Journal of Pediatric and Neonatal Individualized Medicine (JPNIM) <p>The <strong>Journal of Pediatric and Neonatal Individualized Medicine (JPNIM)</strong> is a peer-reviewed interdisciplinary journal which provides a forum on new perspectives in pediatric and neonatal medicine. The aim is to discuss and to bring readers up to date on the latest in research and clinical pediatrics and neonatology. Special emphasis is on developmental origin of health and disease or perinatal programming and on the so-called ‘-omic’ sciences. Systems medicine blazes a revolutionary trail from reductionist to holistic medicine, from descriptive medicine to predictive medicine, from an epidemiological perspective to a personalized approach. The journal will be relevance to clinicians and researchers concerned with personalized care for the newborn and child. Also medical humanities will be considered in a tailored way.</p> <p>Article submission (original research, review papers, invited editorials and clinical cases) will be considered in the following fields: fetal medicine, perinatology, neonatology, pediatrics, developmental programming, psychology and medical humanities.</p> en-US Journal of Pediatric and Neonatal Individualized Medicine (JPNIM) 2281-0692 <p>© Hygeia Press</p> <p> </p> <h3>Copyright and publishing rights</h3> <p>Regarding copyright, before publication, Authors declare that, in consideration of the action of JPNIM in reviewing and editing their submission, they transfer, assign, or otherwise convey all copyright ownership, including any and all rights incidental thereto, exclusively to the JPNIM Publisher (Hygeia Press di Corridori Marinella).</p> <div> <div> <div> <div> <div> <p>Authors have the opportunity to reuse figures, tables and selected text up to 250 words from their article as finally published, providing that full and accurate credit shall be given to publication in JPNIM and that modifications are noted (otherwise no changes may be made).</p> </div> </div> </div> </div> </div> Lectures of the School of Advanced Training on the Pediatric Microbiota [Scuola di Alta Formazione sul Microbiota in Età Pediatrica]; webinar; February-March 2022 <p class="p1"><strong>Lectures of the School of Advanced Training on the Pediatric Microbiota</strong><span class="s1"><strong> [Scuola di Alta Formazione sul Microbiota in Età Pediatrica]</strong></span></p> <p><strong>An all-around view of the microbiota for clinical pediatric practice [Il microbiota a 360 gradi per la pratica clinica pediatrica]</strong></p> <p class="p3"><span class="s3"><strong>Webinar • February-March 2022</strong></span></p> <p class="p4">&nbsp;</p> <p class="p5">The meeting has been organized with the unconditional contribution of BROMATECH.</p> <p class="p5">&nbsp;</p> <p class="p1"><strong>LECT 1. THE SCHOOL OF ADVANCED TRAINING ON THE PEDIATRIC MICROBIOTA [LA SCUOLA DI ALTA FORMAZIONE SUL MICROBIOTA IN ETÀ PEDIATRICA]</strong> • V. Fanos, M. Romeo (Cagliari and Pavia, Italy)<span class="Apple-converted-space">&nbsp;</span></p> <p class="p1"><strong>LECT 2. YOU WILL NEVER FORGET YOUR FIRST MICROBIOTA [IL PRIMO MICROBIOTA NON SI SCORDA MAI]</strong> • V. Fanos (Cagliari, Italy)</p> <p class="p1"><strong>LECT 3. BREASTFEEDING, WEANING AND HEALTHY GROWTH OF THE BABY [ALLATTAMENTO, SVEZZAMENTO E CRESCITA SANA DEL BAMBINO]</strong> • D.G. Peroni (Pisa, Italy)</p> <p class="p1"><strong>LECT 4. THE ROLE OF GUT MICROBIOTA AND PROBIOTICS SUPPLEMENTATION IN THE MANAGEMENT OF INFANTILE COLIC [IL RUOLO DEL MICROBIOTA INTESTINALE E DELL’INTEGRAZIONE PROBIOTICA NELLA GESTIONE DELLE COLICHE INFANTILI]</strong> • M. Romeo (Pavia, Italy)</p> <p class="p1"><strong>LECT 5. A JOURNEY INTO THE MICROBIOTA AMONG ALLERGIES AND IMMUNE SYSTEM DISEASES [VIAGGIO NEL MICROBIOTA TRA ALLERGIE E MALATTIE DEL SISTEMA IMMUNITARIO]</strong> • R. Castagnoli, G.L. Marseglia (Pavia, Italy)</p> <p class="p1"><strong>LECT 6. WHAT IS EVIDENT IN METABOLIC DISORDERS: OBESITY, DIABETES AND MICROBIOTA [EVIDENZE NEI DISORDINI METABOLICI: OBESITÀ, DIABETE E MICROBIOTA]</strong> • G. Banderali (Milan, Italy)</p> <p class="p1"><strong>LECT 7. THE KNOWLEDGE OF THE MICROBIOTA IN PRIMARY CARE [I RISVOLTI PRATICI DELLE CONOSCENZE SUL MICROBIOTA]</strong> • G. Trapani, G. Maiocco, A. Spadavecchia (Sanremo and Turin, Italy)</p> <p class="p1"><strong>LECT 8. MICROBIOTA AND NUTRITION IN PEDIATRIC AGE [MICROBIOTA E NUTRIZIONE IN ETÀ PEDIATRICA]</strong> • L. Emma (Turin, Italy)</p> <p class="p1"><strong>LECT 9. THE MUCO-MICROBIOTIC LAYER: THE INNERMOST COMPONENT OF THE BOWEL WALL [LO STRATO MUCO-MICROBIOTICO: LA COMPONENTE PIÙ INTERNA DELLA PARETE INTESTINALE]</strong> • F. Cappello (Palermo, Italy)</p> <p class="p1"><strong>LECT 10. PROBIOTICS ARE NOT ALL THE SAME [I PROBIOTICI NON SONO TUTTI UGUALI]</strong> • R. Francavilla, F. Cristofori (Bari, Italy)</p> <p class="p1"><strong>LECT 11. IS THERE A MICROBIOME SIGNATURE IN PEDIATRIC INFLAMMATORY BOWEL DISEASE? [VI È UN MICROBIOMA INTESTINALE SPECIFICO NELLE MALATTIE INFIAMMATORIE CRONICHE INTESTINALI PEDIATRICHE?]</strong> • M. Martinelli, A. Staiano (Naples, Italy)</p> <p class="p1"><strong>LECT 12. MICROBIOTA AND NEURODEVELOPMENT [MICROBIOTA E NEUROSVILUPPO]</strong> • P. Rossi (Pavia, Itay)</p> <p class="p1"><strong>LECT 13. MICROBIOMICS AND METABOLOMICS IN AUTISM SPECTRUM DISORDER [MICROBIOMICA, METABOLOMICA E DISTURBI DELLO SPETTRO AUTISTICO]</strong> • M. Mussap (Cagliari, Italy)</p> <p class="p1"><strong>LECT 14. WHAT FUTURE FOR HUMAN HEALTH? [QUALE FUTURO PER LA SALUTE UMANA?]</strong> • A. Maglioni (Civitella di Romagna, Italy)</p> <p class="p5">&nbsp;</p> <p class="p5">&nbsp;</p> --- Various Authors Copyright (c) 2022 © Hygeia Press 2022-06-21 2022-06-21 11 2 e110220 e110220 10.7363/110220 Surgical treatment of acute infectious purpura fulminans in neonates <p>Neonatal purpura fulminans (NPF) is a rare entity due to a deficiency in anticoagulant protein C or S that leads to the development of disseminated intravascular coagulation with formation of microvascular thrombi and skin and soft tissue necrosis.</p> <p>Three forms of NPF are described: congenital, <span class="s1">infectious</span> and idiopathic.</p> <p>Acute <span class="s1">infectious </span>purpura fulminans (AIPF) is related to sepsis. Group B <em>Streptococcus spp.</em> is the most frequent pathogen involved in the development of AIPF in newborns. The clinical severity varies according to the underlying cause. The mortality rate of AIPF ranges from 10% to 50%. Limbs are involved more frequently than other areas. Skin lesions may present early as petechial rashes, which rapidly progress to larger ecchymoses. Later in the course, hemorrhagic bullae may form, which contribute to the classic hard eschars characteristic of NPF. Differential diagnosis with necrotizing fasciitis should be performed.</p> <p>Treatment of NPF should be multidisciplinary. Plastic surgeons are frequently involved in the management of soft tissue defects. Surgical treatment consists in early debridement or amputation in more critical cases and subsequent reconstruction by using skin grafts, pedicled or free flaps. Medical research is now focused on bioengineering solutions that can provide better aesthetic and functional outcomes while minimizing surgical sequelae. The aim of this editorial is to present the available options and the state-of-the-art research and scientific advances in local wound care and surgical management of AIPF.</p> Paola Parisi Diego Ribuffo Copyright (c) 2022 © Hygeia Press 2022-07-01 2022-07-01 11 2 e110215 e110215 10.7363/110215 Pediatric psychology in managing fragility of the child and adolescent in pediatric condition <p class="p1"><span class="s1">This paper seeks to provide guidance for a reference framework to aid in the foundation of the section “Pediatric Psychology and Related </span>Issues” of the <em>Journal of Pediatric and Neonatal Individualized Medicine</em> <span class="s1">(<em>JPNIM</em>). The section represents the opportunity to raise awareness on developmental psychology at “developmental-clinical” level rather than at “clinical-developmental” level. In the former expression, we focus on the object of the study and intervention during the developmental process, highlighting specifically the method, approach and implications in patient management when referring to “clinical”. In the “clinical-developmental” approach, greater focus is given to the clinical implications and to the psychopathological case identified by the clinic.<span class="Apple-converted-space">&nbsp;</span></span></p> <p class="p1"><span class="s1">This paper focuses on the way in which know-how and expertise in pediatric psychology draw on a vast body of evidence and literature produced by the scientific community. This paper has dedicated a great deal of space to background notions as a demonstration of the “fundamentals” which illustrate the significant difference between pediatric psychology and the mere application of psychology in pediatrics. This paper guides the reader towards an analysis of the condition of fragility which often characterizes the pediatric condition, subsequently addressing constructs and methods. It concludes with the identification of several areas of research and intervention within the fields of mother-child well-being and pediatrics.</span></p> Giovanna Perricone Copyright (c) 2022 © Hygeia Press 2022-07-27 2022-07-27 11 2 e110221 e110221 10.7363/110221 Neonatal bleeding disorders. A practical diagnostic approach <p class="p1"><span class="s1">Since developmental hemostasis was introduced by Andrew et al. in the early 90s, age-related variations in coagulation components have been a well-established knowledge. In parallel with age-dependent hemostatic status maturation, coagulation disorders assessment stands as an important prerequisite for bleeding management. However, discrepancies observed between neonatal coagulation reference ranges and standard coagulation assays extrapolated from adults make neonatal disease evaluation and therapeutic management challenging. This study aims to provide a diagnostic approach to neonatal bleeding based on a current literature search on bleeding disorders in the neonatal period.</span></p> Georgios N. Katsaras Dimitra Gialamprinou Euthimia Papacharalampous Ilias Chatziioannidis Georgios Mitsiakos Copyright (c) 2022 © Hygeia Press 2022-07-14 2022-07-14 11 2 e110231 e110231 10.7363/110231 Saffron for mood improvement in children and adolescents: a narrative review <p class="p1">Depressive and anxious disorders could be experienced by children and adolescents worldwide and are associated with psychiatric syndromes diagnosed in adulthood. In this context, the COVID-19 outbreak and digital media arising use have worsened mental conditions in the pediatric population. Older adolescents, girls, and patients living with neurodiversity and/or chronic physical conditions are more likely to develop negative mental health outcomes. </p> <p class="p1"><em>Crocus sativus L.</em> (saffron) is a medicinal plant whose most biologically relevant components are two carotenoids (crocin and crocetin) and two apocarotenoids (picrocrocin and safranal). Crocin seems to inhibit the uptake of dopamine and norepinephrine, while safranal inhibits the serotonin reuptake; in vitro and in animal models, crocin also displayed neuroprotective abilities, increasing the intracellular levels of neurotrophic factors. Further studies are required to strengthen these results; however, multiple studies have already demonstrated significant positive effects of saffron on psychiatric disorders – including depression and anxiety in young patients. Saffron administration appears to reduce depression symptoms and to strengthen antidepressant effects of current drugs (fluoxetine), also lowering adverse events of these therapies. Consequently, saffron could have an important role as a complementary therapy for depressive and anxious disorders in children and teenagers.</p> Gianfranco Trapani Giulia Maiocco Alessia Spadavecchia Copyright (c) 2022 © Hygeia Press 2022-06-27 2022-06-27 11 2 e110222 e110222 10.7363/110222 Family environment, parental stressors, and post-traumatic stress disorder in the parents of premature infants in the Neonatal Intensive Care Unit <p class="p1"><span class="s1"><strong>Background:</strong> The birth of premature infants and their admission to the Neonatal Intensive Care Unit (NICU) causes emotional stress in parents and in the whole family. This event can affect the interaction between family members and disrupt the family’s environment. Therefore, the aim of the present study was to estimate the family environment, the parental stressors and the level of post-traumatic stress disorder (PTSD) in the parents of premature infants admitted to NICU. </span></p> <p class="p1"><span class="s1"><strong>Methods:</strong> This descriptive-analytic study was conducted in the two NICUs of a Specialized and Educational Hospital in South-East of Iran. A total of 140 parents (70 mothers and 70 fathers) were enrolled in the study using convenience sampling method. The data collection tool included a demographic questionnaire of parents and neonates, a Family Environment Scale </span><span class="s2">(FES)</span><span class="s1">, a Parental Stressor Scale (PSS), and the Impact of Event Scale – Revised (IES-R). Data analysis was carried out using descriptive and inferential statistics, including independent t-test, one-way ANOVA, and Pearson correlation co-efficient in SPSS® ver. 18.<span class="Apple-converted-space"> </span></span></p> <p class="p1"><strong>Results:</strong> The family environment was evaluated at the moderate level by mothers and fathers in the <span class="s2">FES</span>, with mean scores of 97.48 ± 11.46 and 98.70 ± 10.50, respectively. The mean score of parental stressors in the <span class="s1">PSS</span> was moderate in mothers (2.90 ± 0.86) and low in fathers (2.55 ± 0.90). Also, the mean PTSD score in the <span class="s1">IES-R</span> was moderate in fathers (35.10 ± 18.79) and in mothers (43.01 ± 17.14). The results showed no significant relationship between family environment and PTSD in mothers (r = 0.11, p = 0.36) and fathers (r = 0.04, p = 0.75), but a significant relationship was found for both parents in terms of parental stressors and PTSD (mothers: r = 0.48, p = 0.0001; fathers: r = 0.59, p = 0.0001). </p> <p class="p1"><span class="s1"><strong>Conclusion:</strong> The results revealed that family environment scores and PTSD scores in parents of premature infants were at the moderate level. The parents who experienced stressors without adequate support were at risk for PTSD. In this regard, parents should be considered as patients by the healthcare team who, recognizing signs of parental stress early, could play an important role in preventing adverse effects of stress on parents themselves and on the infants. Educational and counseling interventions by NICU nurses can help parents to adapt to NICU environment and to use coping strategies to manage stress, promote family cohesion, and reduce the risk of PTSD.</span></p> Mahdieh Arabzadeh Batool Tirgari Jamileh Farokhzadian Sakineh Mohammadalizadeh Copyright (c) 2022 © Hygeia Press 2022-07-22 2022-07-22 11 2 e110232 e110232 10.7363/110232 Allergic rhinitis in children in pneumo-allergology consultation at the Teaching Hospital Campus of Lomé (Togo) <p class="p1"><span class="s1"><strong>Background:</strong> Allergic rhinitis (AR) is one of the most common chronic pathologies in children. The objective of this study was to determine the prevalence of AR in children undergoing pneumo-allergology consultation at the Teaching Hospital Campus of Lomé (Togo). </span></p> <p class="p1"><span class="s1"><strong>Methods:</strong> A cross-sectional study was carried out in the Pneumo-Allergology Unit of the Teaching Hospital Campus of Lomé from January 1, 2018, to December 31, 2019. We included in our study all children (0 to 18 years old) who consulted in our Unit. The parameters studied included demographic and clinical data, home environment (external and internal of the concessions and internal environment of the rooms), total IgE test, results of skin prick tests, and diagnosis. </span></p> <p class="p1"><span class="s2"><strong>Results:</strong> We identified a total of 179 cases of AR (19 of which were excluded) out of 380 children who had consulted during our study period; the prevalence was 47.11%. Children aged 0 to 5 years accounted for 57.50% of patients. There was male dominance, with a sex ratio of 1.5. Clear rhinorrhoea was the symptom found in 100% of cases, followed by sneezing (85.63%) and nasal obstruction (85.00%). Asthma was frequently associated (47.37%). </span>Rhinopharyngitis accounted for 59.86% of the allergic pathologies identified in the families, followed by asthma (34.51%)<span class="s2">. The house was old (&gt; 10 years) in 58.75%, the mattress was old (&gt; 5 years) in 44.38%, and the pillow was old (&gt; 5 years) in 44.22% of cases. </span>The majority (55.63%) of patients had pets in the home, and the predominant pet was the cat (67.42%)<span class="s2">. The skin prick test, carried out in 110 patients, had noted sensitization to dust mites (100%), cat dander (58.18%), cockroaches (58.18%) and molds (28.18%). AR was persistent in 60.63% of cases. Sneezing was more common in moderate to severe persistent AR than in mild persistent AR (p &lt; 0.0001).<span class="Apple-converted-space"> </span></span></p> <p class="p1"><span class="s1"><strong>Conclusion:</strong> The prevalence of AR in children was high. Persistent AR was the most common.</span></p> Mawouto Fiawoo Nadiedjoa Kokou Douti Manani Hemou Koko Lawson-Evi Kokoe Bénédicte Kangni Mananté Kamaga Dzayisse Yawo Atakouma Copyright (c) 2022 © Hygeia Press 2022-06-21 2022-06-21 11 2 e110219 e110219 10.7363/110219 Assessing the phenylketonuria (PKU) neonatal screening program and the incidence rates of PKU in Kerman County, Iran: a health system research <p class="p1"><span class="s1"><strong>Background:</strong> Phenylketonuria (PKU) is a genetic autosomal recessive disorder, which, if not treated on time, can lead to mental retardation and severe developmental delay. The aim of this study was to assess the PKU neonatal screening program in Kerman County, Iran.<span class="Apple-converted-space"> </span></span></p> <p class="p1"><span class="s1"><strong>Methods:</strong> This was a health system research study carried out on all newborns screened for PKU from 2012 to 2018 in Kerman. Data were extracted from the Comprehensive Social Genetics Program forms, genetic records, and the national form for investigation of genetic disease incidence. </span></p> <p class="p1"><span class="s1"><strong>Results:</strong> Totally, 121,533 newborns were screened. 108,972 (89.7%) were Iranian, and 12,561 (10.3%) were non-Iranian. Screening coverage in the Iranian population was 92.1%. 80.9% of Iranian and 62.8% of non-Iranian newborns were screened from 3 to 5 days of age. Timely screening of newborns in the Iranian and non-Iranian populations in 2012 was 70.0% and 46.9%, and in 2018, it was 90.2% and 75.1%, respectively. The first visit at the PKU treatment center in 30.7% of Iranian and 33.3% of non-Iranian neonates was before 14 days of age. In the Iranian population residing in Kerman, the incidence rate of PKU was estimated to be 1.35 per 10,000 live births. 62.5% of parents of Iranian and 100% of parents of non-Iranian PKU patients were relatives. </span></p> <p class="p1"><span class="s1"><strong>Conclusion: </strong>PKU screening coverage in Kerman is relatively acceptable, and most newborns were screened on time. Timely screening of newborns in both populations has increased since the beginning of the program until the time of this study. Interventions are required to improve early diagnosis and start treatment during the first 2 weeks of life. The incidence of PKU in Kerman County is approximately equal to the national average. Due to the fact that most parents of PKU patients are relatives, increasing awareness to prevent consanguineous marriages can be effective in decreasing the incidence of this disease.</span></p> Esmat Rezabeigi Davarani Fatemeh Mohseni Takaloo Salman Daneshi Peimaneh Sanjari Narges Khanjani Kiavash Hushmandi Mehdi Raei Copyright (c) 2022 © Hygeia Press 2022-07-29 2022-07-29 11 2 e110217 e110217 10.7363/110217 Diagnostic and therapeutic outcomes of pediatric colonoscopies in Jordanian children <p class="p1"><strong>Background:</strong> Pediatric colonoscopy is a crucial tool for diagnosing and treating children with colonic diseases. Data from low-volume centers are scarce and, most of the time, not represented in literature. This study aimed to review colonoscopy indications, diagnostic yield, therapeutic interventions, and outcomes in children who underwent a colonoscopy procedure at a university hospital in North Jordan.<span class="Apple-converted-space"> </span></p> <p class="p1"><span class="s1"><strong>Methods:</strong> A retrospective review was conducted on children who underwent </span>colonoscopies between January 2014 and January 2020. Demographic data, procedure indications, and colonoscopy and histopathological findings were collected from patient hospital charts. The appropriateness of colonoscopy indications was judged according to published guidelines.<span class="Apple-converted-space"> </span></p> <p class="p1"><span class="s2"><strong>Results: </strong>We identified 119 procedures performed in 105 children (females: 39 [37.1%]; mean age: 98.2 ± 51.2 months) in our review. The most common cause for undergoing a colonoscopy procedure was lower gastrointestinal bleeding (55 [46.2%]), followed by chronic diarrhea and abdominal pain (17 [14.3%] and 16 [13.4%], respectively). A normal endoscopy was reported in 50 (42.0%) procedures. The most commonly reported abnormalities were polyps and inflammatory bowel disease. Polypectomies were performed in 21 patients during 26 (21.8%) procedures. Most of the polyps were rectal polyps (15 [71.4%]), and all of them were of juvenile pathology. Appropriate colonoscopy indications were associated with a higher rate of an abnormal endoscopy. </span></p> <p class="p1"><strong>Conclusion:</strong> Low-volume centers share a similar spectrum of disorders reported by larger centers. Our study found that the most common colonoscopy indications were rectal bleeding and diarrhea, and the most common findings were colonic inflammation and colorectal polyps. Complying with guideline recommendations will improve the diagnostic yield of colonoscopies.<span class="Apple-converted-space"> </span></p> Eyad Altamimi Yousef Odeh Tuka Al-quraan Elmi Mohamed Naif Rawabdeh Copyright (c) 2022 © Hygeia Press 2022-07-11 2022-07-11 11 2 e110211 e110211 10.7363/110211 Restoration of skin defect using micro-autograft in an infant: the first experience <p class="p1"><strong>Background:</strong> The causes of many pathological conditions in neonates with very low gestational weight and fetal growth retardation remain unclear. One such condition is massive, rapid-onset skin necrosis in various parts of the body. In this article, we present the case of a small for gestational age neonate with extensive necrosis of the skin and subcutaneous tissues of the upper extremities and back. </p> <p class="p1"><strong>Aim:</strong> To provide a detailed review of a clinical case of skin necrosis of the upper extremities and back in a small for gestational age infant.<span class="Apple-converted-space"> </span></p> <p class="p1"><strong>Method:</strong> A report of a single case with a detailed description of an improved skin micro-autografting technique. </p> <p class="p1"><span class="s1"><strong>Result:</strong> Skin integrity was successfully restored after multiple debridements </span>by using this micro-autograft technique in a small for gestational age infant. </p> <p class="p1"><strong>Conclusion:</strong> Timely appropriate debridement followed by micro-autografts, as part of a comprehensive and interdisciplinary care approach, resulted in the successful treatment of a small for gestational age infant with extensive skin necrosis.</p> Vasyl Nagaichuk Roman Chornopyshchuk Oleksandr Dobrovanov Oleksandr Nazarchuk Oksana Moravska Nataliia Chornopyshchuk Kostiantyn Bertsun Marian Vidiscak Copyright (c) 2022 © Hygeia Press 2022-06-30 2022-06-30 11 2 e110201 e110201 10.7363/110201 Correspondence: do not overlook parental grief following an infant death in the Neonatal Intensive Care Unit <p class="p1"><span class="s1">Parents’ bereavement results in high rates of psychological, emotional, physiological, and existential distress after the death of a child during pregnancy, at delivery or in the neonatal period. Parental grief following an infant’s death is usually neglected or overlooked in many Neonatal Intensive Care Units in both developed and developing countries. </span></p> <p class="p1"><span class="s1">We report our observations about grieving parents in order to increase the awareness of health professionals regarding the importance of grief for the death of their infant.</span></p> <p class="p1"><span class="s1">In conclusion, in </span><span class="s1">this report, we would like to emphasize that grieving parents following a perinatal death should be supported not only physically, but also psychosocially and spiritually by health professionals.<span class="Apple-converted-space"> </span></span></p> Hüseyin Çaksen Copyright (c) 2022 © Hygeia Press 2022-06-21 2022-06-21 11 2 e110214 e110214 10.7363/110214