work as a clinical team. The Geriatric Practice Leadership Institute (GPLI) is a collaboration between two universities providing inter-professional teams of early and mid-career professionals the skills and knowledge needed to leverage leadership skills to effectively work within interdisciplinary teams to provide age-friendly care to older adults. The GPLI incorporates the Institute for Healthcare Improvement (IHI) Age-Friendly Health Systems 4Ms’ Framework into the training. The GPLI is an on-line, team-based program which engages 5-7 teams each session. Module topics include Age-Friendly Health Systems, organizational culture, leading self, leading inter-professional teams, and quality improvement. Additionally, teams select and completes a quality improvement project based on the Age-Friendly Health Systems 4Ms and submits a final report and presentation. The teams are also assigned a coach for support. Continuing education credits and a micro-credential are available to participants. The GPLI has trained over 175 health care professionals during the past 7 years with teams representing ambulatory to emergency responder organizations. The GPLI has been funded by the Health Resources and Services Administration (HRSA) Geriatrics Workforce Enhancement Program grant (numberU1QHP2873), which currently covers all costs for participants.


We propose a relational graph to incorporate clinical similarity between patients while building personalized clinical event predictors with a focus on hospitalized COVID-19 patients. Our graph formation process fuses heterogeneous data, i.e., chest X-rays as node features and non-imaging EHR for edge formation. While node represents a snap-shot in time for a single patient, weighted edge structure encodes complex clinical patterns among patients. While age and gender have been used in the past for patient graph formation, our method incorporates complex clinical history while avoiding manual feature selection. The model learns from the patient’s own data as well as patterns among clinically-similar patients. Our visualization study investigates the effects of ‘neighborhood’ of a node on its predictiveness and showcases the model’s tendency to focus on edge-connected patients with highly suggestive clinical features common with the node. The proposed model generalizes well by allowing edge formation process to adapt to an external cohort. Clinical event prediction is one of the key applications of big data and artificial intelligence, and instead of one-size-fits-all approaches, outcome prediction and decision making based on personalized models could be more accurate when patient similarity analysis has been taken into account. Existing literature depends on static similarity formulation based on pre-defined knowledge for predictive analysis without considering learned representation2, Alzheimer’s Disease Neuroimaging Initiative (ADNI)1 and ABIDE2 containing imaging and non-imaging information for patients with Alzheimer and autism spectrum disorder (ASD), respectively, has facilitated the use of GCN for disease prediction7 with innovations in GCN architecture involving kernel size selection and use of recurrence. We build on this research trend and build graphs with imaging data, i.e., X-rays as nodes, and weighted edges based on similarity in patients’ medical history recorded in EMR. We propose a novel framework for fine-grained clinical event prediction for COVID-19 patients by processing our patient-similarity graph through a graph convolutional neural network (GCN).Recent developments in graph convolutional neural networks (GCNN) have opened up the opportunity to learn effective representations for similarities between cases in addition to multi-modal data fusion by representing various modalities as edges and nodes of graphs. Availability of comprehensive public databases such as TADPOLE13, or mortality prediction using clinical risk factors18. In contrast, we propose a comprehensive relational graph approach to fuse information from imaging and non-imaging modalities. Furthermore, we propose a framework for multi-stage predictive modeling of disease trajectory of patients hospitalized with positive diagnosis of COVID-19, in terms of clinical events of discharge from hospital and mortality (Much of the literature regarding predictive modeling for COVID-19 patients has been largely focused on either diagnosis by processing imaging data (chest X-rays) through deep convolutional neural networks (CNN)ortality . While aAs deep learning models are generally opaque and it is a challenge to explain their decisions, we particularly focused on visualization of our models’ results. We designed a dashboard interface for exploration of model decision in clinical setting by drawing panels showing node features of the targeted case (chest X-ray image and relevant demographic features) as well as highlight the characteristics of ‘learned’ similar cases which is the ‘neighborhood’ of the target node, i.e., edge-connected nodes. We performed these visualization experiments for both internal and external sets. Varying neighborhood characteristics for the two sets corresponding to prediction of the same labels also highlight the unique adaptability of the graph-based modeling.We developed a graph-based fusion model to predict COVID-19 disease trajectory by using multi-modal patient data including chest X-ray imaging data, demographic information, and patient’s clinical history.Following approval of the Emory Institutional Review Board (IRB), we collected all chest X-rays of patients with at least one positive RT-PCR test for COVID-19, performed in 12 centers of the Emory Healthcare network from January 2020 to December 2020. As shown in With the approval of Mayo Institutional Review Board, we shipped our Emory trained model to Mayo and evaluated externally on a small set of 50 unique patients admitted to the Mayo Clinic hospital between Jan 2020 – Dec, 2020 with a positive RT-PCR test. The patients have 293 chest X-rays during the period of hospitalization. Demographic and comorbidities statistics of both cohorts are provided in GCN model learns vector embeddings of nodes optimized for a down-stream prediction task. Difference between convolutional neural networks and GCN comes from the definition of neighborhood. CNN allows only spatial proximity to define the neighborhood that may have influence over the representation learning for an instance. GCN leaves the definition of neighborhood upto the designer and receives this information in the form of edges of a graph. Edge-connected nodes may influence the representation learning for a node. Such flexibility is particularly suited to model complex clinical scenarios. In our graph design, we used the chest X-ray embeddings as nodes and edges are decided by similarity in patients’ demographic information or medical history . Therefore, our GCN supports the notion of ‘neighborhoods’ based on clinical and/or demographic similarity between patients and makes predictions for future clinical events by considering trends among similar patients.19 pre-trained on the open-source CheXpert chest X-ray dataset20, and fine-tuned on 199,029 non-COVID chest X-rays from EUH acquired in 2019, for processing normalized images. We dropped the final softmax classification layer of the DenseNet-121 model and extracted 1024-dimensional feature vectors from each image to construct a dense representation of the images for the graph node formulation.We used a DenseNet-121Demographic information: We used one-hot encoding for the following demographic features; gender , self-reported race , ethnic group , age at the time of admission .Current Procedural Terminology codes (CPT): CPT is a five-digit procedure code that reports medical, surgical, and diagnostic procedures and services to entities such as physicians, health insurance companies and accreditation organizations. CPT codes are maintained and grouped in a hierarchical structure by the American Medical Association (AMA). Each CPT code was reduced into a higher-order parent category based on the defined hierarchy3. We selected 21 groups with more than 1000 occurrences.Comorbidities: Past and current diagnoses of patients are structured as International Classification of Disease, 9th edition (ICD-9) codes which are grouped based on hierarchical structure21. We selected 29 groups occurring more than 5000 times in the data.We encoded EMR features of the patient corresponding to a node in a binary vector using only clinical data collected before the study datetime of the chest X-ray to avoid any data leakage. We applied three edge design styles based on different clinical factors - demographic, procedure and comorbidities. Cosine similarity between EMR feature vectors corresponding to two nodes is used to decide the edge between two nodes, while edge weight encodes the strength of the similarity between those nodes.22 that optimizes a sample aggregate function to collect ‘messages’ from neighboring nodes while generating vector embedding of a node. For inference, GraphSAGE employs an optimized aggregate function to generate embedding for unseen nodes in unseen graph structures. GraphSAGE based prediction models can inductively reason to assign predictive labels to unlabeled nodes by learning from labeled nodes in the graph.Many GCN variations are designed for transductive learning such that they can only process graph structures used for training with limited ability to generalize to unseen nodes or new graph structures. To avoid this limitation, we used the SAGE (SAmple and aggreGatE) graph convolution network (GraphSAGE)Our work is focused on forecasting the trajectory of disease, in terms of two clinical events, once the patient has been hospitalized. Given the challenge of collecting a balanced dataset for multi-class classification, we modeled 2 sequential decision points and developed a pipeline for comprehensive prediction of possible clinical events. (Model1) - Prediction of discharge from the hospital: In the first decision point, Model-1 predicts whether the patient will stay in the hospital for more than 3 days (positive label) or not. (Model-2) - Mortality prediction: For negatively labeled instances by Model-1, in the second decision point, Model-2 predicts whether the patient will expire within 3 days (positive label) or not. Distribution of positive and negative class labels is highly imbalanced, especially for Model-2 . We employed undersampling of majority labels and weighted loss to tackle this challenge. A patient is evaluated every time a chest radiograph is taken, while staying in the hospital. Disease trajectory can be indicated as improving (discharge in less than 3 days) or worsening .23 to predict clinical events as well. As PXS scores are based on deep learning based processing of imaging data, we wanted to establish the benefits of our selection of imaging features in our relational graph by comparison. We report the model performance in terms of Area Under the Receiver Operating Characteristics curve (AUCROC), precision, recall and f1- score on held-out test-set from Emory University cohort, as well as on an external test-set composed of patients’ of Mayo Clinic.Evaluation of the proposed modeling framework is focused on two aspects; 1) performance of the fusion graph-based model in comparison to traditional modeling using single modality (either imaging data or non-imaging data), 2) comparative effectiveness of different EMR data sources in terms of graph structure definition to identify optimal similarity metrics for the targeted prediction task. We designed a Random Forest classifier and used the Pulmonary X-ray severity (PXS) scores computed by a CNN24. We use the GNN explainer framework to plot sample nodes predicted as true and false positives by the models on both external and internal datasets using optimized graph models. Edge weights indicate the relative importance of each connection in predicting the label for the center node. We designed a dashboard with Panel 1 showing the GNN explainer similarity analysis. Panel 2 shows chest X-ray forming node features. Panel 3 shows an ordered list of common CPT subgroups in the neighborhood. Panel 4 shows demographic features of the patient corresponding to the center node.The designed graph based neural networks need to be explained in terms of weights assigned to edges to understand the learnt similarity between cases. Ying el al. proposed - ‘GNN explainer’ that learns concise subgraph structures consisting of nodes that play an important role in assigning output labels to a nodeWe report the performance of the two binary predictors  that are part of our framework, and comparative models in terms of class-wise and aggregated (weighted average) precision, recall, and F-score as well as confidence interval (95% confidence) on a randomly held-out set of test samples, in EHR only: Random forest model using all EHR data sources as input , (2) PXS only: Random forest model using only PXS score23 derived from the images as input, using a CNN model which was pretrained on ~160,000 images from CheXpert and fine tuned by transfer learning on 314 CXRs from patients with COVID-19, (3) Image only: softmax classification of the pretrained DensenET-121 using chest X-ray as input, (4) Late Fusion: fusion of label probability estimates from EHR only and Image only models, and (5) GraphSAGE with XX: GraphSAGE network with graph structure based on different EHR sources (XX) like demographics, CPT groups, and ICD-9 groups.For both prediction of discharge from hospital and mortality, GraphSAGE with CPT and ICD achieved the optimal performance , surpassing baseline single modality models - Image-only and EHR only, while PXS-only model also achieved suboptimal performance. Hence, clinical history seems more important for prediction of inpatient outcomes than demographic features. We experimented with combining ICD and CPT codes for graph formation. Such graph formation did not improve performance any further than what is achieved by these graphs based on ICD and CPT codes separately.External validation was performed on data here the common comorbidities  are rare (<20%) compared to our internal training data (>55%) and as a consequence the respective procedures are less common. In such a distribution shift, often the machine learning model failed to generalize. This scenario provides an excellent opportunity to test the generalizability of graph based models. GCN training on internal data requires node features of the external data to be in the same space as node features of the internal data. There is no such strict requirement for edge features. They can be defined by any suitable similarity assessment. We employed common characteristics of external data to build edges for the external set and applied our GCN model trained on the internal data. The AUROC plot is shown in Results of the Dashboard exploration are shown in While predicting adverse outcomes like mortality and stay in the hospital for more than 3 days, the model optimized a ‘neighborhood’ of patients formed due to all patients in the neighborhood undergoing cardiovascular and pulmonary procedures  as shown in panels 3 of Patients corresponding to Dashboard based visualization helps us understand the limitations of graph-based modeling. Some of the common procedures (such as Diagnostic radiology procedures) form an easy way of connecting several patients together while it may lack predictive power. Patients corresponding to 26.We proposed a graph-based framework to preserve interdependencies in multi-modal data and similar cases to predict future clinical events  for the in-patients population tested positive for COVID-19 within 3 days of admission. During graph-based learning, in theory, two-fold information fusion of node features and graph structure ensure that relevant features (nodes and graph structure) for the targeted task are amplified while similar non-relevant attributes are suppressed. To our knowledge, this is the first attempt to encode and learn the patient-wise similarity within imaging data using a GCN model for predictive modeling for hospital resource optimization and interpretation using a dashboard. The proposed framework may face limitations in terms of application scope as it requires imaging data to be collected on a regular interval and was trained on data collected from highly integrated academic healthcare systems. Prediction interval is limited to 3 days which is still longer than most studies done in the past


In parallel to the traditional symptomatology, deficits in cognition  contribute significantly to disability and suffering in individuals with schizophrenia. Cognitive deficits have been closely linked to alterations in early auditory processes (EAP) that occur in auditory cortical areas. Preliminary evidence indicates that cognitive deficits in schizophrenia can be improved with a reliable and safe non-invasive brain stimulation technique called tDCS . However, a significant proportion of patients derive no cognitive benefits after tDCS treatment. Furthermore, the neurobiological mechanisms of cognitive changes after tDCS have been poorly explored in trials and are thus still unclear.n=30) or sham (n=30) tDCS . The anode will be placed over the left dorsolateral prefrontal cortex and the cathode over the left auditory cortex. Cognition, tolerance, symptoms, general outcome and EAP  will be assessed prior to tDCS (baseline), after the 10 sessions, and at 1- and 3-month follow-up. The primary outcome will be the number of responders, defined as participants demonstrating a cognitive improvement ≥Z=0.5 from baseline on the MATRICS Consensus Cognitive Battery total score at 1-month follow-up. Additionally, we will measure how differences in EAP modulate individual cognitive benefits from active tDCS and whether there are changes in EAP measures in responders after active tDCS.The study is designed as a randomized, double-blind, 2-arm parallel-group, sham-controlled, multicenter trial. Sixty participants with recent-onset schizophrenia and cognitive impairment will be randomly allocated to receive either active  with follow-up assessments up to 3 months. In addition, this study will allow identifying and assessing the value of a wide range of neurobiological EAP measures for predicting and explaining cognitive deficit improvement after tDCS. The results of this trial will constitute a step toward the use of tDCS as a therapeutic tool for the treatment of cognitive impairment in recent-onset schizophrenia.st, 2022.ClinicalTrials.gov NCT05440955. Prospectively registered on July 1The online version contains supplementary material available at 10.1186/s13063-023-07160-z. The order of the items has been modified to group similar items , negative (flattened affect/avolition), and disorganization (disorganized thoughts/odd behavior) symptoms, associated with reduced psychosocial functioning. At present, treatment mainly consists of antipsychotic medications combined with psychosocial interventions . TreatmeIn parallel to the traditional symptomatology, deficits in cognition  contribute significantly to disability and suffering in individuals with schizophrenia. Cognitive deficits have been closely linked to alterations in early auditory processing (EAP) that occur in auditory cortical areas –9. MechaPreliminary evidence indicates that cognitive deficits in schizophrenia can be improved with a reliable and safe non-invasive brain stimulation technique called tDCS . tDCS consists of the application of a direct electrical current through two electrodes placed on the scalp to modulate cortical activity. Applied repeatedly over the left frontal and temporal cortices, tDCS significantly improves cognitive performance such as memory and attention in patients with schizophrenia , 18. In Trials are needed to verify the results of cognitive improvements after tDCS in larger schizophrenia cohorts with adequate sham control and randomization. In that sense, additional tDCS trials in schizophrenia are ongoing and receive important funding from governments and foundations across the world , 24. DesZ=0.5 from baseline on the MATRICS Consensus Cognitive Battery total score  versus sham on global cognitive impairment in patients with recent-onset schizophrenia, at 1-month follow-up. At 1-month we will assess the number of responders, defined as patients demonstrating a cognitive improvement greater than or equal to ophrenia –29.We hypothesize that there will be significantly more responders in the active group.Objective 2a is to compare the long-term efficacy of active tDCS versus sham on global cognitive impairment in patients with recent-onset schizophrenia at 3-month follow-up.Objective 2b is to compare the efficacy of active tDCS versus sham on different cognitive aspects  measured with the MCCB in patients with recent-onset schizophrenia at 1- and 3-month follow-up.Objective 2c is to compare the efficacy of active tDCS versus sham on different clinical aspects of schizophrenia  measured with validated symptom rating scales in patients with recent-onset schizophrenia at the end of the tDCS treatment and at 1- and 3-month follow-up.Objective 2d is to compare the efficacy of active tDCS versus sham on the outcome  measured with validated rating scales in patients with recent-onset schizophrenia at the end of the tDCS treatment and at 1- and 3-month follow-up.We hypothesize that subjects randomly allocated to the active group will demonstrate better improvement from baseline cognitive, symptoms, and functional scores than subjects randomly allocated to the sham group.Objective 3 is to compare the clinical tolerance of active tDCS versus sham measured with adverse effects questionnaires in patients with recent-onset schizophrenia at the end of the tDCS treatment.We hypothesize that subjects randomly allocated to the active group will demonstrate no significant difference in questionnaire scores than subjects randomly allocated to the sham group.Objective 4a is to assess how differences in EAP mechanisms modulate individual cognitive benefits from active tDCS measured with a range of EAP measures in patients with recent-onset schizophrenia at 1-month follow-up.Objective 4b is to evaluate whether there are changes in EAP measures in patients associated with cognitive improvement after active tDCS at 1-month follow-up.We hypothesize that baseline EAP measures will distinguish between participants who have improved cognitive deficits after active tDCS and those who do not, and that changes in EAP measures after tDCS will be only observed in participants with improved cognitive deficits after active tDCS.N=30) or sham tDCS (N=30). Psychiatric and neuropsychological assessments will be performed at baseline (time of consent), at the end of the tDCS procedure, and at 1 and 3 months following the end of the tDCS procedure (maintenance effect). Auditory biomarker analyses will involve neurobiological measures  recorded at baseline and at 1 month after tDCS. Study schedule and study flowchart are presented in Figs. The present study is designed as a superiority, double-blind, parallel-group, sham-controlled randomized clinical trial with an allocation ratio of 1:1. Study sites will include 4 University Hospital centers in France. In a 1 × 2 factorial design with sham, patients are randomized into two groups: active tDCS and sham tDCS. A total of 60 patients with schizophrenia will be randomly assigned to receive either active tDCS . Neuroimaging platform: IRMaGE.Centre Hospitalier Alpes-Isère, Department of Psychiatry, Saint-Egrève (10 participants). Neuroimaging platform: IRMaGE.Centre Hospitalier Le Vinatier, Department of Psychiatry, Bron (20 participants). Neuroimaging platform: CERMEP.Centre Hospitalo-Universitaire de Saint-Etienne, Department of Psychiatry, Saint-Etienne (20 participants). Neuroimaging platform: IRMAS.Participant recruitment will be conducted across four French centers:T-score < 40; (5) the subjects should be receiving stable doses of antipsychotics for ≥ 4 weeks; and (6) the subjects are covered by a public health insurance.The inclusion criteria include (1) subjects of both genders, diagnosed with recent-onset schizophrenia (first 3 years of illness), confirmed through the Structured Clinical Interview for the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 5th edition (SCID-5); (2) aged 18–35 years; (3) intelligence quotient (IQ) > 55; (4) cognitive deficit confirmed by a MCCB total score The exclusion criteria include (1) pregnant  or breastfeeding women; (2) unstable or acute medical conditions; (3) subjects who receive involuntary treatment with no third party available, guardianship or protection of the court; (4) history of cranioencephalic trauma with loss of consciousness or central nervous system diseases that affect the brain; (5) current diagnosis of substance abuse or history of substance dependence in the last 6 months, except nicotine; and (6) MRI, PET or tDCS contraindications.Informed consent will be obtained by local investigators (psychiatrists) involved in the study. The investigator who obtains the consent will conduct clinical assessments throughout the clinical trial period. Patients will be truthfully and completely informed in comprehensible terms of the requirements, the objectives, the risks, and safety measures. They will be informed of their right to refuse to participate and to withdraw at any time without incurring any penalty or withholding of treatment on the part of her/his psychiatrist and of the investigator, if different. All of this information is described on an information/consent form that will be provided to the participant. Written consent of the participant will be collected by the investigator prior to final inclusion in the study.No additional consent provisions for collection and use of participant data and biological specimens are planned.tDCS  is a noninvasive brain stimulation technique that involves the passage of a small electric current through the scalp and skull to modulate brain activity . The stu2) placed on the surface of the scalp according to the international 10/10 system of EEG electrode placement. The anode will be placed equidistant from F3 and FP1 . The cathode will be placed equidistant from I7 and P7 . The tDCS montage and current flow modeling are depicted in Fig. The procedure for the subject’s installation and tDCS electrode placement will be standardized between study centers using specific training formation sessions. During the entire tDCS session, the subject is at “rest,” comfortably seated in a chair in a quiet room. The subjects will be asked to relax, keep their eyes open, and not perform any particular activity. A clinician will be present for the entire session duration. The current will be applied via a pair of rubber electrodes  based upon any reasons will not be allowed. In case of tDCS treatment discontinuation, the participant will be withdrawn from the study.The 10 tDCS sessions will be delivered during the shortest possible interval allowed by safety standards (twice daily during 5 consecutive weekdays). In addition, research staff members will regularly contact the participants by phone to improve retention. These strategies may allow for reducing dropout rates and achieving the primary outcome of the study.No concomitant care is prohibited during the trial.After inclusion, no simultaneous participation in other interventional clinical research will be authorized during the trial period. The evaluation of adverse reactions will be carried out for a duration of 3 months.All described instruments are validated in the French language.Z=0.5 from baseline on the MATRICS Consensus Cognitive Battery total score (MCCB). The MCCB is a gold-standard standardized test battery to assess cognitive functions in patients with schizophrenia flumazenil positron emission tomography MRI (PET-MRI).radiotracer binding potential on GABA-A receptors  within left prefrontal and temporal cortical areas measured with resting-state flumazenil) will be carried out simultaneously to the MRI sequences described above (PET-MRI). A preliminary interview with a nuclear physician will be performed on the day of the PET-MRI examination. The PET scanner, associated with the MRI imager, is a Biograph mMR, Siemens Healthcare, with an internal tunnel diameter of 60 cm and a useful field of view of 50×50×50 cm2 in MRI and 59×59×26 cm2 in PET. The PET images produced are volumes of 127 slices of 2mm thickness. The spatial resolution (NEMA standard) is 4.3 mm  and isotropic at the center of the field of view. The combination of PET and MRI scans will, after coregistration, improve the spatial resolution and thus refine the data analysis. PET acquisition is performed simultaneously with the MRI sequences described above. PET-MRI requires the installation of a venous catheter by a medical electroradiology manipulator. In our protocol, carbon-11-labeled flumazenil will be synthesized only once per participant. After MRI tracking and attenuation correction sequences have been performed, the injection of the [11C]flumazenil 2.5 MBq/kg bolus will be performed at the same time as the start of the PET recording. Dynamic PET data will be recorded 60 min after the injection of [11C]flumazenil. Of note, only one of the investigation centers  has a PET-MRI device and will thus participate in the PET-MRI acquisition.PET-MRI: A positron emission tomography acquisition with the GABA marker  to have direct access to original medical records which supports data on the eCRF .Both CRF (electronic and paper versions) will be declared to the CNIL . Paper CRFs will be kept in locked files at the study sites for 15 years. In all study-related documents, participants will appear only in the form of an ID code (see §16c for details) to ensure confidentiality. All members of the research staff who will have direct access to the data before, during, and after the trial will be bound to strict confidentiality rules and will not be allowed to disclose personal or medical information.z-tests and two-sample t-tests for non-normal and normal continuous outcomes, respectively. Categorical data will be compared with chi-square tests. Both intention-to-treat and per-protocol analyses will be conducted. In case of significant interactions, post hoc analyses will be conducted using appropriate contrasts. Analyses will be adjusted or stratified by the study site as part of a sensitivity analysis. The significance threshold will be set at P-value < 0.05 and appropriate effect sizes of significant results will be calculated.In general, the normality of the data distributions will be investigated with Shapiro-Wilk tests. Between-group comparisons will be performed with Mann-Whitney Z-score at 1-month follow-up) will be compared between the active tDCS group (N=30) and the sham tDCS group (N=30) using a chi-square test. In addition, a binomial test will be used to test the superiority of the proportion of responders to active tDCS vs. sham tDCS.The percentage of “responders” showing an improvement in global cognitive improvement  and time  as independent variables.Outcomes 2c: the changes from baseline to endpoints in clinical symptom measures will be analyzed using mixed effects regression models with group (active or sham) and time  as independent variables.Outcomes 2d: the changes from baseline to endpoints in schizophrenia outcome will be analyzed using mixed effects regression models with group (active or sham) and time  as independent variables.Outcome 3: tDCS tolerance questionnaire scores measured after tDCS will be compared between the active tDCS and sham tDCS groups using mean comparison tests.Outcome 4a: the difference at baseline between responders and non-responders in EAP measures will be analyzed using mixed effects regression models with cognitive improvement status (responder or non-responder) and group (active or sham) as independent variables.Outcome 4b: the changes from baseline to 1-month follow-up in EAP measures will be analyzed using mixed effects regression models with cognitive improvement status (responder or non-responder), group (active or sham), and time (before tDCS and 1-month follow-up) as independent variables.http://www.uzh.ch/keyinst/loreta.htm) will be used to examine the temporal activation of brain regions contributing to the observed event-related potential modulation patterns.The electrophysiological data set will be amplified using the BrainAmp™ acquisition system  using a sampling rate of 1 kHz, a resolution of 0.1 μV, and bandpass analog filtering between 0.01 and 500 Hz. A principal component analysis will remove artifactual sources. Temporal periods ranging from −200 ms to 750 ms around the emission of each auditory stimulus will be extracted and normalized to baseline using the standard analysis methods recommended for the MatLab software, version 2017a with relevant toolboxes . Time-frequency analyses by Fourier transform will be conducted with a calculation of inter-trial coherence and average spectral powers over the duration of the per-stimuli time periods. Time domain analyses will be conducted with a calculation of event-related potentials amplitude during the auditory oddball tasks . The sLORETA source imaging technique (https://project.inira.fr/shanoir).The acquired data  will be transferred to a server for centralization . Then, the correlation rates of the preprocessed signals sensitive to BOLD fluctuations will be regressed both on the whole-brain for whole-brain analyses and at the level of cortical areas stimulated by tDCS  for region-of-interest analyses as functional connectivity indices (z-scores) using the SPM CONN toolbox.aMRI and rsfMRI: pre-processing including movements realignment, correction of geometrical distortions, “slice timing,” coregistration to the anatomical image, normalization to the reference MNI  standard space, spatial smoothing, and additional filters will be performed using the SPM software . Then, Glutamine and GABA levels (mM) localized in the cortical areas stimulated by tDCS  will be extracted and normalized to a reference metabolite using a recently developed tool specifically for GABA quantification (GABA MRS http://www.gabamrs.com).MRS: pre-processing of spectroscopy data including ER-filtering of the spectra frequencies, phase dynamics correction (Gabor tool), and the Cadzow procedure for noise reduction (Cadzow procedure) will be conducted using the jMRUI124 software  [11C]flumazenil will be modeled with the SRTM model using the pons as a reference region (region devoid of GABA-A receptors). Regional BPND extraction will be performed for the left prefrontal and temporal cortices. Group voxel-to-voxel statistical analyses will be performed in the MNI space with the SPM toolbox.PET-MRI: Dynamic PET will be corrected for possible subject motion . ThroughThe study will have no interim analysis.Subgroup analyses will be performed regarding possible confounders such as the study site. In case of baseline differences between the 2 groups (active tDCS and sham tDCS), statistical analyses will be adjusted to take into account specific variables that may have influenced the results .N=60), the analyses will be conducted on the intention-to-treat set, including all randomized participants with at least one assessment conducted after the tDCS treatment (10 sessions). Per protocol analyses will be performed using the whole sample (N=60). The last observation carried forward will be used for missing data.Protocol non-adherence will be described as follows: characteristics at inclusion, arm (active tDCS or sham tDCS), withdrawal date and visit number, reason for withdrawing, and last outcomes carried forward. For the trial . The members of this committee have no relationship with the investigators and no competing interest related to the study. The initial committee meeting will take place prior to the start of the trial. The committee will meet at least once a year to assess the trial's progress and safety. Prior to each meeting, no data analysis will be performed. If necessary, the trial expansion will be discussed at the final committee meeting. Throughout the trial period, at least annual onsite monitoring visits will be planned to verify the accuracy and quality of the data.Safety assessment will be conducted according to the requirements of the MDR 2017/745 and MDCG 2020-10/1 statements (European commission) and article of the R1123-46 . The investigator will document in the CRF any adverse event observed of reported by the participant. The causal link with the use of the medical device (tDCS) will be assessed. Any adverse event will be monitored until it is completely resolved.The principal investigator agrees to allow direct access to the study records to independent regulatory authorities for audit or inspection.https://clinicaltrials.gov/) and, if approved, to participating sites.Important protocol modifications will require a formal amendment to be approved by the IRB. The principal investigator will be in charge of communicating protocol modifications to relevant parties  as a treatment of cognitive impairment in a multicenter sample of patients with recent-onset schizophrenia. Given the causal role of cognitive defect in daily functioning , 58, theIn addition, this study will allow identifying and assessing the value of a wide range of neurobiological EAP measures for predicting and explaining cognitive deficits improvement after tDCS. Alterations in EAP have been demonstrated to lead to poor functional outcomes associated with impaired cognition in patients –12, whicOverall, if the findings from the present trial confirm our hypotheses, they may contribute to the value of tDCS for the treatment of cognitive impairment in recent-onset schizophrenia. As some subtle disabling cognitive impairments are considered as core features of the pre-clinical vulnerability of schizophrenia, we also hypothesize that fronto-temporal tDCS would be clinically relevant in individuals with an at-risk mental state for psychosis and may constitute a preventive intervention against psychotic onset in the future .th December 2021). The trial is currently ongoing. Recruitment will begin in the winter of 2022 and is expected to finish in 2025.The Protocol Version is 1.0 (15Additional file 1. Ethical approval.


Since the coronavirus disease 2019 (COVID-19) pandemic began, evidence suggests that people with underlying mental health disorders have worse outcomes from COVID-19 infection. Our aim was to assess the impact of COVID-19 infection on people with pre-existing mental health or neurocognitive disorder including COVID-19 related mortality and severity.We conducted systematic searches of PubMed, EMBASE, and Cochrane library for articles published between 1 December 2019 and 15 March 2021. The language was restricted to English. We included all case control, cohort and cross sectional studies that reported raw data on COVID-19 associated mortality and severity in participants aged 18 years or older with a pre-existing mental health or neurocognitive disorder compared to those without. Three independent reviewers extracted data according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Methodological quality and risk of bias were assessed using the 9-star Newcastle-Ottawa Scale. We calculated the odds ratio as the summary measure along with the corresponding 95% confidence intervals. The random effects model was used to calculate the overall pooled risk estimates. COVID-19 related mortality was the primary outcome measure. The secondary outcome measure was COVID-19 related severity, defined as intensive care unit admission or use of mechanical ventilation.Fifteen studies were included in the meta-analysis comprising of 8,021,164 participants. There was a statistically significant increased risk of mortality for participants with a pre-existing mental health or neurocognitive disorder compared to those without . Increased mortality risk was found on subgroup analysis for participants with pre-existing schizophrenia  and dementia . There was no statistically significant difference in the severity of illness when comparing the two groups. There was a statistically significant increase in the number of participants with comorbid diabetes and chronic lung disease in those with a pre-existing mental health or neurocognitive disorder compared to those without.The results show that people over 18 years with a pre-existing mental health or neurocognitive disorder have an increased risk of mortality from COVID-19 and are more likely to have comorbid diabetes and chronic lung disease. These results highlight the need for better physical health monitoring and management for this group of people and better integration of mental and physical health services, as well as adding to the evidence that they should be prioritised in the ongoing COVID-19 vaccination schedules worldwide.


To explore the effect of an Early Intensive-Upper Limb intervention (EI-UL) compared to EI-UL with integrated Multisensory Stimulation And Priming (MuSSAP) training on improving manual ability in infants with a unilateral brain lesion.  A pilot randomised clinical trial with pre- and postintervention and follow-up measurements  was conducted. Sixteen infants with a unilateral brain lesion (corrected age is 4-10 months) received home-based intervention with video coaching. Eight infants received EI-UL and eight infants received EI-UL with integrated MuSSAP training. Primary outcome was the Hand Assessment for Infants (HAI) score. Additionally, effects were explored on initiation of goal-directed movements in both groups and on attention in the EI-UL with integrated MuSSAP training group. p = 0.001, Cohen's d = 1.04) and between T0 and T2 ; and the HAI ‘Both Hands Measure' increased between T0 and T1  and between T0 and T2 . At the start of the intervention, six infants (three in both groups) did not demonstrate initiation of goal-directed contralesional upper limb movements. During the intervention one infant receiving EI-UL and all three infants receiving EI-UL with integrated MuSSAP training started to initiate goal-directed movements.  No significant group differences in HAI scores were found. Overall, HAI ‘Affected hand score' increased between T0 and T1 (NCT05533476). The results suggest manual ability of infants with unilateral brain lesion improved with both interventions. We hypothesize that the integrated MuSSAP training may facilitate attention and initiation of contralesional upper limb goal-directed movements. This trial is registered with  Limited hand function in children with unilateral cerebral palsy (uCP) reduces their opportunities to participate in daily life activities and might, in turn, affect their quality of life . About 5International clinical practice guidelines recommend early intervention with intensive task-specific training and parental coaching , 7. TherWe, therefore, developed a novel tool and training aiming to improve attention towards the contralesional upper limb: Multisensory Stimulation and Priming (MuSSAP). Repeatedly applying rhythmically synchronous multisensory stimulation has been proposed to be helpful in provoking attention and to facilitate readiness to initiate a goal-directed movement  at the stimulated side . To traiThe primary aim of this pilot Randomised Controlled Trial (RCT) was to explore the short-term effect of EI-UL compared to EI-UL with integrated MuSSAP training (EI-UL–MuSSAP) on the improvement of manual ability in infants with a unilateral brain lesion. In addition, we aimed to explore the individual developmental trajectories regarding self-initiated goal-directed movements in both groups and attention in the EI-UL–MuSSAP training group, and to evaluate the feasibility of the training.A pilot RCT with pre- and postintervention, and follow-up (at eight weeks postintervention) measurements was undertaken to explore the short-term effects of an eight-week EI-UL intervention compared to an eight-week EI-UL–MuSSAP intervention in infants with a unilateral brain lesion, both in a home-based setting with a video coaching approach. The study was reported in accordance with the CONSORT Statement   were notInfants with a (corrected) age between 4 and 10 months at risk for uCP were recruited from eight hospitals across the Netherlands. Eligibility criteria were a diagnosis of unilateral acquired brain abnormalities  i.e. should be at risk of uCP, based on at least one cerebral imaging study (ultrasound or MRI). Exclusion criteria were severe epilepsy, severe sensory deficits , bilateral involvement, or both parents being unable to communicate in Dutch, English, or German.Parents of eligible infants received an information letter about the study from their medical doctor. If interested, parents were invited for a visit to the rehabilitation center. During the visit an initial observation of the infant's motor performance was conducted by a paediatric rehabilitation physician and an occupational therapist. Parents received additional oral and written information about the intervention and detailed information about the study procedure. All parents of the participating infants signed an informed consent prior to participation. Infants were randomised to the intervention groups by using block randomisation. Every first infant referred by a paediatric neurologist from one of the hospitals was allocated either to EI-UL or EI-UL–MuSSAP by drawing lots (without replacement) by an independent person. Every second infant referred by the same hospital was automatically allocated to the other intervention group.The typically developing infants were age-matched to the infants in the MuSSAP group and recruited from a child daycare centre. These infants had to be born at term and have a normal birth weight as reported by the parents.The EI-UL intervention was designed as an intensive home-based intervention with video coaching of the parents. The training consists of unimanual training (nonconstraining) stimulating child-initiated movements  to improve contralesional upper limb ability by increasing sensory-motor experiences  see Fig. In addiThe intervention consisted of eight weeks training with a frequency of seven days a week and a duration of 30 minutes each day (divided over three 10-minute sessions). Usual care  continued during the intervention.During a home visit at the start, the occupational therapist (>10 years of experience in working with children with CP) of the Sint Maartenskliniek provided detailed oral and written instructions to parents. The paediatric physical therapist was invited to join the parent instruction. In addition, parents received a box filled with carefully selected age and ability-appropriate toys to elicit both unimanual and bimanual actions and a stand for their telephone to be able to record the training sessions.During the EI-UL intervention, the occupational therapist's role shifted from trainer to coach by means of video coaching. Parents were asked to record one of the 10-minute sessions every day and to upload this video on a secure website. An occupational therapist of the Sint Maartenskliniek provided parents with written feedback, training suggestions, and emotional support after analysing the videos. Parents received feedback on subsequent steps in motor skill development, how to match the difficulty of the task to the infants' ability level, how to keep practice fun, how to choose the right toys etc. The frequency of the video coaching differed (with a minimum of twice a week) and was led by the needs of the parents and observations of the therapist about treatment fidelity. Once a week, the primary care paediatric physical therapist (PT) visited parents to support parents at home during a training session.The MuSSAP training was integrated into the EI-UL intervention; the total training frequency and duration was equal to the EI-UL intervention alone. With the integrated MuSSAP training, we aimed to increase infant's attention for the contralesional upper limb and facilitate readiness to initiate a goal-directed movement , 11 by pParents closely observed whether the infant looked at the wristband after it switched on and presented a toy to the infant as soon as the infant shifted its attention to the contralesional upper limb. The toy served as a reward for shifting attention to the wristband, and as a cue to provoke self-initiated goal-directed movements with the contralesional upper limb. In case no shift of attention by the infant was observed, parents prompted attention by bringing the contralesional upper limb into the infants' field of view. No toy was presented if the infant still did not look at the wristband. In case the infant shifted its attention to the contralesional upper limb, but no self-initiated movement was observed, parents placed a toy into infant's contralesional hand to stimulate holding. The infant was left to play with the toy for as long as the contralesional hand was involved and the infant payed attention to the contralesional upper limb . If the infant transferred the toy to its ipsilesional hand or the parent observed only mouthing behaviour, the parent removed the toy. Subsequently, parents started playing peek-a-boo, talking, or singing a song prompting the infant to shift its attention to the parent until the next stimulus by the wristband occurred. In addition to the instructions for the EI-UL intervention as described earlier, parents received a supplemental instructional video demonstrating the specific MuSSAP training procedure.Infants were evaluated just before the start of the intervention (T0), immediately after the eight-week intervention (T1), and at follow-up, eight weeks after the intervention stopped (T2). All infants at risk of uCP were evaluated with the primary outcome measure; the Hand Assessment for Infants HAI , 16), an, an16]),The HAI is a criterion and norm-referenced valid and reliable tool to assess manual ability of each hand separately as well as both hands together in infants aged 3-12 months (corrected age) at risk of uCP , 16.The Each Hand Sum Score (EaHS) is a score for the left and right hand separately (range 0-24), and the Both Hands Measure (BoHM) is the overall logit-based outcome measure of the HAI (range 0-100) . For theAs there was only one trained and certified HAI assessor (AV) in the Sint Maartenskliniek, blinded scoring was not possible. To control for expectation bias, five randomly selected videos were scored by a second trained and certified HAI assessor (TS) from a different rehabilitation clinic in the Netherlands. Outcomes were discussed until consensus was reached.(1) General Gross and Fine Motor Measures. The Bayley Scales of Infant and Toddler Development–Third Edition (Dutch version) (Bayley-III-NL) [-III-NL)  is a nor-III-NL) , 22. TheThe Gross Motor Function Measure (GMFM-88) is a reliable and valid multidimensional instrument to assess change in gross motor abilities in children with CP , 19. The(2) Infant and Toddler Quality of Life Questionnaire Short Form 47. The Infant and Toddler Quality Of Life questionnaire Short Form 47  is a reliable and valid generic parent-completed measure to assess health status and health-related quality of life of children between two months and five years old [ears old . Raw scaears old .(3) Video Observation Attention Affected Hand (VOAAH). To explore the individual developmental trajectories regarding self-initiated goal-directed movements in both groups and attention in the EI-UL–MuSSAP training group, we developed the Video Observation Attention Affected Hand (VOAAH).time to self-initiated goal-directed movement and time to attention, training session videos recorded by parents were scored. Time to self-initiated goal-directed movement was defined as the time between looking at the stimulus (a toy presented by the parent) and initiation of a goal-directed movement (active movement towards the toy) with the contralesional upper limb. In addition, time to attention for the contralesional upper limb was defined as the time between the stimulus (multisensory stimulation by the wristband) and looking at the contralesional upper limb. This latter could only be scored from the videos of the infants who received EI-UL–MuSSAP.To assess We aimed to score two videos of each intervention week with a minimum of two days in between . Videos or trials were excluded if (1) the arms or eyes of the infant could not be observed due to a wrong camera position; (2) the quality of the video was too low to be scored properly; (3) the wristband was switched on by the parent during the trial; (4) a deviation of the intervention protocol was observed ; and (5) obvious environmental distraction by the infant was observed. Selected videos were scored in a nonchronological order to reduce expectation bias. From each video, the first five consecutive trials that met the inclusion criteria were scored.time to self-initiated goal-directed movement and time to attention, respectively .A scoring guideline (Video Observation Attention Affected Hand (VOAAH)) was developed for this purpose. Evaluation of the scoring guideline showed excellent (ICC 0.984) and good (ICC 0.889) intrarater reliability for (4) Feasibility. To evaluate the feasibility of the intervention, we measured training adherence by asking parents to fill out a digital time registration form every day. Additionally, a short closing interview was conducted with parents and the physical therapist immediately postintervention by using open ended questions regarding their experiences with the intervention. These interviews were audio-recorded.t-tests were used. A mixed ANOVA was used to compare the effects of both interventions on HAI with Time  as within factor and Intervention Group (EI-UL/EI-UL – MuSSAP) as between factor. For post hoc analyses Bonferroni correction was used to adjust for multiple comparisons. Effect sizes were calculated using Cohen's d, and were interpreted as small (d <0.5), medium (d = 0.5–0.8), or large (d ≥ 0.8) effects [Descriptive statistics were used to present study data. The Shapiro-Wilk test was used to confirm normality of the data. To test for possible differences between groups at baseline (T0), independent sample  effects . AnalyseThe BSID-III scores and GMFM total scores were used to describe overall motor development and to visually explore differences in the developmental trajectories of infants between groups using graphs. Scores on the different scales of the ITQOL-SF47 were compared between groups. A difference of ≥10 points in mean scores was regarded as a reasonable difference based on the reported standard deviations found in previous studies , 24.time to self-initiated goal-directed movement and for the EI-UL–MuSSAP group time to attention were explored via linear regression performed using GraphPad Prism version 6.07 for Windows, GraphPad Software, La Jolla California USA, http://www.graphpad.com. Individual best-fit regression lines were determined on the best three reaction times per video. These individual regression lines were averaged to compute regression lines per intervention group. No further statistical tests were conducted. Additionally, to explore the individual developmental trajectories regarding self-initiated goal-directed movements, further visual data exploration was used.For both groups, intraindividual Adherence will be calculated as the percentage of the registrated total training time with respect to the total planned training time (28 hours). To analyse the short closing interviews with parents and the physical therapist, interviews were transcribed verbatim and summarized related to the open-ended questions regarding their overall experiences with the intervention, their perception of the outcome of the intervention, their perception of potential barriers in the execution of the training program and their perception of using the multisensory bracelet (only in the EI-UL – MuSSAP intervention group).Seventeen infants with a unilateral brain lesion were assessed for eligibility of which sixteen infants were included .n = 14) or ultrasound (n = 2). Eight infants were randomised to the EI-UL intervention, and eight infants to the EI-UL–MuSSAP intervention. Additionally, eight typically developing infants were enrolled in the study. Unilateral brain lesion had been demonstrated by MRI (Parents of three infants (two receiving EI-UL and one receiving EI-UL–MuSSAP training) reported occasional observations of a swollen, red, and warm contralesional upper limb, which was already present before the start of the intervention in two infants and in one infant from the start of the intervention. In all cases, it was recommended to consult the infants' physician, and no contraindications to proceed with the intervention were determined.F  = 0.576, p = 0.460, F = 0.048, p = 0.953) nor for the HAI Both Hands Measure  = 1.034, p = 0.327, F = 0.017, p = 0.983)  = 12,315, p < 0.001) and HAI Both Hands Measure  = 30.044, p < 0.001) were found. Post hoc analyses showed significant improvements in the HAI Affected Hand Score between T0 and T1  and between T0 and T2  and in the HAI Both Hands Measure between T0 and T1  and between T0 and T2 . In both intervention groups six infants (75%) showed an  see . SignifiIn general, scores on the ITQOL were lower (≥10 points) in the intervention groups compared to scores of the typically developing infants. In case of differences in scores (defined as ≥10 points) between the intervention groups, infants in the EI-UL–MuSSAP group showed lower scores regarding quality of life compared to infants in the EI-UL group, except for the mean score on Physical Abilities on T1 see .In the EI-UL–MuSSAP group scores on Physical Abilities and Parental Impact-Emotional increased (≥10 points) at T1 compared to T0 and the score on the General Health Perceptions scale declined at T1 compared to T0.For 11 infants 16 videos were eligible for scoring. For two infants in both intervention groups the number of eligible video recording ranged from 10-15. For one infant (EI-UL) no video recordings were available due to video-storage failure.time to self-initiated goal-directed movements with the contralesional upper limb. In infants receiving EI-UL–MuSSAP training, the regression lines regarding time to attention also showed a negative slope suggesting faster response times. Infants receiving EI-UL appeared to have faster response times at T0 compared to infants receiving EI-UL–MuSSAP training and remained faster during the intervention period.Based on visual exploration, at group level, the linear regression analysis  showed iThe individual developmental trajectories regarding self-initiated goal-directed movements were visually explored using the figures in Appendix p = 0.313) and there were no dropouts. For two infants receiving EI-UL–MuSSAP adherence rate was <50%  due to multiple hospital admissions and difficulties with fitting the intervention into daily life.The average received training duration of the EI-UL and EI-UL–MuSSAP group was similar in both groups; 93% (26 SD = 2 hrs) and 86% (24 hours SD = 6 hrs), respectively,  training were found. The intervention effects in both intervention groups were similar and in line with previous research exploring the effects of baby-CIMT . The meaIn our study, we observed a large variation in (increase in) manual ability between infants. This observed interindividual variability was larger than observed in the typically developing infants and in accordance with previous studies , 9. DiseVisual data-exploration suggested that infants with lack of goal-directed movements at the start of the intervention and with diminished attention for the contralesional upper limb might benefit from MuSSAP training. Risk for diminished attention and goal-directed movements may be related to the location and the severity of the brain damage. From adult populations it is suggested that impaired attention to the contralesional side commonly occurs following brain damage to the right posterior parietal cortex . Howevern = 1), and due to epilepsy (n = 2) (disclosed during the study) compared to one infant with epilepsy in the EI-UL group.By exploring the outcomes on the measures regarding gross motor development and quality of life, infants in the intervention groups generally showed lower scores and a slower developmental rate compared to typically developing infants, confirming a correct selection of high-risk infants in the intervention groups. Infants receiving EI-UL seem to have slightly higher scores on the quality of life measure compared to infants receiving EI-UL–MuSSAP training. The lower quality of life scores in the infants receiving EI-UL–MuSSAP intervention may be associated with a larger number of infants with lower physical well-being due to respiratory disease  effects of development while growing two (T1) and four (T2) months older cannot be distinguished. Due to ethical concerns that would raise by withholding early intervention programs to infants at high risk of developing uCP, we did not include a group of infants with unilateral brain lesion receiving no intervention. We observed a decline in manual ability in six infants with unilateral brain lesion during follow-up, while in typically developing infants only increases were observed, as expected. The decline in manual ability during follow-up suggests the presence of an intervention effect, although the size remains unknown. It may also suggest that 8 weeks of intervention were too short to give sustained improvement. Though, in most cases, manual ability at follow up was still higher than manual ability at baseline.Another limitation was the lack of a clinical measure for attention  at the start of the study. Therefore, we developed a scoring guideline (VOAAH) for scoring the videos made by the parents of the training sessions at home. The quality of these videos, however, was sometimes poor and scoring of the videos was a time-demanding procedure. For clinical purposes, a technology-based method (for example using gaze detection) may be a more feasible and reliable approach. Furthermore, it must be noted that looking at the wristband is a proxy measure of attention for the contralesional upper limb. Adding brain-based measures  to future studies may be of added value. This is a noninvasive, affordable technique that can be applied in young infants and children with CP , 31.Furthermore, blinded scoring of the outcome measures was not achieved. The occupational therapist who coached the families during the intervention also performed the measurements and scoring, since she was the only certified HAI assessor available in our clinic. By scoring a random selection of HAI assessments by a second certified HAI assessor from a different rehabilitation center in the Netherlands followed by a consensus meeting, reliability of the HAI scoring was enhanced as much as possible.Our pilot study indicated no significant differences between intervention groups on manual ability. Both the EI-UL and EI-UL–MuSSAP home-based intervention with video coaching may be feasible and potentially effective with regard to improving manual ability in infants at high risk of developing uCP. As it is not (yet) possible to predict what intervention and what intervention duration is most likely to induce permanent improvement of upper limb function in each individual infant, the choice of intervention should be based on clinical reasoning, feasibility, and the preferences of the family. From the results of the current pilot study, we could form the following hypothesis: infants who do not (yet) initiate goal-directed movements and who show diminished attention for the contralesional upper limb, may benefit more from an additional (multisensory) MuSSAP training than from EI-UL alone. Our hypothesis should be further investigated in a in a larger study comparing the results of an EI-UL and EI-UL–MuSSAP home-based intervention, stratifying participants by the absence of goal-directed movements of the affected upper limb at baseline. By adding brain-based measures, possible effects of the interventions on cortical reorganisation can be monitored.


Neurogenic lower urinary tract dysfunction is an abnormality in the presence of underlying neurologic disease. A recent systematic review and meta-analysis demonstrated that storage phase symptoms are the predominant symptoms among people with multiple sclerosis (PwMS). Transcutaneous tibial nerve stimulation (TTNS) is a non-invasive treatment for bladder storage symptoms; however, the potential efficacy of stimulation among PwMS is based on a small number of studies with the absence of high-quality evidence. The aim of this study was to evaluate the feasibility, acceptability, and safety of TTNS in PwMS using an affordable transcutaneous electrical nerve stimulation (TENS) unit.A total of 23 participants with MS enrolled in the study. The primary outcomes included recruitment/retention rate, completion of the outcomes and the intervention, adherence to the protocol, adverse events, and acceptability of the intervention. The primary outcomes were assessed using diaries and a satisfaction questionnaire. The secondary outcomes included changes in urinary symptoms and quality of life assessed using a set of validated outcome measures including a 3-day bladder diary, PPIUS, ICIQ-OAB, and KHQ at baseline and post-intervention.Twenty participants completed the study. Three participants (13.04%) withdrew. All 20 participants completed the 6-week intervention and all the outcome measures (100%), with no reported adverse events. Participants were satisfied and found the unit acceptable. Three-day bladder diary showed changes in urinary frequency from a daily median of 10 times to 8 times and daily median urgency changed from 6 times at baseline to 2 times post-intervention. PPIUS showed changes in daily median sever urgency from 3 points (IQR=4) to 1 point (IQR=1) post-intervention. ICIQ-OAB total scores changed from 8 points (IQR=2.25) to 4 points (IQR=2.5) post-intervention. Median and mean scores of KHQ showed a clinical meaningful change of QoL in part-two and part-three of the questionnaire.TTNS is feasible, safe, and acceptable for PwMS. Changes of urinary symptoms scores and QoL post-intervention suggested improvements. Future implications need to consider the treatment protocol including frequency of treatment sessions, duration of treatment, and the electrical stimulation parameters as well as the outcome measures followed in the current study for the implementation of the future pilot RCT.NCT04528784. Registered on 27 August 2020. https://register.clinicaltrials.gov/prs/app/action/LoginUser?ts=1&cx=-jg9qo4.ClinicalTrials.gov The online version contains supplementary material available at 10.1186/s40814-022-01120-1. It was uncertain whether people with multiple sclerosis could be recruited at the required rate for a pilot randomised controlled trial to be conducted in future study. It was uncertain whether Transcutaneous tibial nerve stimulation (TTNS) as an option to manage urinary symptoms could be feasible in terms of acceptability, completion of required outcome measures, and safety of the intervention.The intervention of TTNS using an affordable Transcutaneous electrical nerve stimulation (TENS) unit of 3 sessions/week for 6 weeks was found to be feasible, acceptable, and safe with a high adherence rate to the treatment protocol.Treatment protocol and the outcome measures followed in the current single-arm feasibility study were recommended for the future pilot RCT.Neurogenic lower urinary tract dysfunction (NLUTD) is an abnormality in the presence of underlying neurologic disease . The patIn PwMS, urinary symptoms negatively impacts on emotional wellbeing, physical health, employment opportunities, recreational activities, and social life –11. QualTibial nerve stimulation (TNS) is a form of non-surgical neuromodulation  and its The primary aim of the current study is to assess the feasibility and acceptability of TTNS. The secondary aim is to explore changes in bladder storage symptoms and quality of life following treatmentThis is a single-arm feasibility study conducted and reported in line with the CONSORT extension for pilot and feasibility studies  Additio. A detaiCommunity-dwelling people with any type of MS in the mid-West of Ireland were eligible to participate in the study if they met the following criteria: ambulatory (with or without assistive device), aged ≥18 years old, presented with at least one bladder storage-related symptom such as urinary frequency, urinary urgency, nocturia, with or without incontinence and were willing to give written informed consent.Recruitment to the study commenced in October 11, 2020, and follow-up was completed in March 12th 2021. Recruitment was conducted using two methods: (1) open recruitment for PwMS through MS Ireland’s communication channels including MS News e-zine, social media and direct email to members of the Mid-West branch of MS Ireland took place between October 2020 and January 2021; (2) a convenience sample of PwMS from existing participants who have already participated in our previous qualitative study  and baseOnce the baseline data were completed, participants received a downloadable 3- Day bladder diary by email. Participants were provided with a TENS unit and a short demonstration video for the application of TENS, and two downloadable documents: adverse events report diary and adherence to the treatment protocol. A follow-up virtual meeting was held to discuss the application of the unit with all participants. Weekly virtual meetings were also held with all participants to check adherence to the treatment protocol, adverse events, and address any participant queries.Post-intervention (at the end of week 6), all participants received another link to Qualtrics Survey Software to complete post-intervention measures and a downloadable 3-day bladder diary. Reminders complete measures were sent to all participants within 5 days.Description of intervention is presented in Table The primary outcome for this study was feasibility of the intervention. This was assessed using six different metrics: (1) the number of participants who were recruited to the study, the proportion of those who (2) completed the outcome measures, (3) the 6-week intervention, (4) adhered to the treatment protocol , (5) theSecondary outcomes were used to assess the changes in bladder storage symptoms and quality of life using the International Consultation of Incontinence Questionnaire- Overactive Bladder (ICIQ-OAB) , 26. TheAs this is a single-arm feasibility study and not designed to evaluate the clinical effectiveness, we did not undertake a formal power analysis for sample size for a primary outcome . We adopA minimum of 80% recruitmentA minimum of 80% completion rate of key outcome measuresA priori, our progression criteria to proceed to a pilot trial were determined by exploring if minimum success criteria were achieved in key feasibility aims and objectives including:SPSS software  was used for statistical analysis. All six measures of feasibility were analysed using descriptive statistics and reported as percentages and proportions. Continuous data were assessed for normality using the Shapiro-Wilks test. Means and standard deviations (SD) are reported where data are normally distributed, and medians and interquartile ranges (IQR) are reported as a conservative estimate where data are not normally distributed. The secondary outcomes of the ICIQ-OAB, KHQ  and the Between October 2020 and January 2021, 25 participants expressed an interest in participating in the study; 23 participants enrolled in the study, 20 participants completed the study Three participants (13.04%) discontinued their participation: one withdrew from the study before commencing the intervention due to inability to commit for 6-week, and two participants were lost to follow-up before commencing the study. All 20 participants who completed the 6-week intervention completed all outcome measures (100%). The flow of study participants is outlined in Fig. 1n=20) and those who discontinued/withdrew (n=3). Of the 20 participants who completed the study, 6 (30%) were male and 14 (70%) were female. The duration of MS varied from one to 45 years with the onset of LUTSs varied from one to 25 years. The most common type of MS was relapsing remitting (RRMS) . All participants reported their urinary symptoms as a combination of symptoms  whereas storage symptoms were reported in seven cases (35%). The most frequently reported symptom was urgency  followed by frequency  and nocturia .Table n=1) redness after first stimulation session and (n=1) dry skin at the stimulation site that cleared up after 8 days. This did not impact treatment adherence.There were no reported stimulation-related adverse events in the participants during the study intervention phase. Two (10%) participants reported skin reactions in the site of the stimulation with  are shown in Table Table The daily median urgency scores (grade 3) assessed by PPIUS changed from 3 points (IQR=4) to 1 point (IQR=1) post-intervention with no changes were reported in daily median urgency urinary incontinence (UUI). Daily average fluid consumption remained stable across both timepoints.The ICIQ-OAB median scores are summarised in Table The KHQ scores at baseline and post-intervention are summarised in Table This study demonstrates the feasibility and acceptability of TTNS for bladder storage symptoms in PwMS using an accessible and affordable TENS unit. Our key progression criteria to continue to a pilot randomised controlled trial were achieved. Participants reported high levels of satisfaction with the study protocol and high adherence was reported for completion of the 6 weeks intervention with no serious adverse events reported in the current study.Adherence to the intervention was high and may have been influenced by weekly follow-up calls. A meta-analysis of 127 included studies showed that the odds of patients’ treatment adherence are 2.16 times higher with effective communication and regular monitoring between healthcare providers and patients . TTNS inWe did not seek to examine if participants experienced significant changes in urinary symptoms and quality of life from baseline to post-intervention due to our primary focus on exploring feasibility. However, changes in scores of urinary symptoms using 3-day bladder suggest improvements of urinary frequency and urgency episodes post-intervention of TTNS. In line with our findings, one study  found thThe current study findings demonstrated a positive trend in reducing the urgency severity symptom scores using PPIUS and reducing urgency episodes, and nocturia using ICIQ with a reduction in scores of QoL measures detected by KHQ indicating improvements of urinary symptoms post TTNS. Similar to current study findings, a reduction in urinary urgency scores following TTNS has been shown among 75 non-neurogenic OAB participants , and amoInclusion of long-term follow-up of the intervention (12 months)Include sham-arm to investigate the effectiveness of TTNS on NLUTD in MSProvision of a face-to-face option rather than online only to widen the recruitment and support MS participants who do not have access to the internet.Remaining uncertainty that needs to be addressed in the randomised pilot trial is as follows:TTNS is feasible, acceptable, and safe in clinical practice with PwMS and bladder storage symptomsRates of recruitment and retention to this feasibility study were acceptableFuture Pilot RCT are warranted to assess the effectiveness of TTNS in PwMS and bladder storage symptomsThe current study demonstrates that TTNS is feasible, safe, and acceptable to PwMS. Changes of urinary symptoms scores between baseline and post-intervention suggested improvements in bladder storage symptoms and QoL measures. These findings serve as a preliminary step to inform the development of an evidence-based future pilot randomised controlled trial (RCT) using standardised reporting of outcome measures. We recommend following the treatment protocol, the electrical stimulation parameters, and the outcome measures applied in the current feasibility study for the implementation plan of the future pilot RCT.Additional file 1. CONSORT 2010 checklist of information to include when reporting a pilot or feasibility trial*.