The Birth Prevalence of Congenital Hyperinsulinism: A Narrative Review of the Epidemiology of a Rare Disease.

BACKGROUND: Congenital hyperinsulinism (HI) is a rare pediatric disease and the most common cause of severe, persistent hypoglycemia in childhood. It is characterized by the dysregulation of insulin secretion from the pancreas and can lead to irreversible brain damage with lifelong neurodisability. SUMMARY: The global birth prevalence of HI is currently unknown. An evidence-based estimate of HI birth prevalence is essential to improve diagnosis and patient management, to drive clinical research and the development of new treatments, and to inform public policy. In order to estimate the birth prevalence of persistent HI, a targeted literature review of studies that report HI epidemiological data was undertaken, and the strengths and limitations of each study were analyzed. Overall, eight global studies were identified that reported independently determined HI epidemiological data. KEY MESSAGES: The best estimate for the birth prevalence of persistent HI in European-ancestry populations is 3.5 per 100,000 births. Local consanguinity patterns appear to have a considerable impact on the birth prevalence of persistent HI in each country, precluding the application of this figure to all global populations. More epidemiological studies with robust methodology are needed to enable a reliable approximation of the incidence and prevalence of HI in global populations.

International Guidelines for the Diagnosis and Management of Hyperinsulinism.

Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI, however; there have been almost no new therapeutic modalities since the development of diazoxide. Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in 'developed' countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an "essential medicine" by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.

Global Registries in Congenital Hyperinsulinism.

Congenital hyperinsulinism (HI) is the most frequent cause of severe, persistent hypoglycemia in newborn babies and children. There are many areas of need for HI research. Some of the most critical needs include describing the natural history of the disease, research leading to new and better treatments, and identifying and managing hypoglycemia before it is prolonged and causes brain damage or death. Patient-reported data provides a basis for understanding the day-to-day experience of living with HI. Commonly identified goals of registries include performing natural history studies, establishing a network for future product and treatment studies, and supporting patients and families to offer more successful and coordinated care. Congenital Hyperinsulinism International (CHI) created the HI Global Registry (HIGR) in October 2018 as the first global patient-powered hyperinsulinism registry. The registry consists of thirteen surveys made up of questions about the patient's experience with HI over their lifetime. An international team of HI experts, including family members of children with HI, advocates, clinicians, and researchers, developed the survey questions. HIGR is managed by CHI and advised by internationally recognized HI patient advocates and experts. This paper aims to characterize HI through the experience of individuals who live with it. This paper includes descriptive statistics on the birthing experience, hospitalizations, medication management, feeding challenges, experiences with glucose monitoring devices, and the overall disease burden to provide insights into the current data in HIGR and demonstrate the potential areas of future research. As of January 2022, 344 respondents from 37 countries consented to participate in HIGR. Parents or guardians of individuals living with HI represented 83.9% of the respondents, 15.3% were individuals living with HI. Data from HIGR has already provided insight into access challenges, patients' and caregivers' quality of life, and to inform clinical trial research programs. Data is also available to researchers seeking to study the pathophysiology of HI retrospectively or to design prospective trials related to improving HI patient outcomes. Understanding the natural history of the disease can also guide standards of care. The data generated through HIGR provides an opportunity to improve the lives of all those affected by HI.

Congenital Hyperinsulinism International: A Community Focused on Improving the Lives of People Living With Congenital Hyperinsulinism.

Congenital hyperinsulinism (HI) is a rare disease affecting newborns. HI causes severe hypoglycemia due to the overproduction of insulin. The signs and symptoms of hypoglycemia in HI babies is often not discovered until brain damage has already occurred. Prolonged hypoglycemia from HI can even lead to death. Disease management is often complex with a high burden on caregivers. Treatment options are extremely limited and often require long hospital stays to devise. Cascading from suboptimal treatments and diagnostic practices are a host of other problems and challenges that many with HI and their families experience including continued fear of hypoglycemia and feeding problems. The aim of this paper is (1) to describe the current challenges of living with HI including diagnosis and disease management told from the perspective of people who live with the condition (2), to provide family stories of life with HI, and (3) to share how a rare disease patient organization, Congenital Hyperinsulinism International (CHI) is working to improve the lives of HI patients and their families. CHI is a United States based nonprofit organization with a global focus. The paper communicates the programs the patient advocacy organization has put into place to support HI families through its virtual and in-person gatherings. The organization also helps individuals access diagnostics, medical experts, and treatments. CHI also raises awareness of HI to improve patient outcomes with information about HI and prolonged hypoglycemia in twenty-three languages. CHI drives innovation for new and better treatments by funding research pilot grants, conducting research through the HI Global Registry, and providing patient experience expertise to researchers developing new treatments. The organization is also the sponsor of the CHI Collaborative Research Network which brings medical and scientific experts together for the development of a patient-focused prioritized research agenda.

Navigating the U.S. health insurance landscape for children with rare diseases: a qualitative study of parents' experiences.

BACKGROUND: Parents of children with rare diseases often face uncertainty about diagnosis, treatment, and costs associated with healthcare for their child. Health insurance status impacts each of these areas, but no U.S. study has explored parents' perceptions of the health insurance impacts on their child's care. This study aimed to qualitatively explore how these parents navigate the complex health insurance system for their children and their experiences in doing so. METHODS: Semi-structured interviews were conducted with parents of children with metachromatic leukodystrophy (MLD) and spinal muscular atrophy (SMA), chosen for specific disease characteristics and orphan drug status. Participants were recruited via e-mail through patient advocacy organizations between September and December 2018. Interviews were conducted via Skype, were recorded, and professionally transcribed. Modified grounded theory was utilized as a methodology to analyze transcripts in an iterative process to determine themes and sub-themes based on participant described experiences. RESULTS: Major themes and subthemes that emerged across the 15 interviews included: (1) difficulties obtaining secondary insurance based on state eligibility criteria; (2) difficulty accessing needed healthcare services; and (3) need for repeated interactions with insurance representatives. The absence of clearly documented or widely recognized clinical guidelines exacerbated the difficulty accessing care identified as necessary by their healthcare team, such as therapy and equipment. An explanatory model for parent's experiences was developed from the themes and subthemes. The model includes the cyclical nature of interacting with insurance for redundant reauthorizations and the outside support and financial assistance that is often necessary to address their child's healthcare needs. CONCLUSIONS: With complex health conditions, small setbacks can become costly and disruptive to the health of the child and the life of the family. This study suggests that patients with rare diseases may benefit from time limits for processing coverage decisions, increasing transparency in the claims and preauthorization processes, and more expansive authorizations for on-going needs. Additional studies are needed to understand the full scope of barriers and to inform policies that can facilitate better access for families living with rare diseases.

Co-localization of AMPA-type glutamate receptor immunoreactivity in neurons of the rat subthalamic nucleus.

In order to determine the precise cellular localization of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)-type glutamate receptor subunit immunoreactivity in the rat subthalamic nucleus, single and double immunofluorescence was performed. Intense level of GluR1, GluR2, GluR2/3 and GluR4 immunoreactivity was found in almost all neurons of the subthalamic nucleus. By double immunofluorescence, the subthalamic neurons in the same sections that displayed a strong immunoreactivity for GluR1 were found to display a robust GluR2 immunoreactivity and the subthalamic neurons that displayed GluR2 immunoreactivity were also found to express GluR4 immunoreactivity. The present results thus demonstrate that individual neurons of the subthalamic nucleus are likely to co-express GluR1 and GluR2, and GluR2 and GluR4 immunoreactivity. The native AMPA channels in the subthalamic neurons may, therefore, be composed of heteromeric subunits. The present results provide information of the neuroanatomical localization of AMPA receptor subunits in neurons of the subthalamic nucleus. The localization of AMPA receptor subunits may be related to functional characteristics of AMPA channels in the subthalamic neurons.

Effects of euxanthone on neuronal differentiation.

The growth inhibitory and differentiation inducing effects of euxanthone (1,7-dihydroxyxanthone) from the medicinal plant Polygala caudata on the neuroblastoma (Neural 2A, subclone BU-1) were investigated. At the concentration range of 0-100 microM, euxanthone inhibits the growth of BU-1 cells in a dose dependent manner. The 50% growth inhibitory concentration (IC50) was 41 microM. Significant induction of morphological differentiation and neurite growth was observed at the concentration of 100 microM. Frequency of proliferative neuroblastoma cells was determined after induction of differentiation. The frequency of proliferating BU-1 cells was markedly reduced from 1/1.1 to <1/99. Confocal microscopy also confirmed that the morphological differentiation of BU-1 was associated with the expression of neurite specific marker MAP-2 protein in neurites. These data suggest that euxanthone may be one of the neuropharmacological active compounds in the medicinal plant Polygala caudata.

Endoscopic Nd:YAG laser treatment of inoperable lower gastrointestinal cancer.

Many patients with colorectal cancer are not amenable to curative resection at the time of presentation. Nevertheless, palliative resection still remains as the treatment of choice in the majority of patients. A small group of patients that are poor candidates for surgical resection may benefit from some non-surgical palliative procedures to relieve their symptoms. Electrocoagulation, cryosurgery and radiotherapy are some of the non-surgical procedure used and they are associated with high morbidity and mortality. The use of Neodymium: Yttrium-Aluminium-Garnet (Nd:YAG) laser photoablation to palliate patients with advanced colorectal carcinoma is well documented. It is associated with relatively low morbidity and perioperative mortality. It requires no anaesthesia and is the only non-surgical procedure that can be safely carried out above the peritoneal reflection. Nd:YAG laser had been used in some centres as a preresectional procedure in patient presenting with high grade obstruction. It allows proper bowel preparation followed by primary excision and anastomosis. As a palliative procedure, most patients showed rapid improvement in obstructive symptoms, bleeding and rectal discharge. The size of the lesion and circumferential extent of the tumour base correlate well with the response rate. Most patients remained asymptomatic before they succumb to the advanced disease. In our series, good palliation of obstructive symptoms was achieved in all obstructive cases with one laser treatment, bleeding tumours required an average of two sessions for complete haemostasis. In conclusion, Nd:YAG laser therapy is a safe and efficacious means for palliation of obstructive symptoms and bleeding in advanced rectal carcinoma.

Emergency repair and reconstruction in the severely crushed hand.

Crushing injuries of the hand are a common clinical problem which require judgement and assessment by an experienced hand surgeon for an optimum result. The crushed hand has to be viewed in the perspective of injury to an essential organ with its skin and contents, namely muscles, vessels, nerves, tendons, bone and joints. A poor result is often due to inadequate wound debridement, failure to identify the extent of crushing of the devitalized tissue, closure of the skin under tension in the presence of wound contamination, and complex repairs in an avascular bed. In an emergency situation, the simplest suitable procedure is preferred. Open degloving injuries, grease and paint gun injuries, and especially closed crushing, degloving injuries can be very misleading and need special attention.