Alkindi Sprinkle for Pediatric Patients With Primary Adrenocortical Insufficiency: A Narrative Review.

Adrenocortical insufficiency, also known as adrenal insufficiency (AI), is an endocrine disorder characterized by inadequate production of adrenal hormones, including glucocorticoids and mineralocorticoids (MCs). The condition can be categorized as primary, secondary, or tertiary AI, depending on the location of the defect. Classical symptoms of AI include weakness, fatigue, abdominal pain, tachycardia, hypotension, electrolyte imbalances, and hyperpigmentation. In children, the most common cause of AI is classical congenital adrenal hyperplasia, which results from a deficiency in the 21-hydroxylase enzyme. The 21-hydroxylase enzyme produces all steroids, such as cortisol and aldosterone. AI management primarily involves hormone replacement therapy, typically with oral hydrocortisone and MC supplementation. However, the administration of hydrocortisone to pediatric patients presents challenges related to the lack of available dose-appropriate formulations. Historically, crushed or split adult tablets were used for the pediatric treatment of AI, although this poses an increased risk of under- or overtreatment. Inadequate dosing in the pediatric population can adversely affect growth, development, and metabolic health. Alkindi Sprinkle is a pediatric-specific hydrocortisone oral granule preparation that manages cortisol levels to help facilitate accurate therapeutic dosing. Alkindi offers several advantages, including accurate dosing, taste masking, and ease of administration. The present investigation describes AI, the management of AI, and the treatment of pediatric AI using Alkindi Sprinkle, including clinical efficacy.

Odevixibat: A Novel Bile Salt Inhibitor Treatment for Pruritus in Progressive Familial Intrahepatic Cholestasis.

Chronic pruritus is defined as an itch lasting greater than six weeks. It can manifest from a wide variety of etiologies, as many different substances can act as pruritogens, such as steroids, histamine, progesterone, endogenous opioids, and serotonin. In the setting of cholestatic liver disease, increased bile acids play a major role in chronic pruritus. The itching in cholestatic liver disease is worsened in intensity at night and localized frequently to the palms, soles, knees, and other pressure sites. It can be hard to manage, affecting the quality of sleep and causing irritability, poor attention, and, in some cases, depression. One such disease that results from chronic pruritus is progressive familial intrahepatic cholestasis (PFIC), a group of uncommon hereditary disorders that affects the formation of bile and its outflow from the liver. Previously, the drug ursodeoxycholic acid was used to help manage pruritus or surgical procedures, e.g., partial external biliary diversion or partial internal biliary diversion, to help control complications of the disease. This literature review will discuss three clinical studies covering the effectiveness of odevixibat in treating pruritus in patients with PFIC. Odevixibat (Bylvay) is an oral drug that has been FDA-approved to treat pruritus in patients three months of age and older with PFIC. Odevixibat prevents the reabsorption of bile salts in the intestines, resulting in decreased levels of bile salts via their excretion in stool. Several studies have determined that the drug is well tolerated and provides a nonsurgical, pharmacological treatment alternative for those with PFIC.

Assessment of the Impact of a Head-mounted Augmented Reality Low Vision Aid on Vision and Quality of Life in Children and Young People with Visual Impairment.

Introduction: Electronic head-mounted low vision aids (LVAs) can help children and young people (CYP) to access schoolwork and leisure activities which they would otherwise struggle to be able to do with traditional optical or hand held LVAs. SightPlus uses a smartphone mounted in a virtual reality headset controlled using a Bluetooth joystick. It offers users 0.7-24.3× magnification alongside enhanced modes to maximise vision. Methods: Eighteen participants aged 8-16 years with reduced vision were given SightPlus to use at home for four weeks. Visual acuity was assessed with and without SightPlus along with reading performance, contrast sensitivity, functional vision and quality of life questionnaires. Results: Clinically significant improvements in distance vision (0.633logMAR SD ± 0.359), near vision (0.411logMAR SD ± 0.368), reading acuity (0.454LlogMAR SD ± 0.406) and critical print size (0.285logMAR ± 0.360) were seen when testing with SightPlus.However, there was a mean decrease in contrast sensitivity and reading speed when using SightPlus. Despite this, nine out of the 14 patients included for analysis indicated a preference to continue to use SightPlus. Of note, younger participants were more likely to show a preference for using SightPlus. All seven CYP aged 10 or under wanted to continue to use SightPlus; in contrast, only two of the seven participants aged 11 or over wanted to continue. Conclusions: Like the results in adult populations, SightPlus has been found to improve CYP visual functions. Older participants were less likely to want to continue to use SightPlus, potentially suggesting they have found other methods for managing sight loss.

Topical Cocaine Hydrochloride Nasal Solution: Anesthetic and Surgical Considerations.

Adequate surgical view during various types of nasal procedures is essential for surgical operations to be performed in a safe, efficient, and successful manner. Minimizing bleeding during surgery is an important way of increasing visualization that is commonly achieved by using a vasoconstrictive agent to control intraoperative hemorrhage. Many otolaryngologists choose to employ topical cocaine to minimize bleeding during surgery owing to its vasoconstrictive properties, while simultaneously benefitting from its dual local anesthetic effects. The relative benefit of topical cocaine for otolaryngologic procedures when compared to other topical analgesics and vasoconstrictors remains a topic of discussion due to the multiple potential cardiac and central nervous system side effects associated with cocaine administration. Furthermore, there is not a scientifically backed maximal safe dose published; instead, most of the guidelines for intranasal cocaine use are based on untested clinical practice. Despite this, the short latency, adequate duration of action, and inherent vasoconstrictive and decongestive capabilities make cocaine a valuable anesthetic agent for use in clinical procedures. As the relative benefit of using topical cocaine compared to the use of other vasoconstrictors and analgesics for nasal procedures remains undetermined in the current literature, this leaves the need for a comprehensive review of research that explores the risks and benefits of using topical cocaine in nasal procedures based on clinical trials that compare intranasal cocaine with various other analgesics and vasoconstrictors.

Resolution patterns and duration of retinal haemorrhages measured by two-dimensional retinal area pixel counts from sequential retinal imaging in childhood encephalopathies: a morphometric study.

OBJECTIVE: To determine the time to resolution of different-layered retinal haemorrhages (RHs), and to describe the main patterns of their resolution in a group of children with encephalopathies. METHODS AND ANALYSIS: From a prospective study of 114 children with traumatic and non-traumatic encephalopathies, 429 selected individual RHs (iRHs) from 18 children were serially imaged from admission using a RetCam. Photoshop and Scion Imaging software allowed calculation of RH area in pixels. RESULTS: Two patterns of the resolution were recognised on the basis of area measurements: a progressive decrease (pattern A, 60% of iRHs), and a form of asymmetrical decay in which iRHs first increased in size before then progressively decreasing (pattern B, 35% of iRHs). Within the pattern A group, the Kaplan-Meier median survival time (MST) (95% CI) was 10 (9.3 to 10.7) days for intra-RHs (IRHs) and 38 (10.8 to 65.2) days for pre-RHs (PRHs), log rank (Mantel-Cox) p=0.001. The mean percentage reduction in area per day was 12.5% for all iRHs, 14.5% for IRHs and 6.3% for PRHs. CONCLUSION: Serial area measurements of iRHs revealed that 35% haemorrhages became temporarily larger before decreasing to resolution. Serially imaged selected RHs showed a longer MST for PRHs than for IRHs.

The Heritability of Pigment Dispersion Syndrome and Pigmentary Glaucoma.

PURPOSE: Pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG) are presumed to be inherited in an autosomal dominant manner. We examine relatives of patients with PDS and PG in order to determine the heritability of these diseases. DESIGN: This was a prospective, cross-sectional study. METHODS: One hundred and one patients with PDS were prospectively recruited over 11 months. Four of the patients had PDS without ocular hypertension or glaucoma, 6 had PDS and ocular hypertension, and 91 had PG. Criteria for PDS were 2 of 3 signs: Krukenberg spindle, midperipheral iris transillumination defects, and/or heavy trabecular meshwork pigmentation. Criteria for PG were PDS and 2 of 3 signs: intraocular pressure >21 mm Hg, glaucomatous optic nerve damage, and/or glaucomatous visual field loss. Ninety-nine first-degree relatives living within a 100-mile radius of Iowa City, Iowa were examined in the clinic to determine the probability of familial transmission. RESULTS: A total of 10 of 99 (10.10%) first-degree relatives were diagnosed with PDS (1 with PDS alone, 2 with PDS and ocular hypertension, and 7 with PG). Seven families with ≥2 affected members were identified. The majority of affected family members (8/10) showed moderate to heavy trabecular meshwork pigmentation and either Krukenberg spindle or transillumination defects. CONCLUSIONS: Most of the cases of PDS in our study were sporadic, and the risk to first-degree relatives is lower than previously reported. However, there are families with apparent autosomal dominant inheritance of PDS in which the risk to relatives may be high.

Raised intracranial pressure and retinal haemorrhages in childhood encephalopathies.

AIM: To explore the relationship between raised intracranial pressure (RICP) and retinal haemorrhages in traumatic and non-traumatic childhood encephalopathies. METHOD: A prospective study of 112 children (35 females and 77 males, age range 0.01mo-17y 8.3mo; mean 5y 8.6mo, median 4y 5.6mo) included 57 accidental traumatic brain injuries (ATBIs), 21 inflicted traumatic brain injuries (ITBIs), and 34 non-traumatic encephalopathy cases. Measurements included intracranial pressure (ICP), cerebral perfusion pressure, pressure-time index of ICP, and number, zone, and layer of retinal haemorrhages on retinal imaging. RESULTS: Group I had measured elevated ICP (n=42), Group II had clinical and/or radiological signs of RICP (n=21), and Group III had normal ICP (n=49). In the combined Groups I and II, 38% had retinal haemorrhages. Multiple logistic regression confirmed that the presence of retinal haemorrhages was significantly related to the presence of RICP independent of age and aetiology; however, the occurrence and overall numbers were not significantly related to the specific ICP level. The numbers of intraretinal (nerve-fibre layer and dot blot) retinal haemorrhages were significantly greater in those with RICP. The ITBI population was significantly different from the other combined aetiological categories. INTERPRETATION: The study results indicate a complex RICP/retinal haemorrhage relationship. There was no evidence of existing retinal haemorrhages being exacerbated or new retinal haemorrhages developing during periods of confirmed RICP.

Interferon-alpha-induced hepatitis C virus clearance restores p53 tumor suppressor more than direct-acting antivirals.

The mechanism why hepatitis C virus (HCV) clearance by direct-acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)-stress response. In this study, we examined whether HCV clearance by interferon-alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone-mediated autophagy (CMA) in infected primary human hepatocytes and Huh-7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin-3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome-dependent mechanism because lysosome-associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon-alpha-based antiviral therapies normalizes the ER-stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV-infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV-induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER-stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256-269).

Automated Axon Counting in Rodent Optic Nerve Sections with AxonJ.

We have developed a publicly available tool, AxonJ, which quantifies the axons in optic nerve sections of rodents stained with paraphenylenediamine (PPD). In this study, we compare AxonJ's performance to human experts on 100x and 40x images of optic nerve sections obtained from multiple strains of mice, including mice with defects relevant to glaucoma. AxonJ produced reliable axon counts with high sensitivity of 0.959 and high precision of 0.907, high repeatability of 0.95 when compared to a gold-standard of manual assessments and high correlation of 0.882 to the glaucoma damage staging of a previously published dataset. AxonJ allows analyses that are quantitative, consistent, fully-automated, parameter-free, and rapid on whole optic nerve sections at 40x. As a freely available ImageJ plugin that requires no highly specialized equipment to utilize, AxonJ represents a powerful new community resource augmenting studies of the optic nerve using mice.

Retinal hemorrhage in abusive head trauma: finding a common language.

PURPOSE: To assess the performance of a refined Web-based tool for documenting retinal hemorrhage characteristics in suspected abusive head trauma. METHODS: Using a comprehensive tabular secure platform, with access to digital images in color, black and white, and 4-zone system schematic overlay, four pediatric ophthalmologists performed pilot testing with 80 images for tool refinement. In a second phase, retinal hemorrhages were documented by number, zone, and type. Interobserver agreement was calculated using the Fleiss kappa coefficient. Intraobserver agreement was calculated using Cohen's kappa statistic. We used surface area mapping software for further analysis. RESULTS: Interobserver agreement was good (kappa 0.4-0.6) and very good (kappa 0.6-0.8) for all questions in Zone A (peripapillary). For zones C (midperiphery) and D (peripheral retina), agreement was very good for all questions except number of hemorrhages, for which agreement was good. Zone B (macula) showed good and fair agreement except for superficial hemorrhage, for which agreement was poor. There was very good intraobserver agreement for number (kappa 0.68, 0.65, 0.67) and type of hemorrhages in zones A, B, and C. Surface area mapping results revealed no significant differences between zones A and B. Zones C and D had significantly less hemorrhage than A and B. CONCLUSIONS: Our tool performed with good or very good interobserver and intraobserver agreement in almost all domains. We attribute zone B underperformance to the significant increased area covered by hemorrhages compared to zones C and D and the lack of contrast with normal anatomical structures in zone A.

Prediction of inflicted brain injury in infants and children using retinal imaging.

BACKGROUND: Retinal hemorrhages (RHs) occur in inflicted traumatic brain injury (ITBI), accidental traumatic brain injury (ATBI), and some medical conditions, although the reported number, distribution, type, and frequency vary greatly between these different etiologies. We hypothesize that these RH characteristics reliably help to distinguish ITBI from ATBI and nontraumatic etiologies. METHODS: A 6-year prospective observational study using wide-field retinal imaging (RetCam) was conducted within 24 hours of admission to PICU, on serially recruited children with traumatic and nontraumatic encephalopathies. "Definite" and "probable" ITBI cases were confirmed by multiagency child protection case conferences. Image analysis used digital color and grayscale images for retinal "zoning" and "layering" of hemorrhages. RESULTS: Significant differences were found between the mean numbers of hemorrhages in ATBI/ITBI, and ITBI/nontraumatic etiologies for the 3 retinal zones (range, P = .003-.009) and for the dot-blot hemorrhages (range P = .001-.002). The mean numbers of RHs per ITBI patient in the peripapillary, macula, and peripheral zones were 14, 28, and 31 respectively. RHs in ATBI were near the optic disc and more superficial than in ITBI, where hemorrhages involved deeper layers (range, P = .003-.039) and were more peripheral (P = .03). The positive predictive value for ITBI in children <3 years with >25 dot-blot (intraretinal) hemorrhages was 93%. CONCLUSIONS: This prospective study, which included all potential causes of RHs, with objective retinal methodology, has confirmed that a young age and a high dot-blot count are strong predictors of ITBI. This high predictive value may support medicolegal deliberations.

Retinal haemorrhage description tool.

BACKGROUND: Retinal haemorrhages are an important finding in children with abusive and accidental head trauma. There are no standardised and validated protocols to describe them in a consistent manner. The aim of this web-based study was to establish the reliability and validity of a new retinal haemorrhage description tool. MATERIALS AND METHOD: Our tool is a comprehensive questionnaire, which is applied using a retinal schematic that divides the retina into four independent zones. Four independent observers scored retinal haemorrhages from 80 retinal photographs. Inter- and intra-rater agreement (by repeat assessment of 10 photographs for each examiner) were calculated using Fleiss κ statistics. RESULTS: A high inter-rater agreement was noted for haemorrhages in the peripapillary zones, whereas agreement was only fair for all other zones. Intra-rater agreement was high only for the posterior pole. Photographs may be an unreliable way of documenting retinal haemorrhages particularly from the peripheral retina, thus underscoring the importance of a thorough clinical examination. CONCLUSION: This study shows that the tool achieves some validity for describing haemorrhages in the posterior retina. It performs less well in the peripheral zones.

An inter-observer and intra-observer study of a classification of RetCam images of retinal haemorrhages in children.

BACKGROUND: There is currently no universally accepted classification of childhood retinal haemorrhages. AIM: To measure the inter- and intra-observer agreement of clinical classifications of retinal haemorrhages in children. METHODS: Four examiners (two consultant ophthalmologists and two other clinicians) were shown 142 retinal haemorrhages on 31 RetCam photographs. The retinal haemorrhages were from children with accidental or abusive head injury, or other encephalopathies, and included retinal haemorrhages of different ages. Specified haemorrhages were initially classified by each examiner according to their clinical understanding. Altogether, 26 haemorrhages were re-presented to test intra-observer consistency. Examiners then agreed a common description for each haemorrhage type and five categories were described (vitreous, pre-retinal, nerve fibre layer, intra-retinal/sub-retinal or indeterminate) and the study repeated. RESULTS: There was 'fair agreement' initially (Fleiss' unweighted κ=0.219) and, with the agreed classification, slight improvement (0.356). Intra-observer agreement marginally improved on re-test. The two consultant ophthalmologists showed 'fair' agreement on both occasions (paired κ statistic). The other rater pair improved from 'fair' to 'substantial' agreement with the new classification. CONCLUSIONS: The classification of retinal haemorrhage in children by appearance alone shows only fair agreement between examiners. Clinicians who are not consultant ophthalmologists appear to benefit from the new succinct classification.

Transient visual loss and isolated disk edema in juvenile nasopharyngeal angiofibroma.

Juvenile nasopharyngeal angiofibroma is a well-described but rare benign tumor that mainly affects adolescent boys. Although it is capable of extravagant local extension and tissue destruction, the tumor is amenable to effective therapy. Ocular or visual complications have been little noted in the literature. We report a case whose sole symptom was unilateral transient visual impairment and findings were limited to a nonspecific optic disk edema.

An interrater reliability study of a new 'zonal' classification for reporting the location of retinal haemorrhages in childhood for clinical, legal and research purposes.

BACKGROUND/AIMS: To develop and assess a zonal classification of the retina to facilitate description of the location of retinal haemorrhages in children. METHODS: A novel zonal classification of the retina was devised based on the anatomical landmarks of the optic disc and vascular arcades, by reviewing a large number of wide field digital retinal images drawn from our database of children with accidental and non-accidental head injury and other encepthalopathies. Four expert examiners then independently 'located' 142 retinal haemorrhages by zone, from 31 high quality photographs. RESULTS: Cohen's unweighted kappa scores for all possible pairs of the four raters (ie, six pairs) ranged from 0.86 to 0.92, that is 'almost perfect' agreement. Fleiss' kappa for agreement between multiple raters (four) and for multiple categories (three) was 0.8841, that is 'almost perfect' agreement. Cohen's unweighted kappa statistic for intrarater reliability gave an overall concordance that ranged from 'substantial' to 'perfect' agreement. CONCLUSION: This new retinal zone classification and the use of photographs and templates is a very reliable tool for reporting the location of retinal haemorrhages from multiple aetiologies in children, and may be useful for research and medico-legal reports.