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Objectives: The study aimed to explore the spectrum and trend of causative microbial agents and to identify management challenges and the risk factors for poor outcomes in patients with confirmed otogenic skull base osteomyelitis. Methods: A retrospective observational study was conducted at a tertiary-care academic center from 1999 through 2019 and included 28 adult patients with confirmed otogenic skull base osteomyelitis. Relevant data was extracted from electronic and hard patient medical files. The microbial spectrum of involved microbes was identified and correlated to management options. Deterioration risk factors were investigated using suitable statistical analysis tests. Results: Twenty-eight patients with confirmed skull base osteomyelitis were included; most were males (78.6%) and Saudis (78.6%). All patients were ≥50 years of age (mean ± SD is 69.0±10.2.4). Of 41 identified microbial isolates, 56% were bacterial, 44% were fungal. 32.1% of patients had polymicrobial infections, most patients (92.8%) had received ≥2 systemic antibiotics, 57.1% received systemic antibiotic combinations, and 32.1% underwent surgical interventions. The mean antibiotic and antifungal therapy duration was 58.3 and 45.8 days, respectively. The identified risk factors of deterioration were advanced age and concomitant cardiac failure, with P-values of .006 and .034, respectively. Conclusions: The study findings highlight the microbiological spectrum and trend of otogenic skull base osteomyelitis-causative microbes over two decades, present the management challenges, identify deterioration risk factors, and suggest tissue biopsy as the golden standard for accurately identifying causative microbes.

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BACKGROUND: Early childhood caries (ECC) is one of the most common childhood diseases affecting the primary teeth of children younger than 6 years of age. ECC progression can be reversed in the early stages although these lesions often go undetected. New approaches are needed to detect oral diseases at an early stage when they can be better controlled. The aim of the study is to assess the effectiveness of ECC tele-detection methods combined with referral pathways with and without user fee removal in controlling ECC. METHODS: A randomized factorial trial will be used to compare two tele-dentistry detection methods for ECC (intraoral camera and smartphone camera) and two referral pathways (user fee removal versus conventional care). The study will recruit children younger than 6 years of age in marginalized communities in Alexandria, Egypt. The primary outcome is the percentage of teeth receiving indicated care, while the secondary outcomes are the oral health-related quality of life, acceptance of teledentistry by dentists, procedure time, and child cooperation. Two-way analysis of variance will be used to assess the effect of the two factors as between group variables on the outcomes after 6 and 12 months. The interaction between detection methods and referral pathways will also be assessed, and the effect of confounders will be controlled in a multivariable linear regression model. DISCUSSION: The findings of this study have the potential to inform clinical practice and oral healthcare policies for ECC management. Successful tele-detection and referral pathways could be integrated into oral healthcare systems, leading to improved oral health outcomes for children. TRIAL REGISTRATION: The trial has been registered on ClinicalTrials.gov in August 2023 (initial release) ID: NCT06019884.

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DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: To review causes, risk factors, and consequences of sleep disruption in critically ill patients; evaluate the role of nonpharmacological and pharmacological therapies for management of sleep in the intensive care unit (ICU); and discuss the role of pharmacists in implementation of sleep bundles. SUMMARY: Critically ill patients often have disrupted sleep and circadian rhythm alterations that cause anxiety, stress, and traumatic memories. This can be caused by factors such as critical illness, environmental factors, mechanical ventilation, and medications. Methods to evaluate sleep, including polysomnography and questionnaires, have limitations that should be considered. Multicomponent sleep bundles with a focus on nonpharmacological therapy aiming to reduce nocturnal noise, light, and unnecessary patient care may improve sleep disorders in critically ill patients. While pharmacological agents are often used to facilitate sleep in critically ill patients, evidence supporting their use is often of low quality, which limits use to patients who have sleep disruption refractory to nonpharmacological therapy. Dedicated interprofessional teams are needed for implementation of sleep bundles in the ICU. Extensive pharmacotherapeutic training and participation in daily patient care rounds make pharmacists vital members of the team who can help with all components of the bundle. This narrative review discusses evidence for elements of the multicomponent sleep bundle and provides guidance on how pharmacists can help with implementation of nonpharmacological therapies and management of neuroactive medications to facilitate sleep. CONCLUSION: Sleep bundles are necessary for patients in the ICU, and dedicated interprofessional teams that include pharmacists are vital for their successful creation and implementation.

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BACKGROUND AND AIM: The thrombectomy in the elderly prediction score (TERPS) for functional outcome after anterior circulation endovascular therapy (EVT) in patients ≥ 80 years was recently developed. The aim of this study was to assess predictors of functional outcome in the elderly and validate the prediction model. METHODS: Consecutive patients treated with EVT from the Oslo Acute Reperfusion Stroke Study were evaluated for inclusion. Clinical and radiological parameters were used to calculate the TERPS, and functional outcome were assessed at 3-month follow-up. RESULTS: Out of 1028 patients who underwent EVT for acute ischemic stroke from January 2017 to July 2022, 218 (21.2%) patients ≥ 80 years with anterior ischemic stroke were included. Fair outcome, defined as modified Rankin scale ≤ 3 (mRS), was achieved in 117 (53.7%). In bivariate analyses, male sex (p 0.035), age (p 0.025), baseline National Institute of Health Stroke Scale (NIHSS, p < 0.001), pre-stroke mRS (p 0.002) and Alberta Stroke Program Early Computed Tomography score (ASPECTS, p 0.001) were associated with fair outcome. Significant predictors for fair outcome in regression analyses were lower pre-stroke mRS, adjusted odd ratio, (aOR) 0.67 (95% CI 0.50-0.91, p 0.01), NIHSS, aOR 0.92 (95% CI 0.87-0.97, p 0.002), and higher ASPECTS, aOR 1.22 (95% CI 1.03-1.44, p 0.023). The area under the curve (AUC) using TERPS was 0.74 (95% CI 0.67-0.80). CONCLUSIONS: The risk prediction score TERPS showed moderate performance in this external validation. Other variables may still be included to improve the model and validation using other cohorts is recommended. TRIAL REGISTRATION: NCT06220981.

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BACKGROUND: The emergence of multi-drug-resistant Klebsiella pneumoniae (MDR-KP) represents a serious clinical health concern. Antibiotic resistance and virulence interactions play a significant role in the pathogenesis of K. pneumoniae infections. Therefore, tracking the clinical resistome and virulome through monitoring antibiotic resistance genes (ARG) and virulence factors in the bacterial genome using computational analysis tools is critical for predicting the next epidemic. METHODS: In the current study, one hundred extended spectrum ß-lactamase (ESBL)-producing clinical isolates were collected from Mansoura University Hospital, Egypt, in a six-month period from January to June 2022. One isolate was selected due to the high resistance phenotype, and the genetic features of MDR-KP recovered from hospitalized patient were investigated. Otherwise, the susceptibility to 25 antimicrobials was determined using the DL Antimicrobial Susceptibility Testing (AST) system. Whole genome sequencing (WGS) using Illumina NovaSeq 6000 was employed to provide genomic insights into K. pneumoniae WSF99 clinical isolate. RESULTS: The isolate K. pneumoniae WSF99 was phenotypically resistant to the antibiotics under investigation via antibiotic susceptibility testing. WGS analysis revealed that WSF99 total genome length was 5.7 Mb with an estimated 5,718 protein-coding genes and a G + C content of 56.98 mol%. Additionally, the allelic profile of the WSF99 isolate was allocated to the high-risk clone ST147. Furthermore, diverse antibiotic resistance genes were determined in the genome that explain the high-level resistance phenotypes. Several ß-lactamase genes, including blaCTX-M-15, blaTEM-1, blaTEM-12, blaSHV-11, blaSHV-67, and blaOXA-9, were detected in the WSF99 isolate. Moreover, a single carbapenemase gene, blaNDM-5, was predicted in the genome, positioned within a mobile cassette. In addition, other resistance genes were predicted in the genome including, aac(6')-Ib, aph(3')-VI, sul1, sul2, fosA, aadA, arr-2, qnrS1, tetA and tetC. Four plasmid replicons CoIRNAI, IncFIB(K), IncFIB(pQil), and IncR were predicted in the genome. The draft genome analysis revealed the occurrence of genetic mobile elements positioned around the ARGs, suggesting the ease of dissemination via horizontal gene transfer. CONCLUSIONS: This study reports a comprehensive pathogenomic analysis of MDR-KP isolated from a hospitalized patient. These findings could be relevant for future studies investigating the diversity of antimicrobial resistance and virulence in Egypt.

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Background: Machine learning (ML) can differentiate papilloedema from normal optic discs using fundus photos. Currently, papilloedema severity is assessed using the descriptive, ordinal Frisén scale. We hypothesise that ML can quantify papilloedema and detect a treatment effect on papilloedema due to idiopathic intracranial hypertension. Methods: We trained a convolutional neural network to assign a Frisén grade to fundus photos taken from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). We applied modified subject-based fivefold cross-validation to grade 2979 longitudinal images from 158 participants' study eyes (ie, the eye with the worst mean deviation) in the IIHTT. Compared with the human expert-determined grades, we hypothesise that ML-estimated grades can also demonstrate differential changes over time in the IIHTT study eyes between the treatment (acetazolamide (ACZ) plus diet) and placebo (diet only) groups. Findings: The average ML-determined grade correlated strongly with the reference standard (r=0.76, p<0.001; mean absolute error=0.54). At the presentation, treatment groups had similar expert-determined and ML-determined Frisén grades. The average ML-determined grade for the ACZ group (1.7, 95% CI 1.5 to 1.8) was significantly lower (p=0.0003) than for the placebo group (2.3, 95% CI 2.0 to 2.5) at the 6-month trial outcome. Interpretation: Supervised ML of fundus photos quantified the degree of papilloedema and changes over time reflecting the effects of ACZ. Given the increasing availability of fundus photography, neurologists will be able to use ML to quantify papilloedema on a continuous scale that incorporates the features of the Frisén grade to monitor interventions.

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BACKGROUND: Early diagnosis of CH is a cornerstone and it is important to detect causes leading to diagnostic delay. Limited published data exist regarding CH in Egypt, and with no data showing characteristics of CH or causes of diagnostic delay . AIM: To investigate clinical characteristics, for CH and detect causes of diagnostic delay in Egypt. METHODOLOGY: A cross-sectional study was conducted including all patients (age: 18-60 years) with primary headache disorders in Egypt with CH patients consecutively recruited over 1 year. Demographic and clinical characteristics as well as rate of diagnostic delay were collected. RESULTS: This registry included 1187 patients with primary headaches over a year. CH accounted for 1.9% . The majority of CH patients were males (82%), and a mean age of 37.9 ± 10 years. The mean age of disease onset was 25 ± 8 years. Sixty-five percent had episodic CH, while 34.8% had chronic CH. Most of the patients (95.7%) had strictly unilateral pain (right side 52.2%, left side 43.5%). Autonomic features were rhinorrhea (91%), ptosis (87%), and lacrimation (78%). Migrainous features were found in 26% of patients. Bout duration of CH lasted on an average of 1-4 months. Time interval of diagnostic delay ranged from 0.5 to 29 years, with a mean diagnostic delay of 9.8 ± 7.9 years. CONCLUSION: This study showed that CHs present 1.9% of primary headache disorders in Egypt, with males more affected than females. the incidence of smoking was higher among CH patients. Marked diagnostic delay was found which necessitate an action toward raising awareness.

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Accurate segmentation of retinal layers in optical coherence tomography (OCT) images is critical for assessing diseases that affect the optic nerve, but existing automated algorithms often fail when pathology causes irregular layer topology, such as extreme thinning of the ganglion cell-inner plexiform layer (GCIPL). Deep LOGISMOS, a hybrid approach that combines the strengths of deep learning and 3D graph search to overcome their limitations, was developed to improve the accuracy, robustness and generalizability of retinal layer segmentation. The method was trained on 124 OCT volumes from both eyes of 31 non-arteritic anterior ischemic optic neuropathy (NAION) patients and tested on three cross-sectional datasets with available reference tracings: Test-NAION (40 volumes from both eyes of 20 NAION subjects), Test-G (29 volumes from 29 glaucoma subjects/eyes), and Test-JHU (35 volumes from 21 multiple sclerosis and 14 control subjects/eyes) and one longitudinal dataset without reference tracings: Test-G-L (155 volumes from 15 glaucoma patients/eyes). In the three test datasets with reference tracings (Test-NAION, Test-G, and Test-JHU), Deep LOGISMOS achieved very high Dice similarity coefficients (%) on GCIPL: 89.97±3.59, 90.63±2.56, and 94.06±1.76, respectively. In the same context, Deep LOGISMOS outperformed the Iowa reference algorithms by improving the Dice score by 17.5, 5.4, and 7.5, and also surpassed the deep learning framework nnU-Net with improvements of 4.4, 3.7, and 1.0. For the 15 severe glaucoma eyes with marked GCIPL thinning (Test-G-L), it demonstrated reliable regional GCIPL thickness measurement over five years. The proposed Deep LOGISMOS approach has potential to enhance precise quantification of retinal structures, aiding diagnosis and treatment management of optic nerve diseases.

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In this work, we present an advancement in the encapsulation of lithium yttrium fluoride-based (YLiF4:Yb,Er) upconversion nanocrystals (UCNPs) with silica (SiO2) shells through a reverse microemulsion technique, achieving UCNPs@SiO2 core/shell structures. Key parameters of this approach were optimized to eliminate the occurrence of core-free silica particles and ensure a controlled silica shell thickness growth on the UCNPs. The optimal conditions for this method were using 6 mg of UCNPs, 1.5 mL of Igepal CO-520, 0.25 mL of ammonia, and 50 µL of tetraethyl orthosilicate (TEOS), resulting in a uniform silica shell around UCNPs with a thickness of 8 nm. The optical characteristics of the silica-encased UCNPs were examined, confirming the retention of their intrinsic upconversion luminescence (UC). Furthermore, we developed a reliable strategy to avoid the coencapsulation of multiple UCNPs within a single silica shell. This approach led to a tenfold increase in the UC luminescence of the annealed particles compared to their nonannealed counterparts, under identical silica shell thickness and excitation conditions. This significant improvement addresses a critical challenge and amplifies the applicability of the resulting UCNPs@SiO2 core/shell structures in various fields.

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Copper oxide nanoparticles (CuO-NPs) are commonly used metal oxides. Betaine possesses antioxidant and neuroprotective activities. The current study aimed to investigate the neurotoxic effect of CuO-NPs on rats and the capability of betaine to mitigate neurotoxicity. Forty rats; 4 groups: group I a control, group II intraperitoneally CuO-NPs (0.5 mg/kg/day), group III orally betaine (250 mg/kg/day) and CuO-NPs, group IV orally betaine for 28 days. Rats were subjected to neurobehavioral assessments. Brain samples were processed for biochemical, molecular, histopathological, and immunohistochemical analyses. Behavioral performance of betaine demonstrated increasing locomotion and cognitive abilities. Group II exhibited significantly elevated malondialdehyde (MDA), overexpression of interleukin-1 beta (IL-1ß), and tumor necrosis factor-alpha (TNF-α). Significant decrease in glutathione (GSH), and downregulation of acetylcholine esterase (AChE), nuclear factor erythroid 2-like protein 2 (Nrf-2), and superoxide dismutase (SOD). Histopathological alterations; neuronal degeneration, pericellular spaces, and neuropillar vacuolation. Immunohistochemically, an intense immunoreactivity is observed against IL-1ß and glial fibrillary acidic protein (GFAP). Betaine partially neuroprotected against CuO-NPs associated alterations. A significant decrease at MDA, downregulation of IL-1ß, and TNF-α, a significant increase at GSH, and upregulation of AChE, Nrf-2, and SOD. Histopathological alterations partially ameliorated. Immunohistochemical intensity of IL-1ß and GFAP reduced. It is concluded that betaine neuroprotected against most of CuO-NP neurotoxic effects through antioxidant and cell redox system stimulating efficacy.

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BACKGROUND: The aim of this scoping review was to understand the development of robotics and its accuracy in placing dental implants when compared to other forms of guided surgery. METHODS: An electronic search was conducted on the electronic databases of PubMed, Cochrane, and Science direct with the following queries: ((robotics) AND (dental implant)) AND (accuracy). The search timeline was between 2017 and 2022. RESULTS: A total of 54 articles were screened for title and abstract, of which 16 were deemed eligible for inclusion. Thirty-one articles were excluded mainly because they were out of topic (not relevant) or not in English. In total, 16 articles were included for analysis. CONCLUSIONS: This review thoroughly analyses 5 years of literature concerning the evolution of robotics in dental implant surgery, underscoring the necessity for additional research on nascent technologies reported and a comparative study with static and dynamic systems for clinical efficacy evaluation.

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Guanosine diphosphate-mannose pyrophosphorylase B (GMPPB) catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, which is required as a mannose donor for the biosynthesis of glycan structures necessary for proper cellular functions. Mutations in GMPPB have been associated with various neuromuscular disorders such as muscular dystrophy and myasthenic syndromes. Here, we report that GMPPB protein abundance increases during brain and skeletal muscle development, which is accompanied by an increase in overall protein mannosylation. To model the human disorder in mice, we generated heterozygous GMPPB KO mice using CIRSPR/Cas9. While we were able to obtain homozygous KO mice from heterozygous matings at the blastocyst stage, homozygous KO embryos were absent beyond embryonic day E8.5, suggesting that the homozygous loss of GMPPB results in early embryonic lethality. Since patients with GMPPB loss-of-function manifest with neuromuscular disorders, we investigated the role of GMPPB in vitro. Thereby, we found that the siRNA-mediated knockdown of Gmppb in either primary myoblasts or the myoblast cell line C2C12 impaired myoblast differentiation and resulted in myotube degeneration. siRNA-mediated knockdown of Gmppb also impaired the neuron-like differentiation of N2A cells. Taken together, our data highlight the essential role of GMPPB during development and differentiation, especially in myogenic and neuronal cell types.

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Optical coherence tomography (OCT) has become a key method for diagnosing and staging radiation retinopathy, based mainly on the presence of fluid in the central macula. A robust retinal layer segmentation method is required for identification of the specific layers involved in radiation-induced pathology in individual eyes over time, in order to determine damage driven by radiation injury to the microvessels and to the inner retinal neurons. Here, we utilized OCT, OCT-angiography, visual field testing, and patient-specific dosimetry models to analyze abnormal retinal layer thickening and thinning relative to microvessel density, visual function, radiation dose, and time from radiotherapy in a cross-sectional cohort of uveal melanoma patients treated with 125I-plaque brachytherapy. Within the first 24 months of radiotherapy, we show differential thickening and thinning of the two inner retinal layers, suggestive of microvessel leakage and neurodegeneration, mostly favoring thickening. Four out of 13 eyes showed decreased inner retinal capillary density associated with a corresponding normal inner retinal thickness, indicating early microvascular pathology. Two eyes showed the opposite: significant inner retinal layer thinning and normal capillary density, indicating early neuronal damage preceding a decrease in capillary density. At later time points, inner retinal thinning becomes the dominant pathology and correlates significantly with decreased vascularity, vision loss, and dose to the optic nerve. Stable multiple retinal layer segmentation provided by 3D graph-based methods aids in assessing the microvascular and neuronal response to radiation, information needed to target therapeutics for radiation retinopathy and vision loss.

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Purpose: To visualize and quantify structural patterns of optic nerve edema encountered in papilledema during treatment. Methods: A novel bi-channel deep-learning variational autoencoder (biVAE) model was trained using 1498 optical coherence tomography (OCT) scans of 125 subjects over time from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) and 791 OCT scans of 96 control subjects from the University of Iowa. An independent test dataset of 70 eyes from 70 papilledema subjects was used to evaluate the ability of the biVAE model to quantify and reconstruct the papilledema spatial patterns from input OCT scans using only two variables. Results: The montage color maps of the retinal nerve fiber layer (RNFL) and total retinal thickness (TRT) produced by the biVAE model provided an organized visualization of the variety of morphological patterns of optic disc edema (including differing patterns at similar thickness levels). Treatment effects of acetazolamide versus placebo in the IIHTT were also demonstrated in the latent space. In image reconstruction, the mean signed peripapillary retinal nerve fiber layer thickness (pRNFLT) difference ± SD was -0.12 ± 17.34 µm, the absolute pRNFLT difference was 13.68 ± 10.65 µm, and the RNFL structural similarity index reached 0.91 ± 0.05. Conclusions: A wide array of structural patterns of papilledema, integrating the magnitude of disc edema with underlying disc and retinal morphology, can be quantified by just two latent variables. Translational Relevance: A biVAE model encodes structural patterns, as well as the correlation between channels, and may be applied to visualize individuals or populations with papilledema throughout treatment.

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BACKGROUND: Early childhood caries (ECC) is a public health problem, especially in developing countries like Egypt which has an ECC prevalence of 74%. This research aimed to assess the risk indicators associated with ECC in a rural, socially-disadvantaged population in Alexandria, Egypt. METHODS: A case-control study was conducted in 8 nurseries of preschool children aged 3 to 5 years in rural, deprived areas in Alexandria, Egypt, from October 2019 till January 2020. Two groups, 93 with ECC and 93 without ECC. A validated questionnaire was used to collect sociodemographic data including age, sex, number of siblings, socioeconomic status, oral health practices including toothbrushing frequency, pattern of dental visits, daily frequency of sugary snacks. Also, salivary pH and buffering capacity were assessed. A trained and calibrated dentist assessed caries status clinically according to the World Health Organization (WHO) criteria using the dmft index and oral hygiene status using Silness and Loe Plaque Index. Chi-squared test, followed by multivariable logistic regression were performed to assess the relation between independent variables and ECC, P < 0.05 was considered to be statistically significant. RESULTS: Bivariate analysis showed that age, mother's education, dental visits, dietary habits, Plaque index, salivary pH and buffering capacity were significantly associated with ECC. The significant risk indicators for ECC in multivariable regression were age (AOR = 4.73, 95% CI: 2.76-7.83), mother's education (illiterate vs. university educated, AOR = 28.36, 95% CI: 8.51-112.92), frequency of daily sugary snacks (twice vs. once, AOR = 2.00, 95% CI: 1.29-3.49, and three or more vs. once, AOR = 2.67, 95% CI: 1.72-3.27), night feeding (AOR = 1.89, 95% CI: 1.38-10.21), Plaque index (AOR = 21.34, 95% CI: 5.56-81.99), and salivary pH (AOR = 0.16, 95% CI: 0.05-0.58). CONCLUSION: This study suggests that sociodemographic indicators, dietary habits, plaque accumulation and salivary pH are risk indicators for ECC in the studied population.

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BACKGROUND: Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are important structural components of neural cellular membranes and possess anti-inflammatory properties. Very preterm infants are deprived of the enhanced placental supply of these fatty acids, but the benefit of postnatal supplementation on brain development is uncertain. The aim of this study was to test the hypothesis that early enteral supplementation with ARA and DHA in preterm infants improves white matter (WM) microstructure assessed by diffusion-weighted MRI at term equivalent age. METHODS: In this double-blind, randomized controlled trial, infants born before 29 weeks gestational age were allocated to either 100 mg/kg ARA and 50 mg/kg DHA (ARA:DHA group) or medium chain triglycerides (control). Supplements were started on the second day of life and provided until 36 weeks postmenstrual age. The primary outcome was brain maturation assessed by diffusion tensor imaging (DTI) using Tract-Based Spatial Statistics (TBSS) analysis. RESULTS: We included 120 infants (60 per group) in the trial; mean (range) gestational age was 26+3 (22+6 - 28+6) weeks and postmenstrual age at scan was 41+3 (39+1 - 47+0) weeks. Ninety-two infants underwent MRI imaging, and of these, 90 had successful T1/T2 weighted MR images and 74 had DTI data of acceptable quality. TBSS did not show significant differences in mean or axial diffusivity between the groups, but demonstrated significantly higher fractional anisotropy in several large WM tracts in the ARA:DHA group, including corpus callosum, the anterior and posterior limb of the internal capsula, inferior occipitofrontal fasciculus, uncinate fasciculus, and the inferior longitudinal fasciculus. Radial diffusivity was also significantly lower in several of the same WM tracts in the ARA:DHA group. CONCLUSION: This study suggests that supplementation with ARA and DHA at doses matching estimated fetal accretion rates improves WM maturation compared to control treatment, but further studies are needed to ascertain any functional benefit. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov; ID:NCT03555019.

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Several neurological disorders, neurodevelopmental disorders, and neurodegenerative disorders have a genetic element with various clinical presentations ranging from mild to severe presentation. Neurological disorders are rare multifactorial disorders characterized by dysfunction and degeneration of synapses, neurons, and glial cells which are essential for movement, coordination, muscle strength, sensation, and cognition. The cerebellum might be involved at any time, either during development and maturation or later in life. Herein, we describe a spectrum of NDDs and NDs in seven patients from six Egyptian families. The core clinical and radiological features of our patients included dysmorphic features, neurodevelopmental delay or regression, gait abnormalities, skeletal deformities, visual impairment, seizures, and cerebellar atrophy. Previously unreported clinical phenotypic findings were recorded. Whole-exome sequencing (WES) was performed followed by an in silico analysis of the detected genetic variants' effect on the protein structure. Three novel variants were identified in three genes MFSD8, AGTPBP1, and APTX, and other previously reported three variants have been detected in "TPP1, AGTPBP1, and PCDHGC4" genes. In this cohort, we described the detailed unique phenotypic characteristics given the identified genetic profile in patients with neurological "neurodevelopmental disorders and neurodegenerative disorders" disorders associated with cerebellar atrophy, hence expanding the mutational spectrum of such disorders.

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Germline pathogenic variants in DICER1 predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification is essential for reliable diagnosis of DICER1-related tumor predisposition and identification of individuals who may benefit from surveillance. Since 2015, most labs have followed the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) sequence variant classification guidelines for DICER1 germline variant curation. However, these general guidelines lack gene-specific nuances and leave room for subjectivity. Consequently, a group of DICER1 experts joined ClinGen to form the DICER1 and miRNA-Processing Genes Variant Curation Expert Panel (VCEP), to create DICER1- specific ACMG/AMP guidelines for germline variant curation. The VCEP followed the FDA-approved ClinGen protocol for adapting and piloting these guidelines. A diverse set of 40 DICER1 variants were selected for piloting, including 14 known Pathogenic/Likely Pathogenic (P/LP) variants, 12 known Benign/Likely Benign (B/LB) variants, and 14 variants classified as variants of uncertain significance (VUS) or with conflicting interpretations in ClinVar. Clinically meaningful classifications (i.e., P, LP, LB, or B) were achieved for 82.5% (33/40) of the pilot variants, with 100% concordance among the known P/LP and known B/LB variants. Half of the VUS or conflicting variants were resolved with four variants classified as LB and three as LP. These results demonstrate that the DICER1-specific guidelines for germline variant curation effectively classify known pathogenic and benign variants while reducing the frequency of uncertain classifications. Individuals and labs curating DICER1 variants should consider adopting this classification framework to encourage consistency and improve objectivity.

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