Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia.

BACKGROUND: Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels. METHODS: In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained. RESULTS: A total of 103 participants underwent randomization, of whom 69 were assigned to the crinecerfont group and 34 to the placebo group; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol per liter). At week 4, the androstenedione level was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol per liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol per liter]) (least-squares mean difference, -268 ng per deciliter [-9.3 nmol per liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol per liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol per liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (least-squares mean difference, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events. CONCLUSIONS: In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.).

Tissue-Tracking Mitral Annular Displacement in Neonates: A Novel Index of Left Ventricular Systolic Function.

OBJECTIVES: To assess the feasibility, accuracy, and reproducibility of tissue-tracking mitral annular displacement (TMAD) compared with other measures of left ventricular systolic function in healthy preterm and term neonates in the transitional period. METHODS: This was a prospective observational study. Two echocardiograms were performed at 24 and 48 hours of life. TMAD, shortening fraction (SF), ejection fraction (EF), s', and global longitudinal strain (GLS) were measured offline. Accuracy to detect impaired GLS was tested by ROC curve analysis. DeLong test was used to compare AUCs. Intra and interobserver reproducibility of the off-line analysis was calculated. RESULTS: Mean ± SD gestational age and weight were 34.2 ± 3.8 weeks and 2162 ± 833 g, respectively. TMAD was feasible in 168/180 scans (93%). At 24 hours the AUC (95% CI) of SF, EF, s', and TMAD (%) was 0.51 (0.36-0.67), 0.68 (0.54-0.82), 0.63 (0.49-0.77), and 0.89 (0.79-0.99) respectively. At 48 hours the AUC (95% CI) of SF, EF, s', and TMAD (%) was 0.64 (0.51-0.77), 0.59 (0.37-0.80), 0.70 (0.54-0.86), and 0.96 (0.91-1.00), respectively. The AUC of TMAD was superior to the AUC of SF, EF, s', at both timepoints (P < .02). Intraclass correlation coefficients (95% CI) of intra and interobserver reproducibility of TMAD were 0.97 (0.95-0.99) and 0.94 (0.88-0.97), respectively. CONCLUSION: TMAD showed improved accuracy and optimal reproducibility in neonates in the first 48 hours of life.

Phosphate Uptake and Its Relation to Arsenic Toxicity in Lactobacilli.

The use of probiotic lactobacilli has been proposed as a strategy to mitigate damage associated with exposure to toxic metals. Their protective effect against cationic metal ions, such as those of mercury or lead, is believed to stem from their chelating and accumulating potential. However, their retention of anionic toxic metalloids, such as inorganic arsenic, is generally low. Through the construction of mutants in phosphate transporter genes (pst) in Lactiplantibacillus plantarum and Lacticaseibacillus paracasei strains, coupled with arsenate [As(V)] uptake and toxicity assays, we determined that the incorporation of As(V), which structurally resembles phosphate, is likely facilitated by phosphate transporters. Surprisingly, inactivation in Lc. paracasei of PhoP, the transcriptional regulator of the two-component system PhoPR, a signal transducer involved in phosphate sensing, led to an increased resistance to arsenite [As(III)]. In comparison to the wild type, the phoP strain exhibited no differences in the ability to retain As(III), and there were no observed changes in the oxidation of As(III) to the less toxic As(V). These results reinforce the idea that specific transport, and not unspecific cell retention, plays a role in As(V) biosorption by lactobacilli, while they reveal an unexpected phenotype for the lack of the pleiotropic regulator PhoP.

An update on ophthalmological perspectives in oculodermal melanocytosis (Nevus of Ota).

PURPOSE: To provide a review of the literature on oculodermal melanocytosis (ODM) with a focus on the diagnostic and therapeutic implications of multimodal imaging techniques in the management of ophthalmic complications. METHODS: The authors carried out a literature search on PubMed, Medline, and Scopus of English language articles published on ODM through August 2021. This review presents traditional and novel diagnostic methods in the diagnosis and follow-up of patients with particular emphasis on addressing the role of imaging in the management of the ophthalmic complications of the condition towards improving current practice patterns. RESULTS: ODM is a rare, prevalently unilateral, congenital condition that presents with brown or blue/gray flat asymptomatic lesions of the skin, mucosae, episclera/sclera, and uvea localized within the territory of distribution of the ophthalmic and mandibular branches of the trigeminal nerve. Glaucoma and predisposition to uveal melanoma are the main ophthalmic complications. Diagnosis and management are through comprehensive opthalmological examination and traditional imaging methods such as ultrasonography and fluorescein/indocyanine green angiography as pigmentation of the fundus can conceal subtle retinal and choroidal alterations. Anterior segment optical coherence tomography and ultrasound biomicroscopy are used to evaluate the anterior segment and the ciliary body in the presence of glaucoma or melanoma of the anterior uveal tract. Fundus autofluorescence and retinal pigment epithelium (RPE) alterations are of aid in the differential diagnosis between choroidal nevi and melanoma. Enhanced depth imaging spectral domain optical coherence tomography offers outstanding in vivo evaluation of the dimensions and details of tumors or nevi and surrounding choroidal tissues and small choroidal melanomas may show distortions of the retinal and sub-retinal profile, presence of intra and sub-retinal fluid, abnormalities of the RPE, and compression of the choriocapillaris. CONCLUSIONS: Novel multimodal imaging techniques are significant in the diagnosis and management of the ophthalmic complications of ODM. Fundus autofluorescence and enhanced depth spectral domain optical coherence tomography have adjunctive value in the detection of early-stage melanoma and differential diagnosis between nevi and melanoma. Awareness of current and emerging imaging techniques can propagate improved standardized definition and assessment of the complications of ODM.

Brolucizumab Intravitreal Injections for Wet Age-Related Macular Degeneration: Real-Life Study on a Cohort of Italian Patients.

Background and Objectives: To report the real-life Brolucizumab therapeutical outcomes of treatment-naïve and non-treatment-naïve eyes with neovascular age-related macular degeneration (nAMD) and to analyze the incidence of therapy-related adverse events. Materials and Methods: A total of 56 eyes of 54 patients diagnosed with nAMD were retrospectively evaluated over a 3-month follow-up. Naïve eyes received a 3-month loading phase, whereas non-naïve eyes were treated with one intravitreal injection + ProReNata scheme. The main outcome measures were best-corrected visual acuity (BCVA) and central retinal thickness (CRT) change. In addition, patients were stratified on the basis of fluid accumulation site, whether intra-retinal (IRF), sub-retinal (SRF), or sub-retinal pigmented epithelium (SRPE), to separately assess the eventual BCVA change in each subgroup. Finally, the incidence of ocular adverse events was evaluated. Results: In naïve eyes, a significant improvement of BCVA (LogMar) was observed at all timepoints from baseline (1 month-Mean Difference (MD): -0.13; 2 months MD: -0.17; 3 months MD: -0.24). In non-naïve eyes, a significant mean change was observed at all timepoints, with the exception of 1-month follow-up (2 months MD: -0.08; 3 months MD: -0.05). CRT significantly changed in both groups at all timepoints at a similar pace within the first two months, with naïve eyes displaying a larger overall thickness decrease at the end of the follow-up (Group 1 = MD: -123.91 µm; Group 2 = MD: -110.33 µm). With respect to the location of the edema, a significant BCVA change was observed in naïve patients with fluid in all three sites at the end of the follow-up (SRPE = MD: -0.13 (p = 0.043); SR = MD: -0.15 (p = 0.019); IR = MD: -0.19 (p = 0.041). Non-naïve patients exhibited significant mean BCVA changes only with respect to SR and IR fluid presence (SRPE = MD: -0.13 (p = 0.152); SR = MD: -0.15 (p = 0.007); IR = MD: -0.06 (p = 0.011). One naïve patient experienced acute-onset anterior and intermediate uveitis which completely resolved after therapy. Conclusions: Brolucizumab was demonstrated to be a safe and efficient alternative in improving both the anatomical and functional parameters of eyes with nAMD in this small, uncontrolled, series of patients.

Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4). DESIGN: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries. PATIENTS: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry. MEASUREMENTS: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM). RESULTS: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1-9.2) were taking a median 11.3 mg/m2 /day (8.6-14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0-104.0). Median D4 under 12 years was 0 nmol/L (0-2.0) and above 12 years was 10.5 nmol/L (3.9-21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R2 = 0.29). In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p < 0.001, R2 = 0.08). Neither biomarker varied directly with dose or weight (p > 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m2 /day for every 1 point increase in weight standard deviation score. DISCUSSION: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain.

Impact of Aortic Diameter Measurements at Three Anatomical Landmarks on Left Ventricular Output Calculation in Neonates.

OBJECTIVES: To assess reproducibility and accuracy of left ventricular output (LVO) quantifications in neonates, when left ventricular outflow tract diameter (LVOTD) was measured at the hinges of the aortic valve (AV), at the aortic sinus (AS), and at the sinotubular junction (STJ). METHODS: This was an observational study. In the first cohort of very preterm neonates, we assessed intraobserver and interobserver repeatability of LVOTD measured at the AV, AS, and STJ and of the corresponding LVO. In the second cohort of older neonates, we compared paired LVO measurements by echo and magnetic resonance imaging (MRI). RESULTS: In the first cohort of 48 neonates, mean (standard deviation) weight and age at scan were 1046 (302) g and 28.1 (2.7) weeks. Interobserver bias (95% limits of agreement [LOA]) for LVOTD at the AV, AS, and STJ was 0 (-0.3 to 0.3) mm, 0 (-0.7 to 0.7) mm, and 0 (-0.8 to 0.7) mm, respectively. Interobserver bias (95% LOA) for the corresponding LVO was -1.3 (-31 to 33) ml/kg/min, -0.5 (-88 to 87) ml/kg/min, and -7.2 (-83 to 69) ml/kg/min, respectively. In the second cohort of 10 neonates, median (range) weight and age at scan were 1942 (970-3640) g and 37.2 (31.7-39.8) weeks. LVO measured at the AV showed stronger agreement with MRI: bias (LOA) -10.6 (-74 to 52) ml/kg/min, compared to LVO measured at AS and STJ: 194 (-0.5 to 388) ml/kg/min and 43 (-72 to 159) ml/kg/min respectively. CONCLUSIONS: Reproducibility and accuracy of LVO quantification by echo were better when aortic diameter was measured at AV.

Choroidal Vasculature Changes in Age-Related Macular Degeneration: From a Molecular to a Clinical Perspective.

The contribution of choroidal vasculature to the pathogenesis of age-related macular degeneration (AMD) has been long debated. The present narrative review aims to discuss the primary molecular and choroidal structural changes occurring with aging and AMD with a brief overview of the principal multimodal imaging modalities and techniques that enable the optimal in vivo visualization of choroidal modifications. The molecular aspects that target the choroid in AMD mainly involve human leukocyte antigen (HLA) expression, complement dysregulation, leukocyte interaction at Bruch's membrane, and mast cell infiltration of the choroid. A mechanistic link between high-risk genetic loci for AMD and mast cell recruitment has also been recently demonstrated. Recent advances in multimodal imaging allow more detailed visualization of choroidal structure, identifying alterations that may expand our comprehension of aging and AMD development.

Early corneal and optic nerve changes in a paediatric population affected by obstructive sleep apnea syndrome.

PURPOSE: The relation between OSAS and eye diseases is well known in adults, while very few and contradictory data can be found regarding paediatric ages. The aim of this study is to explore the early corneal, macular and optic nerve changes in paediatric patients with OSAS. METHODS: Prospective study that enrolled children aged ≥ 4 years referred to the Paediatric Pneumology Clinic in Verona for suspected obstructive sleep apnoea syndrome (OSAS) and investigated with the overnight respiratory polygraphy. Patients with apnoea-hypopnea index (AHI) > 1 were classified as OSAS, while those with AHI < 1 were classified non-OSAS. All patients underwent comprehensive eye examination including slit lamp, refraction, intraocular pression (Goldman applanation tonometry), corneal tomography (corneal astigmatism, corneal keratometry at the apex, surface asymmetry index, central corneal thickness and thinnest corneal thickness) and optical coherence tomography (central macular thickness, macular volume and retinal nerve fibre layer). RESULTS: Seventy-two children were enrolled in the study. The overall prevalence of OSAS was 48.6%. Statistically significant differences were found between OSAS and non-OSAS group for corneal asymmetry (0.9 ± 0.5 and 0.6 ± 0.3, respectively; p = 0.02), thinnest corneal thickness (551.8 ± 33.9 and 563.7 ± 32.5; p = 0.04), average retinal nerve fibre layer (102.8 ± 10.5 µm and 98.1 ± 12.3 µm; p = 0.012) and in nasal quadrant (76.2 ± 15.4 µm and 66.5 ± 12.6 µm; p = 0.0002). CONCLUSIONS: A comprehensive eye examination with corneal and optic nerve imaging showed early corneal and optic nerve changes in children newly diagnosed with OSAS. These could be prelude of the known ocular manifestations associated with OSAS in adult patients.

Understanding the role of microperimetry in glaucoma.

PURPOSE: The present narrative review attempts to provide an overview on the use of microperimetry or fundus-driven perimetry in glaucoma, considering the clinical use, the different strategies and limits compared to standard automated perimetry. METHODS: An electronic database (PubMed and Medline) search was performed of articles of any type published in the English language between 1998 and 2020 with a combination of the following terms: microperimetry, glaucoma, primary open-angle chronic glaucoma, visual field, Humphrey visual field, fundus automated perimetry. RESULTS: All the original articles, case reports, and short series analyzed were included in the present review, offering an excursus on the strengths and limitations characterizing the use of microperimetry in glaucomatous patients. The characteristics of a recently introduced fundus-driven perimetry Compass (CMP; Centervue, Padua, Italy) were also included. CONCLUSION: Although there remain several contradictions regarding routine use of microperimetry and the restricted research on this topic limits our ability to draw firm conclusions, microperimetry may be preferable in cases of localized retinal nerve fiber layer defects in patients with primary open-angle glaucoma and normal visual field. However, standard automated perimetry remains the gold standard for monitoring glaucoma, especially in patients with diffuse retinal nerve fiber layer impairment and visual field defects. The newly introduced Compass device can potentially provide a more accurate structural-functional evaluation than standard automated perimetry and can therefore produce superior testing reliability.

Dietary compounds as modulators of metals and metalloids toxicity.

A large part of the population is exposed to metals and metalloids through the diet. Most of the in vivo studies on its toxicokinetics and toxicity are conducted by means of exposure through drinking water or by intragastric or intraperitoneal administration of aqueous standards, and therefore they do not consider the effect of the food matrix on the exposure. Numerous studies show that some components of the diet can modulate the toxicity of these food contaminants, reducing their effect on a systemic level. Part of this protective role may be due to a reduction of intestinal absorption and subsequent tissue accumulation of the toxic element, although it may also be a consequence of their ability to counteract the toxicity directly by their antioxidant and/or anti-inflammatory activity, among other factors. The present review provides a compilation of existing information about the effect that certain components of the diet have on the toxicokinetics and toxicity of the metals and metalloids of greatest toxicological importance that are present in food (arsenic, cadmium, lead, and mercury), and of their most toxic chemical species.

Intrahepatic bile duct primary cilia in biliary atresia.

AIM: The etiopathogenesis of non-syndromic biliary atresia (BA) is obscure. The primary aim was to investigate intrahepatic bile duct cilia (IHBC) in BA at diagnosis and its correlation with clinical outcome. The secondary aim was to analyze IHBC in routine paraffin-embedded liver biopsies using conventional scanning electron microscopy (SEM). METHODS: Surgical liver biopsies taken at diagnosis from 22 BA infants (age range, 39-116 days) and from eight children with non-BA chronic cholestasis (age range, 162 days -16.8 years) were evaluated for IHBC by immunofluorescence (IF) and SEM. A minimum 18-month follow-up after surgery was available for all patients. RESULTS: By IF, cilia were present in 6/8 (75%) non-BA but only in 3/22 (14%) BA cases, and cilia were reduced or absent in 19/22 (86%) BA and 2/8 (25%) non-BA livers (P < 0.01). In BA, cilia presence was found to be associated with clearance of jaundice at 6-month follow-up (P < 0.05). However, high overall survival rates with native liver, >90% at 12 months, and >70% at 24 months post-surgery, were recorded regardless of cilia presence/absence at diagnosis. Electron microscopy was able to detect bile ducts and cilia in routine liver biopsies, revealing significant abnormalities in 100% BA livers. CONCLUSIONS: The presence of IHBC in BA livers at the diagnosis was associated with resolution of cholestasis, although was not predictive of short-term survival with native liver. Scanning electron microscopy represents a powerful new tool to study routine liver biopsies in biliary disorders. Cilia dysfunction in BA pathogenesis and/or disease progression warrants further investigation.

Temperature-induced phenotypic plasticity in the ovipositor of the invasive species Drosophila suzukii.

Drosophila suzukii (Matsumura, 1931) is a highly successful invasive dipteran which represents a serious threat for global fruit industry. Among other adaptive traits, D. suzukii owes its success to the derived morphological features of its ovipositor, which allows the insect to exploit the exclusive ecological niche of fresh fruit, thus avoiding competition with other closely related species. With the aim of investigating temperature-induced phenotypic plasticity of D. suzukii ovipositor, we reared this insect in four different laboratory conditions, represented by the combination of two developmental temperatures and two diet regimes for the larvae. We recorded the effects of these two factors on ovipositor size and shape and overall body size through a combination of distance-based and geometric morphometric analyses. Results showed that insects attain the largest body sizes at lower temperature, whereas the diet does not determine significant difference in size. However, the effect on size of the two factors is less pronounced in the ovipositor, which shows a negative allometry with respect to body size in all treatments. At higher temperature, ovipositor shape tends also to co-vary with its own size. Neither temperature nor diet have significant effect on ovipositor bilateral fluctuating asymmetry. These results confirm the hypothesis that in D. suzukii the toughened valve of the ovipositor are subjected to effective morpho-functional constraints, while probably being under strong selection by reason of their mechanical role.

Prevalence of groups A and C rotavirus antibodies in infants with biliary atresia and cholestatic controls.

OBJECTIVE: To analyze the prevalence of acute asymptomatic group A and C rotavirus (RV-A and RV-C) infection in neonates with cholestasis. STUDY DESIGN: Participants were infants <180 days of age with cholestasis (serum direct or conjugated bilirubin >20% of total and ≥2 mg/dL) enrolled in the Childhood Liver Disease Research and Education Network during RV season (December-May). Forty infants with biliary atresia (BA), age 62 ± 29 days (range, 4.7-13 weeks) and 38 infants with cholestasis, age 67 ± 44 days (range, 3-15.8 weeks) were enrolled. RESULTS: At enrollment, RV-A IgM positivity rates did not differ between infants with BA (10%) vs those without (18%) (P = .349). RV-C IgM was positive in 0% of infants with BA vs 3% in those without BA (P = .49). RV-A IgG was lower in infants with BA: 51 ± 39 vs 56 ± 44 enzyme-linked immunoassay unit, P = .045 but this difference may lack biological relevance as maternal RV-A IgG titers were similar between groups. Infant RV-A IgM titers at 2-6 months follow-up increased markedly vs at presentation in both infants with BA (50 ± 30 vs 9 ± 9) and those without (43 ± 18 vs 16 ± 20 enzyme-linked immunoassay unit) (P < .0001), without differences between groups. CONCLUSIONS: RV-A infection in the first 6 months of life is common in infants with cholestasis of any cause. RV-A could have different pathogenetic effects by initiating different hepatic immune responses in infants with vs without BA or could lack pathogenetic significance.

Clinical report of Bosma arhinia microphthalmia syndrome with a new variant on SMCHD1 gene. A case report.

The Bosma syndrome (BAMS: Bosma arhinia microphthalmia syndrome) is a condition first described in 1972. Since then, several reviews have published the cases looking for diagnostic criteria and associated genetic alterations. The mutation in the SMCHD1 gene (Structural Maintenance of Chromosomes flexible Hinge Domain containing protein 1) seems to explain a part of the development of the phenotype. Not all cases show the same alterations or meet the classic diagnostic criteria, and few have undergone genetic analysis. We present a case with a new variant in this gene and an update of the literature on this syndrome with the aim of improving the diagnosis and follow-up of these patients.