Heterogeneous Spectrum Research Articles

Tree-based Multicast Routing and Channel Assignment for Enhanced Throughout in Emerging Cognitive Radio Networks

In future multi-hop wireless networks like 5G and B5G, efficient large-scale video sharing and data dissemination are expected to rely heavily on multicast routing and Cognitive Radio (CR) technology. While multicast routing is efficient when the network always has access to the spectrum, the dynamic nature of Primary User (PU) activities, heterogeneous spectrum across the CR Network (CRN), and PU access priority make it challenging to implement efficient multicast routing protocols in CRNs. This paper proposes a hierarchical multicast routing mechanism for multi-hop CRNs that exploits the Shortest Path Tree (SPT) and Minimum Spanning Tree (MST) concepts. The proposed multicast routing mechanism consists of tree construction and channel assignment algorithms. The tree-construction algorithm models the network topology as a multicast tree rooted at the CR source and spanning all the CR nodes. Based on the constructed tree, the channel assignment algorithm employs the Probability Of Success (POS) metric to assign channels to the various layers defined by the constructed SPT or MST, ensuring that the most reliable channel is used for the multi-hop multicast transmissions. Simulation experiments are conducted to evaluate the mechanism’s effectiveness, revealing significant improvements in throughput and Packet Delivery Rate (PDR) compared to state-of-the-art protocols under different network conditions. The simulations also show that the SPT-based mechanism outperforms the MST-based mechanism in terms of throughput but has a higher tree construction complexity.

Repetitive Transcranial Magnetic Stimulation Improves Hippocampal N-Acetlaspartate Levels and Visual Memory Scores in Alzheimer's Disease.

The latest research into the pathophysiology of Alzheimer's Disease (AD) has included several cognitive deficits related to hippocampal functioning. However, current clinical research fails to consider the full extent of the heterogeneous cognitive spectrum of AD, resulting in a lack of the specific methods required to draw definitive diagnostic and therapeutic conclusions. This also includes in-vivo metabolic measurements for tailoring the diagnostic and therapeutic regimens in humans with AD. Magnetic resonance spectroscopy and repetitive transcranial magnetic stimulation (rTMS) are two novel diagnostic and therapeutic approaches that must be modified to treat AD. In the present study, we aimed to investigate the underlying therapeutic role of rTMS in humans with AD by evaluating the in-vivo hippocampal metabolites before and after rTMS treatment. Based on the data obtained using the fMRI data in our previous study and on the references reported in the literature, in the present study, we decided to use hippocampal NAA data after rTMS stimulation and found a significant increase in NAA levels. To the best of our knowledge, no other study has evaluated the effect of rTMS on hippocampal metabolites in humans with AD.

Paving the Way & Translating PPH Resources towards Autismrelated Care

The link that might exert reliable control over morbidity, mortality and disabling rates as well as significantly optimize the efficacy of autism spectrum disorders (ASDs) treatment for those who had fallen ill and for persons-at-risk is Personalized & Precision Medicine (PPM). Since there are significant molecular and neurobiological overlaps among ASD-related clinical phenotypes, tar-geted and/or smart (intelligent) treatments developed for a specific ASD subtype, may be help-ful in ASD of unknown etiology. Recent changes in diagnostics criteria have contributed to the broadening of the ASDs and left clinicians ill-equipped to treat the highly heterogeneous spec-trum that now includes toddlers and children with sensory and motor issues. And the biomarker discovery and thus the biomarker-driven drug design have the potential to tailor therapeutic inter-ventions to fit individualized ASD-related conditions in order to receive maximum benefits. This review summarizes the current advances in ASD biomarkers and discusses the potential imple-mentation of biomarkers in PPM-affiliated areas in the context of ASDs, whilst stressing the im-pact of PPM as the Science and ART and illustrating application of the different tools of the next step generation at the population, community and individualized levels.

Histopathological Spectrum of Spinal Tumours at a Tertiary Care Hospital, Gujarat, India: A Retrospective Study

Introduction: The anatomic structures in the spinal area are diverse and unpredictable, often representing an excellent test for both the neuroclinicians and neuropathologists, thereby showing a broad heterogeneous spectrum of pathological lesions. Clinical history, radiological features, and pathological examination are required to diagnose spinal tumours. Aim: To study the histopathological spectrum of spinal tumours in a tertiary care teaching hospital in Gujarat, India. Materials and Methods: In this retrospective study, data was collected from the records of 100 patients who had spinal tumours and who attended the Department of Pathology. Histopathological diagnosis of the spinal biopsy specimen was the primary outcome variable. Age, gender, location of the tumour, and clinical features were other study relevant variables. The status of the spinal tumour (benign/malignant) was considered an explanatory variable. Descriptive analysis was carried out by mean and standard deviation for quantitative variables, frequency, and proportion for categorical variables. Categorical outcomes were compared using the Chi-square test. Results: A total of 100 subjects were included, among which 42 participants were males, and 58 were females with the mean age 34.62±17.64 years. The maximum number of spinal tumours were noted in (21-30 year) 3rd decade (29%) of life. Benign spinal tumours (73%) were more common than malignant spinal tumours (27%). Schwannoma was the most common (37%) spinal tumour, followed by meningioma (20%), and ependymoma (14%). The distribution of spinal tumours based on anatomical location, 31% intradural intramedullary, 49% intradural extramedullary, and 20% extradural tumours. There was a significant difference between nerve sheath tumours and meningioma with gender (p-value <0.001). Conclusion: The study identified schwannoma and meningiomas as the most common tumours. The thoracic region was the most frequently involved spinal level, followed by the cervical, and the most affected location was the intradural extramedullary.

The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism.

Thyroglobulin (TG), the predominant glycoprotein of the thyroid gland, functions as matrix protein in thyroid hormonegenesis. TG deficiency results in thyroid dyshormonogenesis. These variants produce a heterogeneous spectrum of congenital goitre, with an autosomal recessive mode of inheritance. The purpose of this study was to identify and functionally characterize new variants in the TG gene in order to increase the understanding of the molecular mechanisms responsible for thyroid dyshormonogenesis. A total of four patients from two non-consanguineous families with marked alteration of TG synthesis were studied. The two families were previously analysed in our laboratory, only one deleterious allele, in each one, was detected after sequencing the TG gene (c.2359 C > T [p.Arg787*], c.5560 G > T [p.Glu1854*]). These findings were confirmed in the present studies by Next-Generation Sequencing. The single nucleotide coding variants of the TG gene were then analyzed to predict the possible variant causing the disease. The p.Pro2232Leu (c.6695 C > T), identified in both families, showing a low frequency population in gnomAD v2.1.1 database and protein homology, amino acid prediction, and 3D modeling analysis predict a potential pathogenic effect of this variant. We also transiently express p.Pro2232Leu in a full-length rat TG cDNA clone and confirmed that this point variant was sufficient to cause intracellular retention of mutant TG in HEK293T cells. Consequently, each family carried a compound heterozygous for p.Arg787*/p.Pro2232Leu or p.Glu1854*/p.Pro2232Leu variants. In conclusion, our results confirm the pathophysiological importance of altered TG folding as a consequence of missense variants located in the ChEL domain of TG.

CoQ Regulates Brown Adipose Tissue Respiration and Uncoupling Protein 1 Expression.

Coenzyme Q (CoQ, aka ubiquinone) is a key component of the mitochondrial electron transport chain (ETC) and membrane-incorporated antioxidant. CoQ10 deficiencies encompass a heterogeneous spectrum of clinical phenotypes and can be caused by hereditary mutations in the biosynthesis pathway or result from pharmacological interventions such as HMG-CoA Reductase inhibitors, and statins, which are widely used to treat hypercholesterolemia and prevent cardiovascular disease. How CoQ deficiency affects individual tissues and cell types, particularly mitochondrial-rich ones such as brown adipose tissue (BAT), has remained poorly understood. Here we show that pharmacological and genetic models of BAT CoQ deficiency show altered respiration that can only in part be explained by classical roles of CoQ in the respiration chain. Instead, we found that CoQ strongly impacts brown and beige adipocyte respiration via the regulation of uncoupling protein 1 (UCP1) expression. CoQ deficiency in BAT robustly decreases UCP1 protein levels and uncoupled respiration unexpectedly, resulting in increased inner mitochondrial membrane potential and decreased ADP/ATP ratios. Suppressed UCP1 expression was also observed in a BAT-specific in vivo model of CoQ deficiency and resulted in enhanced cold sensitivity. These findings demonstrate an as yet unappreciated role of CoQ in the transcriptional regulation of key thermogenic genes and functions.

Spectrum of Mutations and Clinical Manifestations of Rett Syndrome in Girls from Western Ukraine

Rett syndrome is one of the most common causes of mental retardation in girls. The aim of our work was to study a spectrum of genetic heterogeneity and various clinical manifestations of Rett syndrome in girls Western Ukraine. Materials and methods: there were used clinical, molecular and genetic methods. We observed seven girls with Rett syndrome aged from 6 months to 15 years who were diagnosed and followed-up at the Institute of Hereditary Pathology, National Academy of Medical Sciences of Ukraine, Lviv for three years (2019–2021) and underwent molecular genetic analyses confirmed by next-generation sequencing. Results: In this study, patients with Rett syndrome had individual clinical heterogeneity and age variability due to different mutations. Mental retardation was not observed among siblings in families with Rett syndrome. We identified seven different pathogenic mutations among seven girls, including two deletions and one duplication of the MECP2 gene. Microcephaly was observed in two girls with MECP2 c.880C>T (p.Arg294*) and MECP2 Gain (Entire coding sequence) at birth. The following developmental disabilities were found in five girls: lack of independent sitting, lack of independent gait (regression of development). Among musculoskeletal disorders, there were diagnosed scoliosis, X-shaped deformation of the lower extremities and muscular hypotonia. A two-year-old girl with Rett syndrome, along with other clinical symptoms, had breathing problems - hyperventilation (rapid shallow breathing). Conclusions: in cases with unknown cause of delayed developmental disability and mental retardation the patients should be referred for medical genetic counselling.

Age-Related Neurodevelopmental Features in Children with Joubert Syndrome

AbstractJoubert syndrome (JS) is a rare inherited disorder of central nervous system with neonatal/infantile onset, mainly affecting cerebellum and brainstem, and clinically characterized by agenesis or dysgenesis of the cerebellar vermis with accompanying brainstem malformations. More than 20 disease-causing genes have been associated with JS but a clear genotype–phenotype correlation has not been assessed yet. Diagnosis is usually confirmed by detection of the JS neuroradiological hallmark, the molar tooth sign. Patients with JS typically present with neurological manifestations, moreover, a heterogeneous spectrum of multisystemic anomalies may be observed. Signs and symptoms onset varies according to the age range and clinical diagnosis might become complicated. Moreover, specific neurodevelopmental disorders can be associated with JS such as autism spectrum disorders, attention deficit with hyperactivity, and a wide range of behavioral disturbances. Here, we examined the main neurological and neurodevelopmental features of JS according to an age-dependent mode of presentation. Furthermore, differential diagnosis with other neurological syndromes was closely reviewed.

Integrals of life: Tracking ecosystem spatial heterogeneity from space through the area under the curve of the parametric Rao’s Q index

Spatio-ecological heterogeneity is strongly linked to many ecological processes and functions such as plant species diversity patterns and change, metapopulation dynamics, and gene flow. Remote sensing is particularly useful for measuring spatial heterogeneity of ecosystems over wide regions with repeated measurements in space and time. Besides, developing free and open source algorithms for ecological modelling from space is vital to allow to prove workflows of analysis reproducible. From this point of view, NASA developed programs like the Surface Biology and Geology (SBG) to support the development of algorithms for exploiting spaceborne remotely sensed data to provide a relatively fast but accurate estimate of ecological properties in vast areas over time. Most of the indices to measure heterogeneity from space are point descriptors : they catch only part of the whole heterogeneity spectrum. Under the SBG umbrella, in this paper we provide a new R function part of the rasterdiv R package which allows to calculate spatio-ecological heterogeneity and its variation over time by considering all its possible facets. The new function was tested on two different case studies, on multi- and hyperspectral images, proving to be an effective tool to measure heterogeneity and detect its changes over time.

A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations

Limited sensitivity and specificity of current diagnostics lead to the erroneous prescription of antibiotics. Host-response-based diagnostics could address these challenges. However, using 4,200 samples across 69 blood transcriptome datasets from 20 countries from patients with bacterial or viral infections representing a broad spectrum of biological, clinical, and technical heterogeneity, we show current host-response-based gene signatures have lower accuracy to distinguish intracellular bacterial infections from viral infections than extracellular bacterial infections. Using these 69 datasets, we identify an 8-gene signature to distinguish intracellular or extracellular bacterial infections from viral infections with an area under the receiver operating characteristic curve (AUROC)>0.91 (85.9% specificity and 90.2% sensitivity). In prospective cohorts from Nepal and Laos, the 8-gene classifier distinguished bacterial infections from viral infections with an AUROC of 0.94 (87.9% specificity and 91% sensitivity). The 8-gene signature meets the target product profile proposed by the World Health Organization and others for distinguishing bacterial and viral infections.

In silico interpretation of variants identifies novel causes of inherited eye disease in the 100 000 genomes project

AbstractInherited retinal dystrophy (IRD) describes a widely heterogeneous spectrum of disorders with over 270 genes implicated to date across all inheritance patterns and an estimated prevalence of around 1 in 2000 people. Genetic testing for IRD had evolved dramatically since the discovery of the first pathogenic variant in 1990: the advent of massively parallel sequencing means that the more than half of patients are now able to receive a molecular diagnosis although there is still significant missing heritability (up to ~40% of patients). Novel genes, non‐coding variants, structural variants/copy number variants, novel gene/disease associations, non‐Mendelian inheritance and non‐genetic disease are some of the mechanisms thought to account for the missing heritability of rare disease. This presentation will focus on non‐coding variant analysis.Whole genome sequencing (WGS) enables the capture and interrogation of all variants covering up to approximately 95% of the genome, and advances in genomic analysis technology, genome and variant databases, bioinformatics and in silico tools mean that nowadays variant prioritization pipelines are able to filter the huge variant numbers leaving only a handful of candidate pathogenic coding variants per patient.For the missing heritability in patients whose phenotype cannot be fully explained by this approach, however, non‐coding variant analysis is more challenging. Many more variants exist outside of coding exons and our understanding of their effect on transcripts and proteins is limited. Functional assays, especially for retina specific genes may be complex and difficult to establish, so accurate variant effect predictions are critical to enable molecular geneticists and clinical laboratories to maximize their ability to provide a definitive molecular diagnosis.This presentation will focus on the analysis of non‐coding variants in IRD genes in a cohort of patients who underwent WGS in the UK's 100 000 genomes project. Key to this study, patients were identified for study following multidisciplinary team discussion to highlight the most likely gene to be implicated in their disease. Identification of candidate non‐coding variants, filtering and prioritization were performed to identify the most compelling variant, followed by molecular investigation and confirmation of the predicted effect. Exemplar case studies will demonstrate the power of this analysis pipeline and accuracy of in silico predictions.

Abstract IA007: Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma

Abstract Pediatric diffuse high-grade gliomas (HGGs) are a heterogeneous spectrum of disease with abysmal survival rates. Approximately half of diffuse high-grade gliomas in children arise in midline structures predominantly the brainstem, but also thalamus, cerebellum and spinal cord. Approximately 80% of these tumors harbor H3 K27M mutations, which result in dramatic depletion of the post-translational modification H3K27me3. Alternative mutations in diffuse midline gliomas can result in similar reduction of H3K27me3, leading to a redefined classification of this collection of tumors as diffuse midline glioma, H3 K27-altered. In contrast, distinct histone H3 mutations, H3.3 G34R/V, are found in approximately 30% of diffuse gliomas arising in the cerebral hemispheres of older adolescents and young adults, defining the tumor subgroup of diffuse hemispheric glioma, H3 G34-mutant. The striking spatiotemporal pattern of these histone mutations, termed oncohistones, indicates an intimate association between epigenetic dysregulation, brain development, and tumorigenesis. We will discuss use of genetically engineered and patient-derived models to investigate the contribution of oncohistone mutations to disrupted development, epigenetic dysregulation and gliomagenesis. Citation Format: Kaitlin Budd, Chang-Hyuk Kwon, Lawryn H. Kasper, Christopher Roberts, Jordan Roach, Jennifer Ocasio-Adorno, Jon D. Larson, Suzanne J. Baker. Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA007.

DNA methylation-based classification of sinonasal tumors

The diagnosis of sinonasal tumors is challenging due to a heterogeneous spectrum of various differential diagnoses as well as poorly defined, disputed entities such as sinonasal undifferentiated carcinomas (SNUCs). In this study, we apply a machine learning algorithm based on DNA methylation patterns to classify sinonasal tumors with clinical-grade reliability. We further show that sinonasal tumors with SNUC morphology are not as undifferentiated as their current terminology suggests but rather reassigned to four distinct molecular classes defined by epigenetic, mutational and proteomic profiles. This includes two classes with neuroendocrine differentiation, characterized by IDH2 or SMARCA4/ARID1A mutations with an overall favorable clinical course, one class composed of highly aggressive SMARCB1-deficient carcinomas and another class with tumors that represent potentially previously misclassified adenoid cystic carcinomas. Our findings can aid in improving the diagnostic classification of sinonasal tumors and could help to change the current perception of SNUCs.

Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants.

Rett syndrome caused by MECP2 variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.Arg255*, associated to mild and severe phenotype, respectively, and of an RTT male harboring the close to p.Arg255*, p.Gly252Argfs*7 variant. Truncated MeCP2 proteins were revealed by Western blot and immunofluorescence analysis. We compared the mutant versus control neurons at 42 days for morphological parameters and at 120 days for electrophysiology recordings, including girls' isogenic clones. A precocious reduced morphological complexity was evident in neurons with truncating variants, while in p.Arg133Cys neurons any significant differences were observed in comparison with the isogenic wild-type clones. Reduced nuclear size and branch number show up as the most robust biomarkers. Patch clamp recordings on mature neurons allowed the assessment of cell biophysical properties, V-gated currents, and spiking pattern in the mutant and control cells. Immature spiking, altered cell capacitance, and membrane resistance of RTT neurons, were particularly pronounced in the Arg255* and Gly252Argfs*7 mutants. The overall results indicate that the specific markers of in vitro cellular phenotype mirror the clinical severity and may be amenable to drug testing for translational purposes.

PATH-17. DISTINCT MOLECULAR SUBCLASSES OF H3F3A-WILDTYPE, EGFR-ALTERED PEDIATRIC-TYPE DIFFUSE MIDLINE GLIOMAS WHO CNS GRADE 4

Abstract OBJECTIVES Histone gene H3K27-altered diffuse midline glioma (DMG) are malignant tumors that occur in all age groups. In this study, we report comprehensive genomic profiling from H3F3A-wildtype, EGFR-altered DMG, as a distinct and newly recognized subset of pediatric-type DMG. METHODS Tumors were profiled in the comprehensive genomic profiling (CGP) program at Foundation Medicine between 2013-2020. Information from pathology reports, histopathology review, and patient clinical data was assessed. RESULTS We collected demographic and genomic data from 39 pediatric patients with H3F3A-wildtype, EGFR-altered HGG (17 females, 22 males; median age: 8.5 years, range 1-18 years). Female patients were younger at first diagnosis compared to male (median age 7 years vs. 10 years). All cases were microsatellite stable (MSS). The EGFR alterations consisted of 30 mutations and 9 amplifications. The mutations were distributed across the entire gene with no clear hotspot location. Our genomic data converged to identify three distinct molecular patterns. The first and most common group contained TP53 mutations (n = 17, 43.5%), showed no association with patient sex (8 females, 9 males), contained ATRX mutations (n = 3) and CDKN2A deletions (n = 5); these tumors did not harbor pathogenic mutations in TERTp, PIK3CA/PIK3R1, BCOR/BCORL1, STAG2, or SETD2. The second group featured TERTp-mutant tumors (n = 10), were more common in males (70%), and often demonstrated additional mutations in PIK3CA/PIK3R1 (n = 4), BCOR/BCORL1 (n = 4), CDKN2A/B (n = 4), and SETD2 (n = 2). The third group (n = 12) lacked TERTp and TP53 mutations and had a heterogeneous spectrum of non-recurrent mutations, including one CDKN2A/B deletion. CONCLUSIONS We have identified three distinct molecular subclasses that defined specific genomic tumor subgroups in pediatric-type EGFR altered DMG. Overall, these data increase our understanding of the pathobiology of this DMG subset and can guide the design of clinical trials.

The Challenging Diagnosis of Interstitial Lung Disease in Children-One Case Report and Literature Review.

Childhood interstitial lung disease (chILD) includes a heterogeneous spectrum of rare respiratory disorders in children associated with substantial morbi-mortality. Interstitial tissue, and other pulmonary structures, epithelium, blood vessels, or pleura are involved, resulting in a restrictive lung disfunction. Respiratory symptoms set in progressively and are often subtle, making thorough clinical history and physical examination fundamental. The etiology often is obscure. The clinical presentation mimics pneumonia or asthma, leading to a diagnostic delay. Challenging diagnosis may require genetic tests, bronchoalveolar lavage, or lung biopsy. Alongside general supportive therapeutic measures, anti-inflammatory, immunosuppressive or antifibrotic agents may be used, based on data derived from adult studies. However, if accurate diagnosis and treatment are delayed, irreversible chronic respiratory failure may ensue, impacting prognosis. The most frequent chILD is hypersensitivity pneumonitis (HP), although it is rare in children. HP is associated with exposure to an environmental antigen, resulting in inflammation of the airways. Detailed antigen exposure history and identification of the inciting trigger are the cornerstones of diagnostic. This article provides the current state of chILD, revealing specific features of HP, based on a clinical case report of a patient admitted in our clinic, requiring extensive investigations for diagnosis, with a favorable long-term outcome.

Mucolytic and Antioxidant Properties of Carbocysteine as a Strategy in COVID-19 Therapy.

SARS-CoV-2 infection leads to a heterogenous spectrum of clinical conditions ranging from self-limiting upper airway infection to severe respiratory failure. Carbocysteine is a thioether mucolytic with antioxidant and anti-inflammatory activities. Carbocysteine has been shown to have anti-viral effects on human rhinovirus, RSV and the influenza virus as well as interfering with upper airway ciliary motility, the first site of SARS-CoV-2 infection, leading to more effective mucus clearance and potential containment of viral spread towards the lower airway. Positive effects, in terms of limiting superimposed bacterial infection and reducing oxidative stress, have also been documented in COPD patients. Accordingly, Carbocysteine should also be considered in both post-exposure prophylaxis and early-phase treatment of COVID-19 in combination with other agents (monoclonal antibodies, antivirals, non-steroidal anti-inflammatory agents, and inhaled corticosteroids). In this review, we explored the pharmacokinetic and pharmacodynamic aspects of Carbocysteine to delineate its potential therapeutic impact in patients with COVID-19.

Impaired Overall Survival in Young Patients With Acute Myeloid Leukemia and Variants in Genes Predisposing for Myeloid Malignancies.

Impaired Overall Survival in Young Patients With Acute Myeloid Leukemia and Variants in Genes Predisposing for Myeloid Malignancies.

PSAT122 The Changing Face of Drug-Induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System

Abstract Importance: Adrenal insufficiency is a life-threatening condition complicating heterogenous disorders across various disciplines, with challenging diagnosis and a notable drug-induced component. Objective To describe the spectrum and main features of drug-induced adrenal insufficiency through adverse drug event reports received by the Food and Drug Administration (FDA). Design: We conducted a retrospective disproportionality analysis within one of the largest publicly accessible spontaneous reporting system. Setting The FDA Adverse Event Reporting System (FAERS) collecting more than 15 million reports. Participants: Adverse event reports extracted from FAERS over the past 2 decades (2000-2020), with a focus on the 2015-2020 period. Main Outcomes and Measures: Descriptive statistics were used to assess the reporting trend of drug-induced adrenal insufficiency. Cases were selected if they contained any of the preferred terms in the Medical Dictionary for Regulatory Activities describing adrenal hypofunctions. We computed the reporting odds ratio (ROR) with relevant 95% confidence interval (CI) using Bonferroni correction to identify signals of disproportionate reporting for drugs recorded in at least 10 cases as primary suspect. Results We identified 8,496 cases (5,282 in the 2015-2020 period), 97.5% being serious and 41.1% requiring hospitalization. We identified 56 drugs (out of 164) associated with significant disproportionality within various pharmacological classes: glucocorticoids (N=1971, constant over time), monoclonal antibodies (1,330 out of 1,644 cases with immune checkpoint inhibitors, reaching 76% in 2020), hormone therapy (N=291), anti-infectives (N=252), drugs used for hypercortisolism or adrenocortical cancer diagnosis and/or treatment (N=169), protein kinase inhibitors (N=138). Conclusions and Relevance This comprehensive insight into the evolution of drug-induced adrenal insufficiency highlighted the heterogeneous spectrum of culprit drugs classes, including the consolidated role of topical and systemic corticosteroids and the emerging increased reporting of immune checkpoint inhibitors. Targeted screening and educational programs are needed to urgently identify predictive factors. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center.

Background: Pterin profiles or molecular analyses of hyperphenylalaninemia (HPA) caused by phenylalanine hydroxylase (PAH) deficiency or tetrahydrobiopterin deficiency (BH4D) are not always available in low- or middle-income countries, including Mexico, limiting information regarding the phenotypic and genotypic characteristics of patients exhibiting BH4D. Objective: To report the genotypes underlying BH4D and the clinical presentation in unrelated Mexican HPA pediatric patients with normal PAH genotypes who attended a single metabolic reference center in Mexico. Methods: Automated Sanger sequencing of the PTS, QDPR, and PCBD1 genes of 14 HPA patients was performed. Predicted effects on protein structure caused by missense variants were assessed by in silico protein modeling. Results and discussion: A high prevalence of BH4D was noted in our HPA cohort (9.8%, N = 14/142). Clinically relevant biallelic genotypes were identified in the PTS (N = 7/14 patients), QDPR (N = 6/14 patients), and PCBD1 (N = 1/14 patients) genes. Four novel QDPR variants [c.714dup or p.(Leu239Thrfs*44), c.106-1G>T or p.(?), c.214G>T or p.(Gly72*), and c.187_189dup or p.(Gln63dup)] were identified. In silico protein modeling of six missense variants of PTS [p.(Thr67Met), p.(Glu81Ala), and p.(Tyr113Cys)], QDPR [p.(Cys161Phe) and p.(Pro172Leu)], and PCBD1 [p.(Glu97Lys)] supports their pathogenicity. Progressive neurological symptoms (mainly intellectual and motor impairment and even death in three patients) were noted in all patients with biallelic QDPR genotypes and in 5/7 patients bearing biallelic PTS genotypes. The single homozygous PCBD1 p.(Glu97Lys) patient remains asymptomatic. Conclusion: A higher proportion of BH4D (9.8 vs. 1%–2% worldwide), attributable to a heterogeneous mutational spectrum and wide clinical presentation, was noted in our Mexican HPA cohort, with the PTS-related HPA disorder being the most frequent. Sequencing-based assays could be a reliable approach for diagnosing BH4D in our population.