Deep learning-guided discovery of an antibiotic targeting Acinetobacter baumannii.

Acinetobacter baumannii is a nosocomial Gram-negative pathogen that often displays multidrug resistance. Discovering new antibiotics against A. baumannii has proven challenging through conventional screening approaches. Fortunately, machine learning methods allow for the rapid exploration of chemical space, increasing the probability of discovering new antibacterial molecules. Here we screened ~7,500 molecules for those that inhibited the growth of A. baumannii in vitro. We trained a neural network with this growth inhibition dataset and performed in silico predictions for structurally new molecules with activity against A. baumannii. Through this approach, we discovered abaucin, an antibacterial compound with narrow-spectrum activity against A. baumannii. Further investigations revealed that abaucin perturbs lipoprotein trafficking through a mechanism involving LolE. Moreover, abaucin could control an A. baumannii infection in a mouse wound model. This work highlights the utility of machine learning in antibiotic discovery and describes a promising lead with targeted activity against a challenging Gram-negative pathogen.

Amelioration of endothelial integrity by 3,5,4'-trihydroxy-trans-stilbene against high-fat-diet-induced obesity and -associated vasculopathy and myocardial infarction in rats, targeting TLR4/MyD88/NF-κB/iNOS signaling cascade.

Exacerbated expression of TLR4 protein (foremost pattern recognition receptor) during obesity could trigger NF-κB/iNOS signaling through linker protein (MyD88), predisposed to an indispensable inflammatory response. The induction of this detrimental cascade leads to myocardial and vascular abnormalities. Molecular docking was studied for protein-ligand interaction between these potential targets and resveratrol. The pre-treatment of resveratrol (20 mg/kg/p.o/per day for ten weeks) was given to investigate the therapeutic effect against HFD-induced obesity and associated vascular endothelial dysfunction (VED) and myocardial infarction (MI) in Wistar rats. In addition to accessing the levels of serum biomarkers for VED and MI, oxidative stress, inflammatory cytokines, and histopathology of these tissues were investigated. Lipopolysaccharide (for receptor activation) and protein expression analysis were introduced to explore the mechanistic involvement of TLR4/MyD88/NF-κB/iNOS signaling. Assessment of in-silico analysis showed significant interaction between protein and ligand. The involvement of this proposed signaling (TLR4/MyD88/NF-κB/iNOS) was further endorsed by the impact of lipopolysaccharide and protein expression analysis in obese and treated rats. Moreover, resveratrol pre-treated rats showed significantly lowered cardio and vascular damage measured by the distinct down expression of the TLR4/MyD88/NF-κB/iNOS pathway by resveratrol treatment endorses its ameliorative effect against VED and MI.

Green synthesis of zinc oxide nanoparticles (ZnO-NPs) by Streptomyces baarnensis and its active metabolite (Ka): a promising combination against multidrug-resistant ESKAPE pathogens and cytotoxicity.

Various eco-friendly techniques are being researched for synthesizing ZnO-NPs, known for their bioactivity. This study aimed at biosynthesizing ZnO-NPs using Streptomyces baarnensis MH-133, characterizing their physicochemical properties, investigating antibacterial activity, and enhancement of their efficacy by combining them with a water-insoluble active compound (Ka) in a nanoemulsion form. Ka is a pure compound of 9-Ethyl-1,4,6,9,10-pentahydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione obtained previously from our strain of Streptomyces baarnensis MH-133. Biosynthesized ZnO-NPs employing Streptomyces baarnensis MH-133 filtrate and zinc sulfate (ZnSO4.7H2O) as a precursor were purified and characterized by physicochemical investigation. High-resolution-transmission electron microscopy (HR-TEM) verified the effective biosynthesis of ZnO-NPs (size < 12 nm), whereas dynamic light scattering (DLS) analysis showed an average size of 17.5 nm. X-ray diffraction (XRD) exhibited characteristic diffraction patterns that confirmed crystalline structure. ZnO-NPs efficiently inhibited both Gram-positive and Gram-negative bacteria (MICs: 31.25-125 µg/ml). The pure compound (Ka) was combined with ZnO-NPs to improve effectiveness and reduce dose using checkerboard microdilution. Niteen treatments of Ka and ZnO-NPs combinations obtained by checkerboard matrix inhibited Klebsiella pneumonia. Eleven combinations had fractional inhibitory concentration index (FICi) between 1.03 and 2, meaning indifferent, another five combinations resulted from additive FICi (0.625-1) and only one combination with FICi of 0.5, indicating synergy. In the case of methicillin-resistant S. aureus (MRSA), Ka-ZnO-NPs combinations yielded 23 treatments with varying degrees of interaction. The results showed eleven treatments with indifferent interaction, eight additive interactions, and two synergies with FICi of 0.5 and 0.375. The combinations that exhibited synergy action were transformed into a nanoemulsion form to improve their solubility and bioavailability. The HR-TEM analysis of the nanoemulsion revealed spherical oil particles with a granulated core smaller than 200 nm and no signs of aggregation. Effective dispersion was confirmed by DLS analysis which indicated that Ka-ZnO-NPs nanoemulsion droplets have an average size of 53.1 nm and a polydispersity index (PI) of 0.523. The killing kinetic assay assessed the viability of methicillin-resistant Staphylococcus aureus (MRSA) and K. pneumonia post-treatment with Ka-ZnO-NPs combinations either in non-formulated or nanoemulsion form. Results showed Ka-ZnO-NPs combinations show concentration and time-dependent manner, with higher efficacy in nanoemulsion form. The findings indicated that Ka-ZnO-NPs without formulation at MIC values killed K. pneumonia after 24 h but not MRSA. Our nanoemulsion loaded with the previously mentioned combinations at MIC value showed bactericidal effect at MIC concentration of Ka-ZnO-NPs combination after 12 and 18 h of incubation against MRSA and K. pneumonia, respectively, compared to free combinations. At half MIC value, nanoemulsion increased the activity of the combinations to cause a bacteriostatic effect on MRSA and K. pneumonia after 24 h of incubation. The free combination showed a bacteriostatic impact for 6 h before the bacteria regrew to increase log10 colony forming unit (CFU)/ml over the initial level. Similarly, the cytotoxicity study revealed that the combination in nanoemulsion form decreased the cytotoxicity against kidney epithelial cells of the African green monkey (VERO) cell line. The IC50 for Ka-ZnO-NPs non-formulated treatment was 8.17/1.69 (µg/µg)/ml, but in nano-emulsion, it was 22.94 + 4.77 (µg/µg)/mL. In conclusion, efficient Ka-ZnO-NPs nanoemulsion may be a promising solution for the fighting of ESKAPE pathogenic bacteria according to antibacterial activity and low toxicity.

Clinical and endoscopic characteristics of patients undergoing gastrointestinal endoscopic procedures in Egypt: a nationwide multicenter study.

BACKGROUND: Egypt faces a significant public health burden due to chronic liver diseases (CLD) and peptic ulcer disease. CLD, primarily caused by Hepatitis C virus (HCV) infection, affects over 2.9% of the population nationwide, with regional variations. Steatotic liver disease is rapidly emerging as a significant contributor to CLD, especially in urban areas. Acid-related disorders are another widespread condition that can significantly impact the quality of life. These factors and others significantly influence the indications and findings of gastrointestinal endoscopic procedures performed in Egypt. AIM: We aimed to evaluate the clinico-demographic data, indications, and endoscopic findings in Egyptian patients undergoing gastrointestinal endoscopic procedures in various regions of Egypt. METHODS: This study employed a retrospective multicenter cross-sectional design. Data was collected from patients referred for gastrointestinal endoscopy across 15 tertiary gastrointestinal endoscopy units in various governorates throughout Egypt. RESULTS: 5910 patients aged 38-63 were enrolled in the study; 75% underwent esophagogastroduodenoscopy (EGD), while 25% underwent a colonoscopy. In all studied patients, the most frequent indications for EGD were dyspepsia (19.5%), followed by hematemesis (19.06%), and melena (17.07%). The final EGD diagnoses for the recruited patients were portal hypertension-related sequelae (60.3%), followed by acid-related diseases (55%), while 10.44% of patients had a normally apparent endoscopy. Male gender, old age, and the presence of chronic liver diseases were more common in patients from upper than lower Egypt governorates. Hematochezia (38.11%) was the most reported indication for colonoscopy, followed by anemia of unknown origin (25.11%). IBD and hemorrhoids (22.34% and 21.86%, respectively) were the most prevalent diagnoses among studied patients, while normal colonoscopy findings were encountered in 18.21% of them. CONCLUSION: This is the largest study describing the situation of endoscopic procedures in Egypt. our study highlights the significant impact of regional variations in disease burden on the utilization and outcomes of GI endoscopy in Egypt. The high prevalence of chronic liver disease is reflected in the EGD findings, while the colonoscopy results suggest a potential need for increased awareness of colorectal diseases.

Promising Therapeutic Targets for Recurrent/Metastatic Anaplastic Thyroid Cancer.

OPINION STATEMENT: Anaplastic thyroid cancer presents formidable challenges, particularly in cases of recurrence or metastasis. Timely BRAF V600E testing is imperative at diagnosis, initially through immunohistochemistry, followed by comprehensive genomic profiling encompassing genes such as NTRK, RET, ALK, and assessment of tumor mutation burden (TMB). FDA-approved treatment options include dabrafenib and trametinib for patients with BRAF mutations, while those exhibiting high TMB may benefit from pembrolizumab. Further therapeutic decisions hinge upon mutational profile, urgency of response required, airway integrity, and access to targeted therapies There is growing use of immunotherapy for ATC based on published reports of activity, but currently there is no FDA approved agent for ATC. The off-label utilization of "precision medicine" combinations imposes a considerable financial strain, underscoring the necessity for further clinical trials to elucidate promising therapeutic avenues for this orphan disease. There is a pressing need for the development and support of clinical trials investigating genomically driven and immune-based therapies for anaplastic thyroid cancer.

Walking capacity and its association with quality of life among children with down syndrome in Saudi Arabia.

BACKGROUND: Walking ability, which has been connected to better health and independence, is one of the daily activities that is negatively impacted by Down syndrome. Thus, the objective of this study was to examine the walking capacity and its association with the quality of life of children who have Down syndrome compared to those who do not have Down syndrome in Saudi Arabia. METHODS: For this cross-sectional study, we recruited 68 Arabic-speaking children aged 6 to 12 using a convenience sampling method from August to November 2021. Children were divided into two groups: those who do not have Down syndrome (n = 38) and those who have Down syndrome (n = 30). Children in the Riyadh region of Saudi Arabia who do not have Down syndrome were chosen randomly from two schools. Children who have Down syndrome were selected from multiple associations and centers in the same region. A 6-minute walk test was used to measure the child's walking capacity. The Arabic version of the Pediatric Quality of Life Inventory scale was used to assess the child's or parent's perceptions of the child's quality of life and its physical, emotional, social, and school functioning domains. RESULTS: The difference in the mean 6-minute walk test scores between children who have and who do not have Down syndrome was statistically significant, with a mean difference = 105.6, 95% confidence limit = 57.2-154.0, p < .0001. The linear regression analysis after adjusting for age, height, weight, and body mass index revealed that walking capacity was found to be significantly associated with the worst score on the Pediatric Quality of Life Inventory scale (ß = -2.71, SE = 0.49, p < .0001) and its domains of physical, social, and school functioning (ß = -2.29, SE = 0.54, p < .0001; ß = -2.40, SE = 0.58; p = .001; ß = -3.71, SE = 0.56, p = .002, respectively) in children who have Down syndrome, but they had better emotional functioning than children who do not have Down syndrome. CONCLUSIONS: Children who have Down syndrome were less able to walk and were highly associated with the worst possible quality of life, which included the lowest levels of physical, social, and school functioning. Early interventions with techniques must be developed to improve the quality of life for these children.

Assessing bone density on MRI: comparison between routine MRI sequences and DEXA scans.

PURPOSE: Magnetic Resonance Imaging (MRI) is frequently utilised to aid in the comprehensive assessment of back pain, while dual-energy x-ray absorptiometry (DEXA) is the gold standard test for the assessment of bone density. Assessing bone density on MRI could reduce costs and avoid exposing patients to ionising radiation. The aim of this paper is to investigate whether the relative signal intensity of vertebral bodies compared to other structures can detect osteoporosis on MRI. METHODS: 100 patients that had undergone both a lumbar spine MRI and a DEXA scan were identified. The T1 and T2 signal intensity of L1-L4 vertebral bodies (VB), cerebro-spinal fluid (CSF), and psoas muscle were measured within a 1-cm2 region of interest (ROI), and the signal intensity ratios were calculated. The ratios were stratified as normal, osteopenic, or osteoporotic based on DEXA T-scores. RESULTS: The T1 VB /T1 CSF ratio was significantly higher in the osteoporotic group than the normal and osteopenic groups (p < 0.001). The T1 VB /T1 CSF ratio had excellent discrimination (AUC = 0.841) for the presence of osteoporosis. The Pearson correlation coefficient between the DEXA T-score and the T1 VB/T1 CSF ratio was -0.474 (p < 0.001). The intra-observer (ICC = 0.910, 95% CI = 0.757-0.966) and inter-observer reliability (ICC = 0.927, 95% CI = 0.824-0.970) were excellent. In our cohort, a T1 VB / T1 CSF ratio of greater than 4 is 66.7% sensitive but 90.0% specific for the presence of osteoporosis. CONCLUSION: A high T1 VB/T1 CSF ratio suggests osteoporosis on MRI. Prospective validation is needed to confirm these findings.

Optimal Control and Optimization of Grid-Connected PV and Wind Turbine Hybrid Systems Using Electric Eel Foraging Optimization Algorithms.

This paper presents a comprehensive exploration of a hybrid energy system that integrates wind turbines with photovoltaics (PVs) to address the intermittent nature of electricity production from these sources. The necessity for such technology arises from the sporadic nature of electricity generated by PV cells and wind turbines. The envisioned outcome is an emissions-free, more efficient alternative to traditional energy sources. A variety of optimization techniques are utilized, specifically the Particle Swarm Optimization (PSO) algorithm and Electric Eel Foraging Optimization (EEFO), to achieve optimal power regulation and seamless integration with the public grid, as well as to mitigate anticipated loading issues. The employed mathematical modeling and simulation techniques are used to assess the effectiveness of EEFO in optimizing the operation of grid-connected PV and wind turbine hybrid systems. In this paper, the optimization methods applied to the system's architecture are described in detail, providing a clear understanding of the intricate nature of the approach. The efficacy of these optimization strategies is rigorously evaluated through simulations of diverse operating scenarios using MATLAB/SIMULINK. The results demonstrate that the proposed optimization strategies are not only capable of precisely and swiftly compensating for linked loads, but also effectively controlling the energy supply to maintain the load's power at the desired level. The findings underscore the potential of this hybrid energy system to offer a sustainable and reliable solution for meeting power demands, contributing to the advancement of clean and efficient energy technologies. The results demonstrate the capability of the proposed approach to improve system performance, maximize energy yield, and enhance grid integration, thereby contributing to the advancement of renewable energy technologies and sustainable energy systems.

A Scalable Microstructure Photonic Coating Fabricated by Roll-to-Roll "Defects" for Daytime Subambient Passive Radiative Cooling.

The deep space's coldness (∼4 K) provides a ubiquitous and inexhaustible thermodynamic resource to suppress the cooling energy consumption. However, it is nontrivial to achieve subambient radiative cooling during daytime under strong direct sunlight, which requires rational and delicate photonic design for simultaneous high solar reflectivity (>94%) and thermal emissivity. A great challenge arises when trying to meet such strict photonic microstructure requirements while maintaining manufacturing scalability. Herein, we demonstrate a rapid, low-cost, template-free roll-to-roll method to fabricate spike microstructured photonic nanocomposite coatings with Al2O3 and TiO2 nanoparticles embedded that possess 96.0% of solar reflectivity and 97.0% of thermal emissivity. When facing direct sunlight in the spring of Chicago (average 699 W/m2 solar intensity), the coatings show a radiative cooling power of 39.1 W/m2. Combined with the coatings' superhydrophobic and contamination resistance merits, the potential 14.4% cooling energy-saving capability is numerically demonstrated across the United States.

Biosynthesis and Characterization of Aeonium arboreum-Derived Silver Nanoparticles: Antimicrobial Activity, Biofilm Inhibition, Antihemolytic Activity, and In Silico Studies.

Environmentally friendly biosynthesis of silver nanoparticles (AgNPs) from Aeonium arboreum (L.) Webb & Berthel is reported for the first time. The synthesized AgNPs were characterized using UV-Vis, FTIR, TEM, Zeta potential, and XRD analysis, revealing high stability (-29.1 mV), spherical shape, and an average size of 100 nm. The antimicrobial activity levels of both A. arboreum extract and biosynthesized AgNPs were evaluated against five uropathogens (Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans). Both the extract and the AgNPs exhibited significant efficacy, particularly against E. coli, with inhibition zones of 27 mm and 30 mm, respectively. LC-MS analysis tentatively identified 11 secondary metabolites in the extract, including quercetin-3-O-glucoside, quercetin-3-O-rhamnoside, myricetin 3-glucoside, and daphneresinol. In silico docking studies revealed promising binding affinities of these metabolites in relation to key enzymes involved in bacterial folate synthesis (dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS)) and DNA replication (DNA gyrase). These findings demonstrate the potential of A. arboreum-based AgNPs and their associated metabolites as a novel therapeutic approach for combating urinary tract infections. Their antimicrobial, antihemolytic, and antibiofilm properties warrant further investigation.

Removal of pollutants through photocatalysis, adsorption, and electrochemical sensing by a unique plasmonic structure of palladium and strontium oxide nanoparticles sandwiched between 2D nanolayers.

The redesigned engineering building of nanocomposite (NCP) depends on metal oxides of palladium oxide (PdO) nanoparticles (NPs) conjugate with the n-type semiconductor of strontium oxide (SrO) NPs on the electron carrier surface of graphene oxide (GO) and reduce graphene oxide (rGO) nanosheet is the main target of the current work. The low efficiency of PdO (n-type) and SrO (p-type) gave an overview of the increasing generation electron efficiency via building the ohmic area on the GO and rGO surface using the Z-scheme mechanism. The efficiency of the NCP surface for destroying organic pollutants such as mixed dyes of Rhodamine B and methylene blue (RhB/MB), as against insecticides like imidacloprid, and the removal of heavy metals such as chromium ions was studied. The production of clean water against pollutants materials was investigated through adsorption and photocatalytic processes, electrochemical, and spectroscopy methods to detect the activity of NCP. The rate constant of the adsorption pollutants is 0.1776 min-1 (MB), 0.3489 min-1 (RhB), 0.3627 min-1 (imidacloprid), and 0.5729 min-1 (Cr3+). The photocatalytic rate recorded at 0.01218 min-1 (MB), 0.0096 min-1 (RhB), appeared degradation rate at 0.0086 min-1 (imidacloprid), 0.0019 min-1 (Cr6+), and 0.0471 min-1 (Cr3+). The adsorption and photocatalytic efficiency of nanocatalyst (NCP) was calculated at 91% (RhB), 93% (MB), 73% (imidacloprid), 63% (Cr3+), while the photocatalytic efficiency is 63% (RhB), 94% (MB), 86% (imidacloprid), 33% (Cr3+). The recyclability of NCP was tested for five cycles, and the efficiency was discovered at 55% after the fifth cycle. The cytotoxicity of NCP was studied to detect the safety of the fabricated materials. The study validates that the fabricated nanocomposite exhibits great potential as an innovative material for producing clean water.

Tibiotalocalcaneal nail and primary closure for the management of open ankle fractures in the elderly patient; results from a major trauma centre.

INTRODUCTION: Open ankle fractures in elderly patients are challenging injuries to manage. The aim of this study was to assess the outcome of elderly patients with open ankle fractures treated with a tibiotalocalcaneal nail and primary wound closure. METHODS: We identified all open ankle fractures in patients over 65 referred to our major trauma centre managed with a tibiotalocalcaneal nail and primary wound closure over 10 years. We recorded patient demographics, comorbidities, injury mechanism, length of stay, operation, weightbearing status, re-operations, infections and mortality. RESULTS: We included 34 patients with an average age of 87 (73-99). We found 56 % of patients' mobility status declined post-operatively and 21 % of patients were discharged directly home. Four patients required further unplanned surgery including two deep infections requiring amputation. We had a 6 % three month mortality rate. CONCLUSION: Use of a tibiotalocalcaneal nail with primary wound closure offers a reasonable treatment option for open fractures of the ankle in the elderly patient.

Radiotherapy and paclitaxel plus pazopanib or placebo in anaplastic thyroid cancer (NRG/RTOG 0912): a randomised, double-blind, placebo-controlled, multicentre, phase 2 trial.

BACKGROUND: Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population. METHODS: Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0-2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2-3 weeks of weekly paclitaxel (80 mg/m2) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m2), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete. FINDINGS: The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002-4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0-12·8) in the pazopanib group versus 7·3 months (4·3-10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52-1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1-53·2) in the pazopanib group and 29·0% (13·2-44·8) in the placebo group. The incidence of grade 3-5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3-4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group). INTERPRETATION: To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated. FUNDING: National Cancer Institute and Novartis.

Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients.

PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD. METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review. RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation. CONCLUSION: We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.

Early initiation of B-vitamin supplementation may reduce symptoms and explain intrafamilial variability: Insights from two sibling pairs from the TANGO2 natural history study.

TANGO2-deficiency disorder (TDD) is an autosomal recessive condition arising from pathogenic biallelic variants in the TANGO2 gene. TDD is characterized by symptoms typically beginning in late infancy including delayed developmental milestones, cognitive impairment, dysarthria, expressive language deficits, and gait abnormalities. There is wide phenotypic variability where some are severely affected while others have mild symptoms. This variability has been documented even among sibling pairs who share the same genotype, but reasons for this variability have not been well understood. Emerging data suggest a potential link between B-complex or multivitamin supplementation and decreased metabolic crises in TDD. In this report, we describe two sibling pairs from unreladiagnosed with TDD with marked differences in symptoms. In both families, the older siblings suffered multiple metabolic crises and are clinically more affected than their younger siblings who have very mild to no symptoms; they are the least impaired among 70 other patients in our ongoing international natural history study. Unlike their older siblings, the two younger siblings started taking B-complex vitamins early between 9 and 16 months. This report delineates the mildest presentation of TDD in two families. These data may support a role for early diagnosis and initiation of vitamin supplementation to not only prevent metabolic crises but also improve neurologic outcomes in this life-threatening disorder.

The Association Between Bone Remodeling Markers, genes polymorphisms with Incidence of Osteopenia Among Young Saudi Female.

Osteopenia and osteoporosis, are prevalent skeletal systemic conditions, cause weaker bones and an increased risk of fragility fractures. This work is aimed to evaluate the relation between bone-remolding markers and genotypes of four single nucleotide polymorphisms in young Saudi females (rs2297480 of farnesyl diphosphate synthase (FDPS), rs3736228 of Low-density lipoprotein receptor-related protein 5 (LRP5), rs1234612 of sclerostin (SOST), and rs9934438 of Vitamin K epoxide reductase complex subunit 1  (VKORC1) ). For this purpose, 750 premenopausal females aged 18 to 40 years old, either university students, postgraduates, or university employees were recruited and divided into three groups according to bone mineral density BMD (g/cm2) divided by T score into osteoporosis (n = 12), osteopenia (n = 147), and normal (n = 591). Serum SOST, BALP, calcium, phosphate, ALP, albumin, beta-CTXs and human VDR levels were determined. TaqMan SNP Genotyping assays were used to genotype four polymorphisms using real-time PCR (applied biosystem). Results showed that BALP, CTX-1 and SOST were significantly higher in the osteoporosis and osteopenia groups than in the normal group. Bone mineral density readings were considerably lower in females with the GG genotype in FDPS rs2297480 and TT genotype in LRP5 rs3736228, which increase the risk for osteopenia by 3. 6-fold and 3. 06-fold than control respectively. Also, females with the TT genotype in LRP5 rs3736228 have decreased average values for Bone Mineral Density. In conclusion, the GG genotype of FDPS rs2297480 and the TT genotype of LRP5 rs3736228 was shown to be strongly associated with osteopenia in young Saudi females with low bone mineral density and SOST levels.

Effects of COVID-19 on Pediatric Cancer Care: A Multicenter Study of 11 Middle Eastern Countries.

During the COVID-19 pandemic, major challenges are facing pediatric cancer centers regarding access to cancer centers, continuity of the anti-cancer therapy, hospital admission, and infection protection precautions. Pediatric oncologists actively treating children with cancer from 29 cancer centers at 11 countries were asked to answer a survey from May 2020 to August 2020 either directly or through the internet. COVID-19 pandemic affected the access to pediatric cancer care in the form of difficulty in reaching the center in 22 (75.9%) centers and affection of patients' flow in 21 (72.4%) centers. Health care professionals (HCP) were infected with COVID-19 in 20 (69%) surveyed centers. Eighteen centers (62%) modified the treatment guidelines. Care of follow-up patients was provided in-hospital in 8(27.6%) centers, through telemedicine in 10 (34.5%) centers, and just delayed in 11 (38%) centers. Pediatric oncologists had different expectations about the future effects of COVID-19 on pediatric cancer care. Seventy-six percent of pediatric oncologists think the COVID-19 pandemic will increase the use of telemedicine. Fifty-five percent of pediatric oncologists think if the COVID-19 pandemic persists, we will need to change chemotherapy protocols to less myelosuppressive ones. Collaborative studies are required to prioritize pediatric cancer management during COVID-19 era.

Isolated lesions of the pubis.

The osseous pelvis is a well-known area of various primary and secondary bone tumours, tumour mimics, and infections. Isolated lesions of the pubis (ILP) are rare, with few case reports in the literature. Given their sparsity, such lesions may pose a great diagnostic challenge due to varied clinical presentations and imaging features. In this study, we report the largest case series of ILP. We discuss the patient demographics, differentials, surgical approaches, and management.

Sonochemical synthesis of lanthanum ferrite nanoparticle-decorated carbon nanotubes for simultaneous electrochemical determination of acetaminophen and dopamine.

A new nanocomposite consisting of lanthanum ferrite nanoparticles (LaFeO3 NPs) integrated with carbon nanotubes (CNTs) was fabricated via facile sonochemical approach. The engineered nanocomposite was applied to simultaneously determine acetaminophen (ACP) and dopamine (DA) in a binary mixture. The LaFeO3 NPs@CNT probe possesses several advantages such as superior conductivity, large surface area, and more active sites, improving its electrocatalytic activity towards ACP and DA. Under optimized conditions, the anodic peak currents (Ipa) linearly increased with increasing concentration of ACP and DA in the range 0.069-210 µM and 0.15-210 µM, respectively. The sensitivity of LaFeO3 NPs@CNTs/glassy carbon electrode (GCE) for detecting ACP and DA is 7.456 and 5.980 µA·µM-1·cm-2, respectively. The detection limits (S/N = 3) for ACP and DA are 0.02 µM and 0.05 µM, respectively. Advantages of LaFeO3 NPs@CNTs/GCE for the detection of ACP and DA include wide linear ranges, low-detection limits, good selectivity, and long-term stability. The as-fabricated electrode was applied to determine ACP and DA in pharmaceutical formulations and human serum samples with recoveries ranging from 97.7 to 103.3% and an RSD that did not exceed 3.7%, confirming the suitability of the proposed sensor for the determination of ACP and DA in real samples. This study not only presents promising opportunities for enhancing the sensitivity and stability of electrochemical sensors used in the detection of bioanalytes but also significantly contributes to the progress of unique and comprehensive biochemical detection methodologies.

Mental health of siblings of children with physical illness or physical-mental comorbidity.

OBJECTIVES: This study examined the mental health of siblings of children with physical illness (PI), with or without co-occurring mental illness. METHODS: The sample included children aged 2 to 16 years with a chronic PI and their aged-matched healthy siblings (n = 169 dyads). Physical-mental comorbidity (PM) was present if children screened positive for ≥1 mental illness on the Mini International Neuropsychiatric Interview for Children and Adolescents. Parents completed the Strengths and Difficulties Questionnaire (SDQ) to measure child and sibling mental health. RESULTS: Within child-sibling dyads, siblings of children with PI had significantly worse mental health related to conduct problems (d = 0.31), peer problems (d = 0.18) and total difficulties (d = 0.20). Siblings of children with PM had significantly better mental health related to emotional problems (d = 0.42), hyperactivity/inattention (d = 0.23) and total difficulties (d = 0.32). Siblings of children with PI had similar mental health compared with child population norms used in the development of the SDQ. In contrast, siblings of children with PM had significantly worse mental health across all SDQ domains, with the exception of prosocial behaviour. After adjusting for parent psychopathology and family functioning, no statistically significant differences between siblings of children with PM versus siblings of children with PI were found. CONCLUSIONS: Differences in mental health exist between children with PI or PM versus their healthy siblings. However, differences between siblings of children with PI versus siblings of children with PM can be explained by parental and family factors (e.g. marital status, education and income). Findings reinforce family-centred care approaches to address the needs of children with PI or PM and their families.