Dispatcher-assistance in lay rescuer infant CPR: Promoting the enhancement of the guiding protocol.

In the 2021 guidelines of the European Resuscitation Council (ERC) on infant CPR, a two-thumb encircling technique (TTET) is advised instead of the former two-finger technique (TFT), even for single rescuers. It is however unclear if this is also feasible and effective in case of dispatcher-assisted CPR by untrained bystanders and was explored in a cross-over infant manikin study including CPR-trained students and lay people. Both groups performed the TTET and the TFT, with dispatcher-assistance (according to Belgian protocol) only being provided to the CPR-untrained group. Results suggest it is feasible to advice single lay rescuers to perform TTET as part of a dispatcher-assisted CPR protocol, although we identified an ongoing risk, regardless of the technique advised, of suboptimal compression depth. Further research should be performed to confirm these preliminary data and explore optimal protocols for dispatcher-assisted infant CPR.

Clinician-reported outcome measures for the assessment of vitiligo: A scoping review.

Clinician-reported outcome measures (ClinROMs) are essential for assessment of vitiligo in clinical trials and daily practice. Several instruments have been developed and tested to measure, for example, vitiligo extent, repigmentation and activity. The goal of this review was to identify all introductory publications of ClinROMs for vitiligo that include at least some aspects of validation and to describe the instruments' characteristics, intention for use and practical strengths and limitations. A search strategy was conducted in PubMed, Embase and Cochrane Library (CENTRAL) from inception to July 2022. Based on the literature search (n = 2860), 10 articles were identified, describing 14 different ClinROMs. Six ClinRoms measured disease extent and/or repigmentation, seven evaluated disease activity and one was a composite score. The Vitiligo Area Scoring Index (VASI), and Vitiligo Extent Score (VES and VESplus) measure overall disease extent and/or repigmentation. The VASI relies on hand units (1% body surface area), whereas the VES and VESplus use a picture-based scoring technique. The Vitiligo Extent Score for a Target Area (VESTA) measures repigmentation percentage for target lesions. One global assessment score for extent has been validated. Vitiligo disease activity scores included a static measure of clinical activity signs (Vitiligo Signs of Activity Score [VSAS]) and two measures assessing dynamic evolution (Vitiligo Disease Activity Score [VDAS] and Vitiligo Disease Improvement Score [VDIS]). The Vitiligo European Task Force assessment tool (VETFa) is a composite score. Depending on the practical strengths and limitations as well as the research question and setting (clinical trials vs. daily practice), the choice of an appropriate ClinROM may differ. Fourteen ClinROMs in vitiligo were identified to measure vitiligo extent, repigmentation, and activity. Further research evaluating the validity, reliability, and responsiveness of each instrument and worldwide consensus on which instrument to use for a specific outcome (domain) is greatly needed.

Five vs. two initial rescue breaths during infant basic life support: A manikin study using bag-mask-ventilation.

Background and objectives: Children are more likely to suffer a hypoxic-ischaemic cause for cardiac arrest. Early ventilation may provide an advantage in outcome during paediatric cardiopulmonary resuscitation [CPR]. European Resuscitation Council guidelines recommend five initial rescue breaths [IRB] in infants, stemming from the hypothesis that rescuers might need 5 attempts in order to deliver 2 effective ventilations. This study aimed to verify this hypothesis. Methods: Participants (n = 112, convenience sample) were medical students from the Faculty of Medicine and Health Sciences Ghent University, Belgium. Students were divided into duos and received a 15 min just-in-time training regarding the full CPR-cycle using BMV. Participants then performed five cycles of 2-person CPR. The IRB were given by 1-person BMV, as opposed to a 2-persons technique during the further CPR-cycle. Correct ventilations for the infant were defined as tidal volumes measured (Laerdal® Q-CPR) between 20 and 60 ml, with n = 94 participants included in the analysis. The primary outcome consisted of the difference in the % of medical student duos providing at least 2 effective IRB between 2 and 5 attempts. Results: Off all duos, 55,3% provided correct volumes during their first 2 initial ventilations. An increase up to 72,4% was noticed when allowing 5 ventilations. The proportional difference between 2 and 5 IRB allowed was thus significant [17,0%, 95% confidence interval (5.4; 28.0)]. Conclusion: In this manikin study, 5 IRB attempts during infant CPR with BMV increased the success rate in delivering 2 effective ventilations. Besides, students received training emphasizing the need for 5 initial rescue breaths. This study provides evidence supporting European Resuscitation Council guidelines.

Credibility and Generalization of the Minimally Important Difference Concept in Dermatology: A Scoping Review.

Importance: The minimally important difference (MID) represents the point at which a difference in an outcome measure (eg, Dermatology Life Quality Index) is important enough that it warrants a change in treatment, and, to the authors' knowledge, the robustness and limitations of MIDs have not been thoroughly evaluated in skin diseases. The MID is increasingly used in clinical trials to demonstrate that an intervention is worthwhile for patients; furthermore, MIDs also contribute to sample size calculations in clinical trials, influence treatment guidelines, and can guide clinicians to modify treatment. Objective: To evaluate the credibility and generalization of MIDs for patient-reported outcome measures (PROMs) in skin disorders. Evidence Review: A systematic search was conducted in PubMed and Embase for all original articles using the MID concept for skin disorders from inception to December 29, 2021. The credibility of MIDs obtained via an anchor-based approach (eg, global rating of change scale) was assessed with a previously developed credibility instrument. The validity of generalizing established MIDs to other patient groups was evaluated based on the diagnosis and the patient characteristics. Findings: A total of 126 articles were selected, and 84 different MIDs were identified for PROMs. A total of 13 of 84 MIDs (15.5%) for PROMs displayed acceptable credibility. The anchors used had varying capacity to assess minimal important changes from a patient's perspective and were deemed inappropriate for this purpose in 52 of 84 cases (61.9%). Correlations between the anchors and PROMs were frequently not determined (39 of 84; 46.4%). The time interval for anchor questions assessing a change in the experienced disease burden was not optimal for 10 of 32 transition anchors (>3 months), introducing potential recall bias. Previously reported MIDs were widely used to examine relevant changes in other study populations. However, the diagnosis and disease severity were different from the original MID population in 39 of 70 (55.7%) and 45 of 70 (64.3%) cases, respectively. Conclusions and Relevance: In this scoping review, only a minority of MIDs for PROMs demonstrated sufficient credibility in dermatology. Inappropriate generalization of previously reported MIDs to patient populations with different disease characteristics was found to be a major concern. Furthermore, the study supported the use of multiple anchors and encouraged consistent reporting of the correlation between changes in the anchor and changes in the outcome measures.

The Meaning and Reliability of Minimal Important Differences (MIDs) for Clinician-Reported Outcome Measures (ClinROMs) in Dermatology-A Scoping Review.

Background: Clinician-reported outcome measures (ClinROMs) are frequently used in clinical trials and daily practice to evaluate the disease status and evolution of skin disorders. The minimal important difference (MID) represents the smallest difference that decreases the disease impact enough to make a treatment change worthwhile for patients. As no clear guidance exists on the preferred method to calculate MIDs for ClinROMs, we evaluated how the published values for different skin disorders should be interpreted. Methods: A systematic search was performed for MIDs of ClinROMs that focus on skin disorders and/or symptoms. The results of the questions in the credibility instrument for MIDs of Devji et al., 2020 were analyzed to gain insights into the meaning of these MIDs. Results: 29 MIDs were identified. The most common skin diseases were atopic dermatitis/eczema, followed by bullous disorders and psoriasis. A minimal important difference from the patients' perspective was determined in 31% of the cases. However, in 41.4% of the cases, it concerned a substantial rather than a minimal difference in disease severity rated by physicians. Over half (55.1%) of the studies contained an inadequate number of patients (n < 150). MID values increased substantially in patients with severe compared to mild disease. Conclusions: MIDs of ClinROMs for skin disorders should be carefully interpreted due to the substantial differences in methodology between the studies. There is an urgent need for a consensus method to report reliable MIDs. Otherwise, this lack of uniformity could not only affect the design and conclusion of clinical trials but also skew treatment decisions.

Image analysis systems to calculate the surface area of vitiligo lesions: A systematic review of measurement properties.

Several digital image analysis systems have been developed for surface calculation of vitiligo lesions. Critical assessment of their measurement properties is crucial to support evidence-based recommendations on the most suitable instruments and will reveal the need for future research. A systematic review was performed to systematically summarize, compare, and critically assess the measurement properties of digital and analogue analysis systems for surface calculation of vitiligo lesions following the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) recommendations. Nineteen clinical trials were selected including 25 different instruments. Manual tracing on transparent sheets (contact planimetry) combined with digital measurement or point counting can be considered as the best validated method for the evaluation of target lesions taking into account the skin curvatures. Two-dimensional digital imaging analysis on photographs seems also robust although confirmatory data of different research groups using the same digital instrument in a wide range of skin types are missing. Analysis based on 3D photography is still in its early stage but is promising for whole-body analysis. However, the reported data on the quality of the instruments for surface area calculation of vitiligo lesions were in general rather limited. Therefore, future high-quality validation studies are required also including full body evaluations.

Syncope in Dental Practices: A Systematic Review on Aetiology and Management.

INTRODUCTION: This systematic review aimed to give an overview of the current evidence surrounding the aetiology and management in terms of treatment and prevention of syncope in dental practices. Alongside the occurrence, the practitioner's competence, and the association between syncope and local anaesthetics were discussed. METHODS: An electronic search in EMBASE, Web of Science, PubMed, Cochrane databases and a hand search were performed by 2 independent reviewers to identify studies up to November 2019. Eligibility criteria were applied and relevant data was extracted. Inclusion criteria covered all types of dental treatment under local anaesthesia or conscious sedation performed by a wide range of oral health care workers in their practices. Risk of bias of the included studies was assessed using the methodological tools recommend by Zeng et al.1 No restrictions were made to exclude papers from qualitive analysis based on risk of bias assessment. RESULTS: The search yielded a total of 18 studies for qualitative analysis. With the exception of one prospective cohort study, all articles were considered having a high risk of bias. Meta-analysis showed that dentists encountered on average 1.2 cases of syncope per year. The male gender (RR = 2.69 [1.03, 7.02]), dental fear (RR = 3.55 [2.22, 5.70]), refusal of local anaesthesia in non-acute situations (OR = 12.9) and the use of premedication (RR = 4.70, [1.30, 16.90]) increased the risk for syncope. Treatment and prevention were underreported as both were solely discussed in one study. The supine recovery position with raised legs and oxygen administration (15l/min) was presented as an effective treatment. The Medical Risk-Related History (MRRH) system was proposed as prevention protocol, yet this protocol was ineffective in reducing incidence rates (p = 0.27). The majority of dentists (79.2%) were able to diagnose syncope, yet most (86%) lacked the skills for appropriate treatment. Only 57,6% of dental practices were equipped with an oxygen cylinder. CONCLUSIONS: Syncope is the most common emergency in dental practices. Nonetheless, the vast majority of dentists do not seem competent nor prepared to manage this emergency. Psychogenic factors seem to play an important role in provoking syncope. Placing the patient in a supine reclined position with raised legs in combination with the administration of oxygen seems effective for regaining consciousness. Although valuable in many aspects, risk assessment by medical history taking is not proven to result in fewer episodes. The strength of these conclusions is low based on GRADE guidelines.2.

The PKA-p38MAPK-NFAT5-Organic Osmolytes Pathway in Duchenne Muscular Dystrophy: From Essential Player in Osmotic Homeostasis, Inflammation and Skeletal Muscle Regeneration to Therapeutic Target.

In Duchenne muscular dystrophy (DMD), the absence of dystrophin from the dystrophin-associated protein complex (DAPC) causes muscle membrane instability, which leads to myofiber necrosis, hampered regeneration, and chronic inflammation. The resulting disabled DAPC-associated cellular pathways have been described both at the molecular and the therapeutical level, with the Toll-like receptor nuclear factor kappa-light-chain-enhancer of activated B cells pathway (NF-ƘB), Janus kinase/signal transducer and activator of transcription proteins, and the transforming growth factor-ß pathways receiving the most attention. In this review, we specifically focus on the protein kinase A/ mitogen-activated protein kinase/nuclear factor of activated T-cells 5/organic osmolytes (PKA-p38MAPK-NFAT5-organic osmolytes) pathway. This pathway plays an important role in osmotic homeostasis essential to normal cell physiology via its regulation of the influx/efflux of organic osmolytes. Besides, NFAT5 plays an essential role in cell survival under hyperosmolar conditions, in skeletal muscle regeneration, and in tissue inflammation, closely interacting with the master regulator of inflammation NF-ƘB. We describe the involvement of the PKA-p38MAPK-NFAT5-organic osmolytes pathway in DMD pathophysiology and provide a clear overview of which therapeutic molecules could be of potential benefit to DMD patients. We conclude that modulation of the PKA-p38MAPK-NFAT5-organic osmolytes pathway could be developed as supportive treatment for DMD in conjunction with genetic therapy.

Description of a Novel Mechanism Possibly Explaining the Antiproliferative Properties of Glucocorticoids in Duchenne Muscular Dystrophy Fibroblasts Based on Glucocorticoid Receptor GR and NFAT5.

Glucocorticoids are drugs of choice in Duchenne muscular dystrophy (DMD), prolonging patients' ambulation. Their mode of action at the protein level is not completely understood. In DMD, muscle tissue is replaced by fibrotic tissue produced by fibroblasts, reducing mobility. Nuclear factor of activated T-cells 5 (NFAT5) is involved in fibroblast proliferation. By treating one DMD fibroblast cell culture and one of unaffected skeletal muscle fibroblasts with methylprednisolone (MP) or hydrocortisone (HC) for 24 h or 12 d, the antiproliferative properties of glucocorticoids could be unraveled. NFAT5 localization and expression was explored by immunocytochemistry (ICC), Western blotting (WB) and RT-qPCR. NFAT5 and glucocorticoid receptor (GR) colocalization was measured by ImageJ. GR siRNA was used, evaluating GR's influence on NFAT5 expression during MP and HC treatment. Cell proliferation was monitored by IncuCyte ZOOM. In DMD fibroblasts, treatment with MP for 24 h induced dots (ICC) positive for NFAT5 and colocalizing with GR. After 12 d of MP or HC in DMD fibroblasts, NFAT5 expression was decreased (RT-qPCR and WB) and growth arrest was observed (Incucyte ZOOM), whereas NFAT5 expression and cell growth remained unchanged in unaffected skeletal muscle fibroblasts. This study may help understand the antiproliferative properties of glucocorticoids in DMD fibroblasts.

Abnormal NFAT5 Physiology in Duchenne Muscular Dystrophy Fibroblasts as a Putative Explanation for the Permanent Fibrosis Formation in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by chronic inflammation and fibrotic tissue production by fibroblasts. The promyogenic factor nuclear factor of activated T-cells 5 (NFAT5) is virtually present in all cells, responding to hyperosmolar or pro-inflammatory stress. In embryogenic fibroblasts, absence of NFAT5 results in cell cycle arrest. Here, unaffected skeletal muscle fibroblasts from one healthy donor showed NFAT5 nuclear translocation upon hyperosmolar stress and normal cell viability. Absence of NFAT5 translocation under pro-inflammatory conditions resulted in decreased cell growth (Incucyte ZOOM). In DMD skeletal muscle fibroblasts from one DMD patient, NFAT5 was merely located in the nucleus. Exposure to hyperosmolar conditions or pro-inflammatory cytokines IFN-γ, IL-1ß and TNF-α had no influence on NFAT5 physiology (immunofluorescence, western blotting, RT-qPCR). Hyperosmolarity resulted in decreased cell viability and pro-inflammatory stress in unaltered cell growth. These findings suggest that NFAT5 is vital to DMD fibroblast survival. Exposure to pro-inflammatory or hyperosmolar stress in DMD fibroblasts results in an unexpected NFAT5 response, where fibroblasts are not triggered by inflammatory cytokines and do not withstand hyperosmolarity. Chronic inflammation could be viewed as a non-restrictive factor in the formation of fibrosis in DMD. Abnormal NFAT5 physiology could provide a molecular explanation for permanent fibrotic matrix production by DMD fibroblasts.

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents.

In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.

Immune checkpoint failures in inflammatory myopathies: An overview.

Dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), immune mediated necrotizing myopathy (IMNM) and overlap myositis (OM) are classified as inflammatory myopathies (IM) with involvement of autoimmune features such as autoreactive lymphocytes and autoantibodies. Autoimmunity can be defined as a loss in self-tolerance and attack of autoantigens by the immune system. Self-tolerance is achieved by a group of immune mechanisms occurring in central and periphal lymphoid organs and tissues, called immune checkpoints, that work in synergy to protect the body from harmful immune reactions. Autoimmune disorders appear when immune checkpoints fail. In this review, the different immune checkpoint failures are discussed in DM, PM, IBM and IMNM. Exploring research contribution in each of these immune checkpoints might help to highlight research perspectives in the field and obtain a more complete picture of IM disease pathology.

Localization and Expression of Nuclear Factor of Activated T-Cells 5 in Myoblasts Exposed to Pro-inflammatory Cytokines or Hyperosmolar Stress and in Biopsies from Myositis Patients.

Aims: Regeneration in skeletal muscle relies on regulated myoblast migration and differentiation, in which the transcription factor nuclear factor of activated T-cells 5 (NFAT5) participates. Impaired muscle regeneration and chronic inflammation are prevalent in myositis. Little is known about the impact of inflammation on NFAT5 localization and expression in this group of diseases. The goal of this study was to investigate NFAT5 physiology in unaffected myoblasts exposed to cytokine or hyperosmolar stress and in myositis. Methods: NFAT5 intracellular localization and expression were studied in vitro using a cell culture model of myositis. Myoblasts were exposed to DMEM solutions enriched with pro-inflammatory cytokines IFN-γ with IL-1ß or hyperosmolar DMEM obtained by NaCl supplementation. NFAT5 localization was visualized using immunohistochemistry (IHC) and Western blotting (WB) in fractionated cell lysates. NFAT5 expression was assessed by WB and RT-qPCR. In vivo localization and expression of NFAT5 were studied in muscle biopsies of patients diagnosed with polymyositis (n = 6), dermatomyositis (n = 10), inclusion body myositis (n = 11) and were compared to NFAT5 localization and expression in non-myopathic controls (n = 13). Muscle biopsies were studied by means of quantitative IHC and WB of total protein extracts. Results: In unaffected myoblasts, hyperosmolar stress ensues in NFAT5 nuclear translocation and increased NFAT5 mRNA and protein expression. In contrast, pro-inflammatory cytokines did not lead to NFAT5 nuclear translocation nor increased expression. Cytokines IL-1ß with IFN-γ induced colocalization of NFAT5 with histone deacetylase 6 (HDAC6), involved in cell motility. In muscle biopsies from dermatomyositis and polymyositis patients, NFAT5 colocalized with HDAC6, while in IBM, this was often absent. Conclusions: Our data suggest impaired NFAT5 localization and expression in unaffected myoblasts in response to inflammation. This disturbed myogenic NFAT5 physiology could possibly explain deleterious effects on muscle regeneration in myositis.

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism.

Alongside well-known nuclear factor κB (NFκB) and its associated cytokine networks, nuclear factor of activated T cells 5 (NFAT5), the master regulator of cellular osmoprotective programs, comes forward as an inflammatory regulator. To gain insight into its yet unexplored role in muscle disease, we studied the expression of NFAT5 target proteins involved in osmolyte accumulation: aldose reductase (AR), taurine transporter (TauT), and sodium myo-inositol co-transporter (SMIT). We analyzed idiopathic inflammatory myopathy and Duchenne muscular dystrophy muscle biopsies and myotubes in culture, using immunohistochemistry, immunofluorescence, and western blotting. We report that the level of constitutive AR was upregulated in patients, most strongly so in Duchenne muscular dystrophy. TauT and SMIT expression levels were induced in patients' muscle fibers, mostly representing regenerating and atrophic fibers. In dermatomyositis, strong staining for AR, TauT, and SMIT in atrophic perifascicular fibers was accompanied by staining for other molecular NFAT5 targets, including chaperones, chemokines, and inducible nitric oxide synthase. In these fibers, NFAT5 and NFκB p65 staining coincided, linking both transcription factors with this important pathogenic hallmark. In sporadic inclusion body myositis, SMIT localized to inclusions inside muscle fibers. In addition, SMIT was expressed by a substantial subset of muscle-infiltrating macrophages and T cells in patient biopsies. Our results indicate that osmolyte pathways may contribute to normal muscle functioning, and that activation of AR, TauT, and SMIT in muscle inflammation possibly contributes to the tissue's failing program of damage control.