Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa.

The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom's national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB.

Consensus-based guidelines for the provision of palliative and end-of-life care for people living with epidermolysis bullosa.

BACKGROUND: Inherited epidermolysis bullosa (EB) is a cluster of rare, genetic skin and mucosal fragility disorders with multi-system and secondary effects, in which blistering and erosions occur in response to friction/mechanical trauma. Considering the incurable and potentially life-limiting nature of the condition and the challenges posed by its symptoms, a palliative approach to EB-related care is necessary. However, knowledge and experience related to the provision of EB palliative care is minimal. Evidence-based, best care guidelines are needed to establish a base of knowledge for practitioners to prevent or ease suffering while improving comfort at all stages of the illness, not just the end of life. METHODS: This consensus guideline (CG) was begun at the request of DEBRA International, an international organization dedicated to improvement of care, research, and dissemination of knowledge for EB patients, and represents the work of an international panel of medical experts in palliative care and EB, people living with EB, and people who provide care for individuals living with EB. Following a rigorous, evidence-based guideline development process, the author panel identified six clinical outcomes based on the results of a survey of people living with EB, carers, and medical experts in the field, as well as an exhaustive and systematic evaluation of literature. Recommendations for the best clinical provision of palliative care for people living with EB for each of the outcomes were reached through panel consensus of the available literature. RESULTS: This article presents evidence-based recommendations for the provision of palliative healthcare services that establishes a base of knowledge and practice for an interdisciplinary team approach to ease suffering and improve the quality of life for all people living with EB. Any specific differences in the provision of care between EB subtypes are noted. CONCLUSIONS: Because there is yet no cure for EB, this evidence-based CG is a means of optimizing and standardizing the IDT care needed to reduce suffering while improving comfort and overall quality of life for people living with this rare and often devastating condition.

Characteristics and Outcomes of Squamous Cell Carcinoma and Other Cutaneous Malignancies in Epidermolysis Bullosa: A Systematic Review.

OBJECTIVE: To identify cases and summarize outcomes of cutaneous malignancies in patients with epidermolysis bullosa (EB). DATA SOURCES: MEDLINE and EMBASE databases were searched on February 8, 2022. STUDY SELECTION: Original observational or experimental studies with cases of cutaneous malignancy in patients with inherited EB were included. DATA EXTRACTION: Data were extracted by two reviewers in duplicate. DATA SYNTHESIS: A total of 87 articles with 367 patients were included in this systematic review. Squamous cell carcinomas were the most common malignancy (94.3%) with a median survival of 60 months. The presence of metastasis was investigated at diagnosis in 77 patients; 18.8% of patients had detectable metastasis. Patients with squamous cell carcinoma with metastasis at diagnosis had significantly shorter median survival (16.8 months) than those without (72 months; P = .027). The remission rate was 47.6%. At the end of follow-up, 15.1% were alive with disease, and 41.6% were deceased. Other malignancies included malignant melanoma and basal cell carcinoma. The most common initial modes of management were excisions (71.9%) and amputations (17.6%). Other modes included chemotherapy (4.6%), radiation (3.9%), and no treatment (2.6%). The overall rate of recurrence or new lesions was 38.8%, with a median time of 16 months to recurrence or new lesions. Immediate recurrence was lowest following amputation (4.3%). There were no statistically significant differences in median survival among initial excision, amputation, and all other modes combined ( P = .30). CONCLUSIONS: Squamous cell carcinomas in patients with EB have a high likelihood of metastasis and mortality. Surgical excision is the most common intervention. There are no significant differences in survival among different initial management options. There is a need for research that documents and monitors outcomes of the treatment options.

Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond.

Nonsense mutations trigger premature translation termination and often give rise to prevalent and rare genetic diseases. Consequently, the pharmacological suppression of an unscheduled stop codon represents an attractive treatment option and is of high clinical relevance. At the molecular level, the ability of the ribosome to continue translation past a stop codon is designated stop codon readthrough (SCR). SCR of disease-causing premature termination codons (PTCs) is minimal but small molecule interventions, such as treatment with aminoglycoside antibiotics, can enhance its frequency. In this review, we summarize the current understanding of translation termination (both at PTCs and at cognate stop codons) and highlight recently discovered pathways that influence its fidelity. We describe the mechanisms involved in the recognition and readthrough of PTCs and report on SCR-inducing compounds currently explored in preclinical research and clinical trials. We conclude by reviewing the ongoing attempts of personalized nonsense suppression therapy in different disease contexts, including the genetic skin condition epidermolysis bullosa.

Epidermolysis Bullosa in Pediatric Palliative Care: A Case Series.

Background: Epidermolysis bullosa (EB) comprises a group of rare genetic conditions that are characterized by fragility of the skin and mucous membranes and formation of blisters with minor trauma. Severe forms can be life limiting. The palliative care needs of children with severe EB are poorly described. Aim: The aim of this case series was to examine the contribution of a pediatric palliative care service to the complex health care needs of children with severe EB. Methods: We present a case series of five children with severe forms of EB who were known to the state-wide Victorian Paediatric Palliative Care Service, with a discussion of our learnings in caring for these children and their families. Results: Medical treatment decision making in EB provokes complex ethical, psychological, personal, and professional dilemmas. This case series highlights the diversity of management approaches that may be considered, each tailored to the unique context of the child and family.

Multidisciplinary care for patients with epidermolysis bullosa from birth to adolescence: experience of one Italian reference center.

BACKGROUND: Epidermolysis bullosa (EB) is a disabling and chronic genodermatosis characterized by mucocutaneous fragility with blister formation after minimal trauma. Severity ranges between very mild forms to extremely severe or lethal subtypes. Depending on disease subtypes, blisters may be localized also in larynx, bladder, esophagus, and most frequent disease complications are malnutrition, chronic anemia, osteoporosis, limb contracture and early development of squamous cell carcinomas. EB is classified into four major groups: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and Kindler EB (KEB). No specific treatment is available; however, a multidisciplinary management is mandatory in order to treat the lesions, to prevent complication, and to give a psychological support to the patient and family members. OBJECTIVE: To report the experience on a therapeutic education plan of an Italian reference center for epidermolysis bullosa in the last 30 years. METHODS: In our study we included all patients with EB from 1990 to the present, dividing them into three age groups (< 5 years, > 5-12 years and > 12-18 years). The therapeutic plan involved all multidisciplinary team members, since born until adolescence. The multidisciplinary team has been progressively established; the dermatologists act as patient case manager, in collaboration with the pediatrician, endocrinologist, dietician, dentist, plastic surgeon, digestive surgeon, geneticist, psychologist and a dedicated nurse. Other dedicated specialists are involved upon patient needs. RESULTS: Two hundred fifteen patients have been recruited and followed in our hospital since 1990. One hundred forty patients (65%) are on follow-up, 27 patients (13%) died and only 11 (5%) were lost to follow-up. Our patients manifested the specific complications related to their EB subtype in keeping with the data reported in the literature. Eighteen (8%) patients affected with JEB severe died within the first year of life, 9 patients (5%) died for squamous cell carcinoma in adulthood and were affected with recessive DEB; only 1 patient died for squamous cell carcinoma at the age of 16. CONCLUSIONS: An adequate management of EB patients require a multidisciplinary approach with an educational plan to guarantee an appropriate treatment and to support and accompany patients and their families since birth along life. The dynamic educational plan adopted in our hospital showed good clinical and psychological outcome in our population, allowing adherence to treatment, reducing the frequency of complications and improving life expectancy and quality of life.

Review of transition of care literature: Epidermolysis bullosa-A paradigm for patients with complex dermatologic conditions.

BACKGROUND: Transition from pediatric to adult care is a critical component of health care for children with long-term needs. The characteristics of epidermolysis bullosa (EB) demand higher than average levels of provider support. There is consensus among health care professionals regarding the importance of transition; however, there is a scarcity of practical information regarding models for patients with EB. OBJECTIVE: To review transition of care programs in varying specialties. Highlight practical considerations to facilitate the development of programs for patients with EB and other complex dermatologic conditions. METHODS: Articles were identified via MEDLINE and EMBASE health literature databases and screened for relevance to transition of care. RESULTS: Various models for transition exist. A well-executed formal transition program, early introduction, interdisciplinary collaboration, and psychosocial support were themes associated with successful outcomes. LIMITATIONS: Transition of care programs that have not been described in the literature are not reflected in this review. CONCLUSIONS: Patients with EB have unique needs that affect transition and span expertise across traditional boundaries, such as dependency on others for daily skin care, failure to thrive, and risk of squamous cell carcinoma. Given the rarity of the disease, patients with EB will benefit from collaborative efforts to develop programs to optimize successful transition.

Epidermolysis Bullosa: Pediatric Perspectives.

Epidermolysis bullosa (EB) is a group of rare congenital genetic conditions that result in painful blistering of the skin and mucous membranes, which occur with minor trauma or friction. There are many types and subtypes of EB that need to be distinguished, as the management and prognosis of each can vary significantly. We aim to perform an up-to-date literature review on congenital EB for healthcare providers in pediatrics. We performed a review of existing literature in the English language on EB via PubMed Clinical Queries, using key words such as "epidermolysis bullosa", "congenital" and "children". We reviewed EB based on the following subheadings: epidemiology, diagnosis, therapy, prognosis, and clinical prediction guidelines. EB is due to mutation in a number of genes, some types are autosomal dominant while others are autosomal recessive. The underlying mechanism is a defect in attachment between or within the epidermis and dermis of the skin. There are four main types: epidermolysis bullosa simplex, dystrophic epidermolysis bullosa, junctional epidermolysis bullosa, and Kindler syndrome. The diagnosis is suspected based on symptoms and confirmed by skin biopsy and definitive genetic testing. The severity of EB can range from mild to fatal. Severe complications may arise in some EB types and subtypes within the eye, ear, nose, upper airway, gastrointestinal and genitourinary tracts. There is no cure for the condition to date. Optimal management must be multidisciplinary, and involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications. EB presents in different forms. Treatment is supportive. The prognosis of milder forms is good. Children severely affected with EB and their families live a misery life with impaired quality of life. Health care workers must be aware of the suffering in these families and proactively support them.

Evaluating the use of laparoscopic-assisted gastrostomy tube feeding in children with epidermolysis bullosa: A single-center retrospective study.

BACKGROUND: Nutritional management of children with epidermolysis bullosa (EB) presents multiple challenges including reduced oral intake compounded by mucosal fragility. Gastrostomy tube feeding is effective in improving nutritional status however there is limited data on the safety and tolerance of this technique in EB children. We aim to review the effectiveness and morbidity of our minimally invasive two-port laparoscopic-assisted gastrostomy (LAG) approach using Seldinger techniques with serial dilatations in children with EB. METHODS: A retrospective, observational cohort study was conducted on all consecutive EB patients who underwent LAG tube insertion between 2009 and 2019. Patient demographics, admission details and 12-month clinical outcomes were reported. RESULTS: 32 EB patients underwent LAG placement. Median age at insertion was 7.3 (IQR ± 6.3) years, with 8 (25.0%) and 3 (9.4%) of patients also undergoing oesophageal dilatation and fundoplication, respectively. Minor complications arose in 58.1% of patients including: peri-stomal overgranulation (25.8%), gastrostomy infection (22.6%), pain (22.6%), mild gastrostomy leakage (16.1%), blockage (9.7%) and device failure (3.2%). 2 patients (6.5%) developed major complications with extensive gastrostomy site leakage. Improvements in growth were reflected in mean height Z-scores (-1.99 to -1.71). Mean weight Z-scores improved in patients aged 0-10 years (-2.30 to -1.61) and mean BMI Z-scores increased in patients more than 10 years (-2.71 to -1.46). No cases of gastrostomy-related mortality were reported. CONCLUSION: LAG is well-tolerated in EB patients with improvements in growth and minimal morbidity 12-months post-gastrostomy insertion. An extended follow-up period is required to ascertain the long-term implications of gastrostomy feeding.

The potential of gene therapy for recessive dystrophic epidermolysis bullosa.

Epidermolysis bullosa (EB) encompasses a heterogeneous group of inherited skin fragility disorders, with mutations in genes encoding the basement membrane zone (BMZ) proteins that normally ensure dermal-epidermal integrity. Of the four main EB types, recessive dystrophic EB (RDEB), especially the severe variant, represents one of the most debilitating clinical entities, with recurrent mucocutaneous blistering and ulceration leading to chronic wounds, infections, inflammation, scarring and ultimately cutaneous squamous cell carcinoma, which leads to premature death. Improved understanding of the molecular genetics of EB over the past three decades and advances in biotechnology have led to rapid progress in developing gene and cell-based regenerative therapies for EB. In particular, RDEB is at the vanguard of advances in human clinical trials of advanced therapeutics. Furthermore, the past decade has witnessed the emergence of a real collective, global effort involving academia and industry, supported by international EB patient organizations such as the Dystrophic Epidermolysis Bullosa Research Association (DEBRA), among others, to develop clinically relevant and marketable targeted therapeutics for EB. Thus, there is an increasing need for the practising dermatologist to become familiar with the concept of gene therapy, fundamental differences between various approaches, and their human applications. This review explains the principles of different approaches of gene therapy, summarizes its journey, and discusses its current and future impact in RDEB.

New options to manage epidermolysis bullosa.

RDEB is a genetic skin disorder involving COL7A1, the gene encoding C7, which is a component of the fibers anchoring the epidermis to the dermis. Affected patients (about 1.35 per million persons in the United States) experience lifelong painful itching, blistering, fibrosis, impaired healing, and scarring, with increased likelihood of infection and cancer. RCT involving those affected by RDEB are rare with limited sample sizes due to the low prevalence of this genetic disorder. Treatment with topical or systemic agents has not consistently improved patient outcomes. Therapies focused on replacing C7 using autologous bone marrow or keratinocyte grafts have been difficult, with high complication rates, and have been met with mixed success. Recent HSV-1 vector research4 led to development of HSV-1 vectors capable of transferring the COL7A1 coding sequence to keratinocytes and fibroblasts in vitro and to mice deficient in C7, as well as to RDEB human skin xenografts. This research offered new opportunities for gene therapy for patients with RDEB. In this final Evidence Corner, readers are invited to consider the implications of 2 small RCTs that suggest fruitful avenues for RDEB research and practice. The first study describes a pioneering phase 1 and 2 RCT of topical gene therapy for RDEB. The second study describes a small crossover RCT exploring the effect of topical calcipotriol (VD3) ointment on wound healing and pruritis in patients with RDEB.

INHERITED EPIDERMOLYSIS BULLOSA IN NEWBORN (CASE STUDY).

Inherited epidermolysis bullosa (IEB) is a group of genetically and clinically heterogeneous diseases characterized by the formation on the skin and mucous membranes blisters and erosion due to injury. Different forms of IEB can be accompanied by various extracutaneous complications, such as blisters and erosion on the cornea and mucous membranes, stenoses and strictures of the respiratory system, gastrointestinal tract, urinary system, muscle dystrophy, and malignant tumors. Therefore diagnosis and prescribing appropriate treatment and follow-up care is an important task for neonatologists and pediatric dermatologists. Because the manifestations of IEB are numerous, a specialized center is required for optimal care, where multidisciplinary care will be provided (neonatologists, pediatric surgeons, pediatric dermatologists, etc.). The purpose of this case report is to pay attention of specialists to a disease that is rare, to present clinical case of IEB in newborn who was admitted to the intensive care unit of newborns of Vinnitsa Regional Children's Clinical Hospital.

Investigational Treatments for Epidermolysis Bullosa.

Epidermolysis bullosa (EB) is a heterogeneous group of rare inherited blistering skin disorders characterized by skin fragility following minor trauma, usually present since birth. EB can be categorized into four classical subtypes, EB simplex, junctional EB, dystrophic EB and Kindler EB, distinguished on clinical features, plane of blister formation in the skin, and molecular pathology. Treatment for EB is mostly supportive, focusing on wound care and patient symptoms such as itch or pain. However, therapeutic advances have also been made in targeting the primary genetic abnormalities as well as the secondary inflammatory footprint of EB. Pre-clinical or clinical testing of gene therapies (gene replacement, gene editing, RNA-based therapy, natural gene therapy), cell-based therapies (fibroblasts, bone marrow transplantation, mesenchymal stromal cells, induced pluripotential stem cells), recombinant protein therapies, and small molecule and drug repurposing approaches, have generated new hope for better patient care. In this article, we review advances in translational research that are impacting on the quality of life for people living with different forms of EB and which offer hope for improved clinical management.

Diagnosis and Care of the Newborn with Epidermolysis Bullosa.

Epidermolysis bullosa (EB) is a group of rare genetic disorders that are characterized by fragile skin. Because of its rarity, many neonatologists may not be familiar with the current diagnosis and treatment recommendations for EB. The classification of EB was updated in 2020. The diagnosis of EB is now more heavily based on genetic rather than clinical or histologic features. In this review, we summarize the basic classification of EB, the preferred methods of diagnosis including a panel of next-generation sequencing for all types of EB, as well as specific immunofluorescence and electron microscopy of skin biopsies in special circumstances. We also review the principles of skin care for the newborn with EB and discuss the possible associated comorbidities including infectious, gastrointestinal, respiratory, and genitourinary complications. Lastly, we discuss the approach to educating the family about the diagnosis, prognosis, and care of an infant with EB and describe resources for the successful transition of the infant from the hospital to the home.

Epidermolysis bullosa dystrophica pretibialis - Clinical snapshot and management of a rare orphan disease.

If blistering occurs in childhood, the possibility of hereditary epidermolysis bullosa should be considered even if the symptoms are mild. Besides clinical and histological examination, molecular genetic screening is diagnostically relevant. For localized forms, symptomatic, topical therapy options are currently still the primary choice. Of particular interest is the new option of topical therapy with diacerein 1 % cream. In the case of a pronounced clinical picture with extracutaneous organ involvement, multidisciplinary management is required. In the future, new forms of therapy such as autologous epidermal stem cell transplantation and gene therapeutic procedures may be applied. Human genetic counselling is indispensable.

Pathogenetic Therapy of Epidermolysis Bullosa: Current State and Prospects.

Epidermolysis bullosa is a severe hereditary disease caused by mutations in genes encoding cutaneous basement membrane proteins. These mutations lead to dermal-epidermal junction failure and, as a result, to disturbances in the morphological integrity of the skin. Clinically, it manifests in the formation of blisters on the skin or mucosa that in some cases can turn into non-healing chronic wounds, which not only impairs patient's quality of life, but also is a live-threatening condition. Now, the main approaches in the treatment of epidermolysis bullosa are symptomatic therapy and palliative care, though they are little effective and are aimed at reducing the pain, but not to complete recovery. In light of this, the development of new treatment approaches aimed at correction of genetic defects is in progress. Various methods based on genetic engineering technologies, transplantation of autologous skin cells, progenitor skin cells, as well as hematopoietic and mesenchymal stem cells are studied. This review analyzes the pathogenetic methods developed for epidermolysis bullosa treatment based on the latest achievements of molecular genetics and cellular technologies, and discusses the prospects for the use of these technologies for the therapy of epidermolysis bullosa.

Patient-reported outcomes and quality of life in recessive dystrophic epidermolysis bullosa: A global cross-sectional survey.

BACKGROUND: A spectrum of skin disease severity exists in patients with recessive dystrophic epidermolysis bullosa (RDEB). OBJECTIVE: To characterize the patient-reported outcomes and quality of life (QOL) in patients with RDEB. METHODS: A cross-sectional study of patients with RDEB surveyed through the global EBCare Registry. Patient-reported outcomes included skin disease severity, wound characteristics, pain, itch, extracutaneous symptoms, and medications. QOL was measured by using the validated Quality of Life in Epidermolysis Bullosa instrument. RESULTS: A total of 85 patients with RDEB reported 1226 wounds (937 recurrent wounds and 289 chronic open wounds). Overall skin disease severity was self-reported as mild (26%; 22/83), moderate (48%; 40/83), or severe (25%; 21/83). Worsening skin disease severity was significantly associated with larger wounds, increased opiate use, anemia, gastrostomy tube use, infections, osteoporosis, and squamous cell carcinoma. Larger wound size was associated with worse quality of life scores. LIMITATIONS: All data were self-reported from an online epidermolysis bullosa patient registry. CONCLUSIONS: This study shows a significant correlation between larger wound size with worsening skin disease severity and quality of life in participants with RDEB. Worsening skin disease severity significantly correlated with key clinical manifestations. These results show that patients with RDEB are able to self-report their skin disease severity and wounds.

Translational perspectives to treat Epidermolysis bullosa-Where do we stand?

Epidermolysis bullosa (EB) is the prototypical example of genetic skin fragility disorders. Genotypic heterogeneity, modifier genes, epigenetic, biochemical and environmental factors alter and determine pathogenic traits and, ultimately, the wide and striking phenotypic variability in EB. Besides the primary structural-functional defect, chronic tissue damage with induction and dysregulation of inflammatory pathways is a common pathogenic mechanism in EB. In localized variants, the inflammatory aberrations may mainly affect the micromilieu of lesional skin, while a systemic inflammatory response was shown to contribute to the systemic morbidity in severe EB subtypes with extensive cutaneous involvement. Our continued understanding of the pathophysiology of EB, as well as advances in molecular technologies, has paved the way for translational therapeutic approaches. The spectrum comprises of corrective and symptom-relieving therapies that include innovative therapeutic options garnered from the bench, repurposed drugs approved for other diseases, as well as strategies for gene-, protein- and cell-based therapies. Immunological traits further define new targets of therapy, aimed at improving skin barrier restoration, microbial surveillance and infection control, wound healing and anti-neoplastic effects. Clinical availability and feasibility of these approaches for all EB patients and subtypes are currently limited, reflecting issues of efficacy, specificity, tolerability and safety. A multistep targeting approach and highly individualized, risk-stratified combinatory treatment plans will thus be essential for sustained efficacy and improved overall quality of life in EB.

Emerging therapies in genodermatoses.

The human genome project yielded a compendium of genetic material that has allowed rapid advancement both in the technique of whole exome sequencing and also in the ability to identify single gene defects. The next generation of genetics has investigated how these genes interact in the development of disease, identifying pathways of illness and end organ tissue abnormal development. From the knowledge of single genes and pathways of genodermatosis development arises the opportunity to produce genetic therapies. This contribution reviews some of the exciting, emerging genetic therapies in genodermatoses.

Epidermolysis bullosa.

Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma. A broad phenotypic spectrum has been described, with potentially severe extracutaneous manifestations, morbidity and mortality. Over 30 subtypes are recognized, grouped into four major categories, based predominantly on the plane of cleavage within the skin and reflecting the underlying molecular abnormality: EB simplex, junctional EB, dystrophic EB and Kindler EB. The study of EB has led to seminal advances in our understanding of cutaneous biology. To date, pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion. Precise diagnosis is reliant on correlating clinical, electron microscopic and immunohistological features with mutational analyses. In the absence of curative treatment, multidisciplinary care is targeted towards minimizing the risk of blister formation, wound care, symptom relief and specific complications, the most feared of which - and also the leading cause of mortality - is squamous cell carcinoma. Preclinical advances in cell-based, protein replacement and gene therapies are paving the way for clinical successes with gene correction, raising hopes amongst patients and clinicians worldwide.