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Monoacylglycerol lipase (MAGL) is a gatekeeper in regulating endocannabinoid signaling and has gained substantial attention as a therapeutic target for neurological disorders. We recently discovered a morpholin-3-one derivative as a novel scaffold for imaging MAGL via positron emission tomography (PET). However, its slow kinetics in vivo hampered the application. In this study, structural optimization was conducted and eleven novel MAGL inhibitors were designed and synthesized. Based on the results from MAGL inhibitory potency, in vitro metabolic stability and surface plasmon resonance assays, we identified compound 7 as a potential MAGL PET tracer candidate. [11C]7 was synthesized via direct 11CO2 fixation method and successfully mapped MAGL distribution patterns on rodent brains in in vitro autoradiography. PET studies in mice using [11C]7 demonstrated its improved kinetic profile compared to the lead structure. Its high specificity in vivo was proved by using MAGL KO mice. Although further studies confirmed that [11C]7 is a P-glycoprotein (P-gp) substrate in mice, its low P-gp efflux ratio on cells transfected with human protein suggests that it should not be an issue for the clinical translation of [11C]7 as a novel reversible MAGL PET tracer in human subjects. Overall, [11C]7 ([11C]RO7284390) showed promising results warranting further clinical evaluation., European Journal of Medicinal Chemistry, 243, ISSN:0223-5234, ISSN:1768-3254

Introduction Juvenile idiopathic arthritis (JIA) is a chronic disease characterized by persistent joint inflammation. JIA is the most common pediatric chronic rheumatic disease and no curative therapy is currently available. Methotrexate (MTX) is an important treatment for JIA even though a high inter-individual variability in response is observed in patients. Among the factors of this variability, genetics and epigenetics might play an important role. Areas covered This review summarizes the results of pharmacogenetic and pharmacoepigenetic studies regarding MTX response in JIA. Studies considering epigenetic factors in JIA patients are still very limited, therefore this review includes also studies performed in adult patients with rheumatoid arthritis. Moreover, the relevance of biomarkers measured in blood or urine of JIA patients in relation to MTX treatment is discussed. Expert opinion Nowadays, even though many pharmacogenomics studies have been published, a specific genetic marker predictor of MTX efficacy or adverse events has not yet been identified. Encouraging results are available and great expectations rely on the study of epigenetics. Future studies are needed in order to identify genetic and epigenetic biomarkers that can be implemented in the clinical practice.

Background Italy was the first Western country to be hit by the SARS-CoV-2 epidemic. There is now mounting evidence that a minority of children infected with SARS-CoV2 may experience a severe multisystem inflammatory syndrome, called Multisystem inflammatory Syndrome associated with Coronavirus Disease 2019 (MIS-C). To date no universally agreed approach is available for this disease. Main body as Italy is now facing a second hity of COVID-19 cases, we fear a recrudescence of MIS-C cases. We have, therefore, decided to prepare a report that will help clinicians to face this novel and challenging disease. We propose a diagnostic algorithm, to help case definition and guide work-up, and a therapeutic approach. MIS-C should be promptly recognized, based on the presence of systemic inflammation and specific organ involvement. Early treatment is crucial, and it will be based on the combined use of corticosteroids, high-dose immunoglobulins and anti-cytokine treatments, depending on the severity of the disease. Ancillary treatments (such as. aspirin and thrombo-profilaxis) will be also discussed. Conclusions we propose a document that will help physicians to diagnose and treat MIS-C patients. Given the level of evidence available and the methodology used, this document should not be interpreted as a guideline; the final decision about the optimal management should still be taken by the caring physician, on an individual basis.

Background Recurrent aphthous stomatitis with systemic signs of inflammation can be encountered in inflammatory bowel disease, Behçet’s disease (BD), Systemic Lupus Erythematosus (SLE). In addition, it has been proposed that cases with very early onset in childhood can be underpinned by rare monogenic defects of immunity, which may require targeted treatments. Thus, subjects with early onset recurrent aphthous stomatitis receiving a clinical diagnosis of BD-like or SLE-like disease may deserve a further diagnostic workout, including immunologic and genetic investigations. Objective To investigate how an immunologic, genetic and transcriptomics assessment of interferon inflammation may improve diagnosis and care in children with recurrent aphthous stomatitis with systemic inflammation. Methods Subjects referred to the pediatric rheumatologist for recurrent aphthous stomatitis associated with signs of systemic inflammation from January 2015 to January 2020 were enrolled in the study and underwent analysis of peripheral lymphocyte subsets, sequencing of a 17-genes panel and measure of interferon score. Results We enrolled 15 subjects (12 females, median age at disease onset 4 years). The clinical diagnosis was BD in 8, incomplete BD in 5, BD/SLE overlap in 1, SLE in 1. Pathogenic genetic variants were detected in 3 patients, respectively 2 STAT1 gain of function variants in two patients classified as BD/SLE overlap and SLE, and 1 TNFAIP3 mutation (A20 haploinsufficiency) in patients with BD. Moreover 2 likely pathogenic variants were identified in DNASE1L3 and PTPN22, both in patients with incomplete BD. Interferon score was high in the two patients with STAT1 GOF mutations, in the patient with TNFAIP3 mutation, and in 3 genetic-negative subjects. In two patients, the treatment was modified based on genetic results. Conclusions Although recurrent aphthous stomatitis associated with systemic inflammation may lead to a clinical diagnosis of BD or SLE, subjects with early disease onset in childhood deserve genetic investigation for rare monogenic disorders. A wider genetic panel may help disclosing the genetic background in the subset of children with increased interferon score, who tested negative in this study.

BackgroundSARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD).ObjectiveWith this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations.MethodsWe investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission.ResultsPatients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19.ConclusionsOur results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C.

Needle procedures are among the most common causes of pain and distress for individuals seeking health care. While needle pain is especially problematic for children needle pain and associated fear also has significant impact on adults and can lead to avoidance of appropriate medical care. Currently there is not a standard definition of needle pain. A taxonomy, or classification system, for acute needle pain would aid research efforts and enhance clinical care. To meet this need, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the U.S. Food and Drug Administration, the American Pain Society, and the American Academy of Pain Medicine formed the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society-American Academy of Pain Medicine Pain Taxonomy initiative. One of the goals of this initiative was to develop taxonomies for acute pain disorders, including needle pain. To accomplish this, a working group of experts in needle pain was convened. Based on available literature and expert opinion, the working group used a 5-dimenional structure (diagnostic criteria, common features, modulating factors, impact and/or functional consequences, and putative mechanisms) to develop an acute pain taxonomy that is specific needle pain. As part of this, a set of 4 diagnostic criteria, with 2 modifiers to account for the influence of needle associated fear, are proposed to define the types of acute needle pain. PERSPECTIVE: This article presents a taxonomy for acute needle pain. This taxonomy could help to standardize definitions of acute pain in clinical studies of patients undergoing needle procedures.

In this retrospective multicentre study based on cardiac MR, the cardiological outcome of MIS-C patients does appear favourable regardless of severity of the cardiac involvement during the acute phase.

Most Cystic Fibrosis (CF) patients succumb to airway inflammation and pulmonary infections due to Pseudomonas aeruginosa. D-BMAP18, a membrane-permeabilizing antimicrobial peptide composed of D-amino acids, was evaluated as a possible antibacterial aimed to address this issue. The antipseudomonal activity of D-BMAP18 was tested in a pathophysiological context. The peptide displayed activity against CF isolates of Pseudomonas aeruginosa in the presence of CF sputum when combined with sodium chloride and DNase I. In combination with DNase I, D-BMAP18 discouraged the deposition of new biofilm and eradicated preformed biofilms of some P. aeruginosa strains. In addition, D-BMAP18 down regulated the production of TNF-&alpha, IL1-&beta, and TGF-&beta, in LPS-stimulated or IFN-&gamma, macrophages derived from THP-1 cells indicating an anti-inflammatory activity. The biocompatibility of D-BMAP18 was assessed using four different cell lines, showing that residual cell-specific cytotoxicity at bactericidal concentrations could be abolished by the presence of CF sputum. Overall, this study suggests that D-BMAP18 may be an interesting molecule as a starting point to develop a novel therapeutic agent to simultaneously contrast lung infections and inflammation in CF patients.

Objective-The aim of the study is to evaluate the compliance rate to secondary prophylaxis and the presence of Rheumatic Heart Disease (RHD) in a cohort of Italian patients with Acute Rheumatic Fever (ARF). Methods-This is a multicentre retrospective study. Patients were divided into two groups according to the presence or absence at last follow-up of RHD. Clinical features, ARF recurrences and the rate of compliance to secondary prophylaxis were evaluated. Results-wo hundred and ninety patients were enrolled (137 females, 153 males). Carditis at onset was present in 244 patients (84.7%). At the end of follow-up, 173 patients showed RHD. Adherence to secondary prophylaxis was low in 26% of patients. The presence of RHD at follow-up was associated with the presence of carditis and its severity at onset (p = 0.001), but it was not related to secondary prophylaxis adherence (p = NS). No association between prophylaxis adherence and ARF recurrence was found p = NS) nor between ARF recurrence and RHD at the end of follow-up (p = NS). Conclusions-Poor adherence to secondary prophylaxis does not seem to be associated with increased risk of RHD in developed countries. Further studies are needed to confirm the reported data in a larger population.

Background FBLIM1 gene has been recently demonstrated to be involved in the pathogenesis of bone sterile inflammation. The aim of the study is to evaluate the prevalence of FBLIM1 gene variants in a cohort of 80 Italian patients with Chronic Non-bacterial Osteomyelitis (CNO). Methods The coding regions of FBLIM1 gene were sequenced in a cohort of 80 patients with CNO using DNA extracted from blood lymphocytes, and PCR products were sequenced. Only rare (global MAF Results Eighteen out of 80 patients (~ 22%) presented at least one rare coding variant in FBLIM1. Eight patients presented a variant never associated before with CNO. All patients presented classical features of CNO and no statistical difference between patients with presence of FBLMI1 variants and those without were found in terms of clinical manifestation, treatment, and outcome. Conclusion Considering the high frequency of rare variants in our CNO cohort, our data seem to confirm a possible role of FBLIM1 in the pathogenesis of CNO suggesting that CNO is a disorder of chronic inflammation and imbalanced bone remodeling.

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Background Systemic lupus erythematosus (SLE) is a complex multi-system disease, characterized by both autoimmune and autoinflammatory clinical and laboratory features. The role of type I interferon (IFN) in SLE has been demonstrated from the 2000s, by gene expression analyses showing significant over-expression of genes related to type I IFN signalling pathway (IFN signature). However, several studies questioned the role of measuring the intensity of IFN signature (IFN score) to chase SLE activity. We would assess if the IFN signature can help the clinical and therapeutic stratification of patients with pediatric SLE. Methods We measured the IFN score in peripheral whole blood from a series of subjects with childhood-onset SLE and correlated the results with clinical and laboratory parameters. Results Thirty-one subjects were included in the study, among which the 87% displayed a positive IFN score. The only significant relation was found for high IFN score in subjects with normocomplementemia. No correlation was observed between IFN score and SLEDAI-2K, BILAG-2004 and SLICC. Patients with high IFN score and normal complement levels also presented lower anti-dsDNA antibodies. Conclusions The integration between IFN signature analysis and complement levels may easily distinguish two groups of subjects, in which the autoimmune or autoinflammatory component of the disease seems to be prevalent.

A 3-year-old boy presented with a 5-day history of bullous skin lesions localised mainly in the upper and lower limbs and in the genital region (figure 1). Lesions were not pruritic nor painful and showed a central crust. There was no family history of skin disorders or autoimmune diseases. The child never had fever and his physical examination was otherwise unremarkable.Figure 1Bullous skin lesions forming around a central crust, localised in the upper and lower limbs.QuestionsWhat is the most likely diagnosis based on this clinical presentation?Bullous impetigo.Bullous pemphigoid.Linear IgA bullous dermatosis.Dermatitis herpetiformis.What would be the next step in the investigation to confirm your diagnosis?Skin biopsy.Swab test for bacterial culture with an antibiogram.Anti-transglutaminase antibody detection.What is the mainstay of management?Dapsone.Systemic steroids.Topical steroids.All of the above answers are correct, according to the severity of the disease.Answers can be found on page 02.

Introduction: Italy was affected by the SARS-CoV-2 epidemic after its outbreak in China. With a 4-weeks delay after the peak in adults, we observed an abnormal number of patients with characteristics of a multi-inflammatory disease and similarities with Kawasaki Disease (KD). Others reported similar cases, defined PIMS-TS or MIS-C.1,2 Objectives: To better characterize clinical features and treatment response of PIMS-TS and to explore its relationship with KD. Methods: We conducted an observational, retrospective, multicenter study. On April 24th-2020 the Rheumatology Study Group of the Italian Pediatric Society launched a national online survey, to enroll patients diagnosed with KD or with a multisystem inflammatory disease between February 1st 2020 and May 31st. The population was then divided into two different groups: 1) Classical and incomplete KD, named Kawasaki Disease Group (KDG); 2) KD-like multi-inflammatory syndrome, named KawaCOVID (KCG). An expert panel of pediatric rheumatologists re-analyzed every single patient to ensure appropriate classification. Data were collected with an online database. Results: 149 cases were studied, 96 with KDG and 53 with KCG. The two population significantly differed for clinical characteristics (see table 1). Lymphopenia, higher CRP levels, elevated Ferritin and Troponin-T characterized KCG such as lower WBC and platelets (all p values

Aim: To investigate the role of endothelial PV-1 in patients with untreated celiac disease (CD)-associated liver injury. Materials & methods: PV-1 and PV-1 mRNA were measured in intestinal biopsies from untreated CD patients with elevated or normal alanine transaminase levels, controls, patients with inflammatory bowel disease and patients with toxic liver injury. Circulating PV-1 levels were also evaluated. Results: Circulating PV-1 levels were significantly increased in the serum of patients with CD-associated liver injury and reverted to normal following a gluten-free diet. Mucosal PV-1 and PV-1 mRNA were no different in patients with CD-associated liver injury. Conclusion: Serum but not mucosal PV-1 represents a marker of gluten-dependent liver injury and response to a gluten-free diet in patients with untreated CD.

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Off-label use of medications is still a common practice in pediatric rheumatology. JAK inhibitors are authorized in adults in the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. Although their use is not authorized yet in children, JAK inhibitors, based on their mechanism of action and on clinical experiences in small series, have been suggested to be useful in the treatment of pediatric interferon-mediated inflammation. Accordingly, an increased interferon score may help to identify those patients who might benefit of JAK inhibitors. We describe the clinical experience with JAK inhibitors in seven children affected with severe inflammatory conditions and we discuss the correlation between clinical features and transcriptomic data. Clinical improvements were recorded in all cases. A reduction of interferon signaling was recorded in three out of seven subjects at last follow-up, irrespectively from clinical improvements. Other signal pathways with significant differences between patients and controls included upregulation of DNA repair pathway and downregulation of extracellular collagen homeostasis. Two patients developed drug-related adverse events, which were considered serious in one case. In conclusion, JAK inhibitors may offer a valuable option for children with severe interferon-mediated inflammatory disorders reducing the interferon score as well as influencing other signal pathways that deserve future studies.

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Objective Many students are fearful of vaccine injection-associated pain. In prior research, we created Knowledge Translation (KT) tools to address school vaccinations and associated pain, fear, and fainting. The objectives of this pilot implementation project were to determine the acceptability and impact of these KT tools on student knowledge, attitudes, and perceptions of their vaccination experience. Methods Pre-post mixed methods design. Students in an independent school in the Greater Toronto Area, Ontario, participated in two separate focus groups before and after school vaccinations. In both sessions, they independently completed a knowledge and attitudes survey, reviewed three KT tools (two videos and one pamphlet) and then repeated the knowledge and attitudes survey. They provided structured and qualitative feedback about the KT tools and described the impact of the education on the vaccination experience. Results Altogether, 11 grade 7 students participated. Knowledge scores were higher post-tool review compared to baseline in the first focus group. There was no significant difference in fear scores and attitudes about getting vaccinated. Qualitative feedback was categorized into two themes: intervention characteristics and characteristics of the school environment. Students reported the KT tools helped them to prepare for vaccination. They used the information on vaccination day to reduce their own fear and pain and to assist peers. They believed all students should view the KT tools. Students reported that teachers and nurses did not do enough to make vaccinations a positive experience. For example, they did not provide a private setting as an option for vaccination and prevented them from using some coping strategies recommended in the KT tools. Discussion This study provides preliminary evidence of the acceptability and positive impact of the KT tools on students' vaccination experiences. Future research is recommended that involves inclusion of all students and adults in the KT intervention.

Background: Students experience fear, pain, and fainting during vaccinations at school. While evidence-based interventions exist, no Knowledge Translation (KT) interventions have been developed to mitigate these symptoms. A multidisciplinary team-the Pain Pain Go Away Team- was assembled to address this knowledge-to-care gap. This manuscript provides an overview of the methodology, knowledge products, and impact of an evidence-based KT program developed and implemented to improve the vaccination experience at school. Methods: We adapted knowledge and assessed the barriers to knowledge use via focus group interviews with key stakeholder groups involved in school-based vaccinations: Students, nurses, school staff, and parents. Next, we developed project-specific goals and data collection tools and collected baseline data. We then created a multifaceted KT intervention called The CARDTM System (C-Comfort, A-Ask, R-Relax, D-Distract) to provide a framework for planning and delivering vaccinations using a studentcentred approach. Selected KT tools from this framework were reviewed in additional focus groups held in all stakeholder groups. The multifaceted KT intervention was then finalized and implemented in stages in two projects including grade 7 students undergoing school vaccinations and impact on student outcomes (e.g., symptoms of fear, pain, dizziness) and process outcomes (e.g., utilization of interventions that reduce student symptoms, vaccination rate) were assessed. Results: Participants reported that improving the vaccination experience is important. Based on participant feedback, an evidence-based multifaceted KT intervention called The CARDTM System was developed that addresses user needs and preferences. Selected KT tools of this intervention were demonstrated to be acceptable and to improve knowledge and attitudes about vaccination in the stakeholder groups. In two separate implementation projects, CARDTM helped grade 7 students prepare for vaccinations and positively impacted on their vaccination experiences. CARDTM improved vaccination experiences for other stakeholder groups as well. There was no evidence of an impact on school vaccination rates. Conclusion: We developed and implemented a promising multifaceted KT intervention called The CARDTM System to address vaccination-associated pain, fear, and fainting. Future research is recommended to determine impact in students of different ages and in different geographical regions and clinical contexts.

BackgroundMultisystem inflammatory syndrome in children (MIS-C) is a new clinical entity characterized by a systemic hyperinflammation triggered by SARS-CoV-2 infection in children and adolescents. This condition could potentially involve all organs with main complications concerning cardiovascular system. Despite up to 90% of patients complain gastrointestinal symptoms (nausea, vomit and diarrhea), a presentation mimicking acute appendicitis has rarely been reported, and can be the presenting feature of the disease, potentially leading to misdiagnosis and delayed treatment.Case presentationA 15-year-old boy presented to the Emergency Department for a two-day history of fever, vomiting and mild abdominal pain. One month before, the patient complained ageusia and anosmia while his mother tested positive for Sars-CoV2 nasopharyngeal swab. At admission, laboratory tests showed leukocytosis with lymphopenia and elevation of inflammatory markers, while cardiac enzymes, electrocardiogram and echocardiography were unremarkable. An abdominal ultrasound displayed a thickening of terminal ileus and cecum with ascites. Because of the worsening abdominal pain and a physical examination suggestive of acute appendicitis, a laparoscopy was performed but no surgical condition was found. After surgery, fever and generalized malaise persisted, so a cardiac evaluation was repeated, showing a relevant increase in inflammatory markers and cardiac enzymes. Electrocardiogram demonstrated a QTc prolongation with mild decrease in left ventricular ejection fraction at echocardiogram. A MIS-C was diagnosed and intravenous immunoglobulin along with a steroid treatment started. After 36 hours, the patient presented a complete clinical recovery with fever cessation. Cardiac anomalies normalized in three weeks.ConclusionMIS-C has been defined as a systemic inflammation, involving at least two organs, after a previous SARS-CoV2 infection in children and adolescents. Physicians should be aware that while gastrointestinal manifestations are common, a pseudo appendicitis presentation may also occur, leading to misdiagnosis and delayed treatment. This report suggests that in patients with symptoms suggestive of an acute appendicitis, the presence of lymphopenia, hypoalbuminemia and ultrasound images of terminal ileus inflammation, should raise the suspect for MIS-C even without initial overt signs of cardiac involvement.

Background Despite the availability of effective, safe, and feasible pain management strategies, infant pain remains undertreated. Parents can play a key role in advocating for or delivering pain management strategies if they are educated. To date, a quantitative synthesis of the effectiveness of parental education about pain management in the neonatal period has not been performed. Objective To systematically review the effectiveness of parental education during the neonatal period on pain management in infancy. Methods MEDLINE, EMBASE, PsycInfo, CINAHL, and the Cochrane Library were searched for relevant randomized controlled trials (RCTs) and non-randomized trials (NRTs) that evaluated parental education with respect to pain management during the neonatal period in any setting from inception to February 2021. Screening of article titles and abstracts and data extraction were performed in duplicate. The risk of bias was assessed using the Cochrane Risk Bias Tool 2.0 and the Risk of Bias in Non-randomized Studies of Interventions for RCTs and NRTs, respectively. As per the GRADE methodology, critically important and important outcomes were identified. Critically important outcomes included utilization of pain management strategies and infant pain. Important outcomes included parental knowledge about pain mitigation strategies, parental attitudes, compliance with painful procedures, procedure outcomes, and safety. Data were combined and presented as relative risk (RR) or mean or standardized mean difference (MD or SMD) with 95% confidence interval (CI). Results Of the six studies eligible for inclusion, four studies were RCTs and two studies were NRTs. Written information and/or video were used to deliver parental education during the neonatal period in hospital settings in all studies. Four studies (two RCTs and two NRTs) reported on critically important outcomes. The risk of bias was low for the two RCTs and moderate to serious for the two NRTs. Utilization of pain management strategies was assessed for heel lance in the first 48 hours of life in two studies and for vaccine injection at 2 to 6 months of life in two studies. Higher utilization rate for pain management strategies was reported in the pain education group in three studies (RR 1.15, 95% CI 1.04, 1.26; N=2712). There was no difference in the mean number of pain management strategies used in one NRT tracking utilization tracking utilization as continuous data (MD 0.20, 95% CI –0.01, 0.41; N=178). Parent-reported infant pain scores were lower in the pain education group in one RCT (MD –0.16, 95% CI –0.27, –0.06; N=1615). The quality of evidence for the outcome of utilization of pain management strategies was very low while for the outcome of infant pain the quality of evidence was moderate. Five studies (3 RCTs and 2 NRTs) reported on important outcomes. The risk of bias was low for two RCTs and high for one RCT and moderate to serious for the two NRTs. Parental knowledge about pain management strategies (SMD 0.54, 95% CI 0.26, 0.82), parental confidence in their ability to manage pain (SMD 0.24, 95% CI 0.14, 0.34), parental satisfaction with education (MD 1.18, 95% CI 0.84, 1.52) and parental satisfaction with pain management (RR 1.05. 95% CI 1.01, 1.08) were increased in the pain education group. None of the included studies reported on procedural outcomes. No adverse events with the pain education nor the use of pain management interventions were reported in one study. Conclusions Parental education in the neonatal period was effective in increasing utilization of pain management strategies during painful procedures. Reduction of pain in infants is based on one study of moderate quality. Furthermore, parental education increased parental knowledge about pain management strategies, confidence in their ability to manage infant pain, and satisfaction with the education and pain management. Parental pain education should be incorporated into postnatal care.

Additional file 2: Appendix 2. Clinical comparison between Kawasaki Disease patients seen during SARS-CoV-2 epidemic and a Historical Cohort of Kawasaki Disease Patients.

Additional file 1: Appendix 1.