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Two-dimensional Ti 4 C 3 MXene has recently emerged as a promising electrode for Lithium-ion batteries (LIBs) because of its outstanding ion-transport abilities and high Li-absorbability. This study employed molecular dynamics simulation to explore the mechanical stability of Ti 4 C 3 MXene subjected to various temperatures, strain rates, and vacancy concentrations. A slightly superior tensile strength and elasticity modulus have been observed along zigzag directions, measuring 148.14 GPa and 29.17 GPa, respectively. On the other hand, armchair-oriented Ti 4 C 3 MXene shows a considerably greater fracture strain of 0.259 due to its strain-hardening tendency at lower temperatures. Elevated temperature decreases both fracture strength and fracture strain, which is opposite to the effect of strain rate. Armchair loading has been revealed to be more sensitive to strain rate than its counter direction. Unlike temperature and strain rate, point vacancy significantly deteriorates the elastic modulus of Ti 4 C 3 MXene. Carbon vacancies are more probable than titanium vacancies, which have less formation energy. The atomistic deformation profile supports the predicted values of fracture strain from stress-strain behavior. This in-depth study offers a detailed understanding of the mechanical behavior of Ti 4 C 3 MXene under diverse circumstances, which will aid further experimental study and be beneficial for adopting Ti 4 C 3 as anode materials in LIBs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: To unravel the clinical and genetic specifications of Neuronal ceroid lipofuscinosis (NCL)., Methods: This is a retrospective cross-sectional study conducted in the Department of Pediatric Neurology Children Hospital and University of Child Health Sciences, Lahore, Pakistan from March 2017 to March 2022. The primary outcome was to measure genotype-phenotype correlation by segregation of phenotypes according to genotype. The secondary outcomes included a correlation between genotype and distribution of age(s) of onset., Results: One hundred fifty three patients clinically diagnosed with NCL underwent genetic testing and pathologic mutation was identified in 32.7% of patients. About 59.6% were male and 37.2% had an affected sibling. The median age was 5.46±1.95 years at the onset of the first symptom i.e., myoclonic seizures in 68%, and motor difficulty in 24%. Other features found were global developmental delay (56%), hypotonia (23%), visual impairment (80%), ataxia (22%), and disc pallor (56%). The most common type was CLN6 (Ceroid lipofuscinosis neuronal) (42%), CLN2 (16%) followed by CLN7 (12%). When 50 patients with recognized mutations were compared with 103 patients with no mutation, family history (p=0.049), early visual loss (p=0.016), hypotonia (p=0.001), white matter signals (p=0.026) and pan-atrophy(p=0.047) was statistically significant in the genetically confirmed NCL. Multiple pairwise comparisons indicated that the estimated age of onset for the CLN1 and CLN2 mutation group was significantly lower than other genotypes including CLN6 (p 0.012), CLN10 (p 0.007) and CLN12 (p 0.007)., Conclusion: Following a detailed review of NCL symptomatology, a clinically-oriented approach should be used for a rapid diagnosis with confirmation by targeted molecular testing for future genetic counseling., Competing Interests: Conflicts of interest: None., (Copyright: © Pakistan Journal of Medical Sciences.)

Background: Biallelic ZBTB11 variants have previously been associated with an ultrarare subtype of autosomal recessive intellectual developmental disorder (MRT69)., Objective: The aim was to provide insights into the clinical and genetic characteristics of ZBTB11-related disorders (ZBTB11-RD), with a particular emphasis on progressive complex movement abnormalities., Methods: Thirteen new and 16 previously reported affected individuals, ranging in age from 2 to 50 years, with biallelic ZBTB11 variants underwent clinical and genetic characterization., Results: All patients exhibited a range of neurodevelopmental phenotypes with varying severity, encompassing ocular and neurological features. Eleven new patients presented with complex abnormal movements, including ataxia, dystonia, myoclonus, stereotypies, and tremor, and 7 new patients exhibited cataracts. Deep brain stimulation was successful in treating 1 patient with generalized progressive dystonia. Our analysis revealed 13 novel variants., Conclusions: This study provides additional insights into the clinical features and spectrum of ZBTB11-RD, highlighting the progressive nature of movement abnormalities in the background of neurodevelopmental phenotype., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

In line with the importance of Prasium majus L. (Lamiaciatae) in traditional medicine as a calming and sedative remedy, the present study was designed to reveal its chemical constituents and bioactivity potentials. Thus, after extraction and fractionation of the plant material, the obtained butanol fraction (BPm) was subjected to conventional chromatographic separation of its constituents in addition to LC-MS/MS evaluation versus some authentic standards. The study resulted in the isolation and characterisation of 8 compounds, including one new chrysoeriol derivative, majusiode ( 1 ). Structural elucidation of all isolated compounds was based on detailed investigation of their spectral data (NMR (1 & 2D), ESI-MS, IR and UV-Vis). HPLC-MS/MS analysis versus authentic samples lead to the detection of 31 constituents, including all 8 isolated compounds. The new compound ( 1 ) showed moderate AChE inhibition power (IC 50 : 163.3 ± 3.4 µg/mL) as compared to the positive control galanthamine (91.4 ± 5.2 µg/mL) and moderate DPPH • /ABTS •+ scavenging power.

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and Psmf1 conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor.

Additive manufacturing/three-dimensional printing (AM/3DP) processes promise a flexible production modality to fabricate a complex build directly from its digital design file with minimal postprocessing. However, some critical shortcomings of AM/3DP processes related to the build quality and process repeatability are frequently experienced and reported in the literature. In this study, an in situ real-time nondestructive monitoring framework based on the dispersive properties of phononic crystal artifacts (PCAs) to address such quality challenges is described. Similar to a witness coupon, a PCA is printed alongside a build while it is interrogated and monitored with ultrasound. A PCA is substantially smaller than the actual build. Due to its periodic internal structures, a PCA creates pass and stop bands in its spectral response, which are sensitive to the variations in its process and material parameters. These periodic structures, representing the geometric complexities of an actual build, are designed for a specific monitoring objective(s) in AM/3DP. As a model application, in this demonstration study, the effect of the laser scanning speed of a slective laser melting (SLM) printer on the spectral properties of metal PCAs (mPCAs) is ultrasonically evaluated offline. The dependency of the pressure and shear wave speeds, the apparent Young's and shear moduli, and Poisson's ratio on the scanning speed are quantified, and it is found that they are highly sensitive to the laser scanning speed of an SLM printer. The sensitivity of the peaks of the pressure and shear spectral waveforms acquired for the identical mPCA designs printed on the same build plate with the same process parameters is also quantified. For powder-based AM/3DP technologies, where scanning speed is among the crucial process parameters such as laser power and bed temperature, the reported correlations between scanning speeds and the mechanical and spectral features of the mPCAs are expected to be instrumental in developing in situ real-time monitoring systems., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)

The current study was designed to uncover the chemistry and bioactivity potentials of Bupleurum lancifolium growing wild in Jordan. In this context, the fresh aerial parts obtained from the plant material were subjected to hydrodistillation followed by GC/MS analysis. The main components of the HDEO were γ-patchoulene (23.79%), β-dihydro agarofuran (23.50%), α-guaiene (14.11%), and valencene (13.28%). Moreover, the crude thanolic extract was partitioned to afford two main major fractions, the aqueous methanol (BLM) and butanol (BLB). Phytochemical investigation of both fractions, using conventional chromatographic techniques followed by careful inspection of the spectral data for the isolated compounds (NMR, IR, and UV-Vis), resulted in the characterization of five known compounds, including α-spinasteryl ( M1 ), ethyl arachidate ( M2 ), ethyl myristate ( M3 ), quercetin-3- O -β-d-glucopyranosyl-(1-4")-α-L-rhamnopyranosyl ( B1 ), and isorhamnetin-3- O -β-d-glucopyranosyl-(1-4")-α-L-rhamnopyranosyl ( B2 ). The TPC, TFC, and antioxidant activity testing of both fractions and HDEO revealed an interesting ABTS scavenging potential of the BLB fraction compared to the employed positive controls, which is in total agreement with its high TP and TF contents. Cytotoxic evaluation tests revealed that BLM had interesting cytotoxic effects on the normal breast cell line MDA-MB-231 (ATCC-HTB-26) and the normal dermal fibroblast (ATCC ® PCS-201-012) and normal African green monkey kidney Vero (ATCC-CCL-81) cell lines. Despite both the BLB and BLM fractions showing interesting AChE inhibition activities (IC 50 = 217.9 ± 5.3 µg/mL and 139.1 ± 5.6 µg/mL, respectively), the HDEO revealed an interestingly high AChE inhibition power (43.8 ± 2.7 µg/mL) that far exceeds the one observed for galanthamine (91.4 ± 5.2 µg/mL). The HDEO, BLM, and BLB exhbitied no interesting antimicrobial activity against Bacillus cereus , Bacillus subtilis , Staphylococcus aureus , Escherichia coli , or Pseudomonas aeruginosa .

Loss-of-function mutations in the TLDc family of proteins cause a range of severe childhood-onset neurological disorders with common clinical features that include cerebellar neurodegeneration, ataxia and epilepsy. Of these proteins, oxidation resistance 1 (OXR1) has been implicated in multiple cellular pathways related to antioxidant function, transcriptional regulation and cellular survival; yet how this relates to the specific neuropathological features in disease remains unclear. Here, we investigate a range of loss-of-function mouse model systems and reveal that constitutive deletion of Oxr1 leads to a rapid and striking neuroinflammatory response prior to neurodegeneration that is associated with lysosomal pathology. We go on to show that neuroinflammation and cell death in Oxr1 knockouts can be completely rescued by the neuronal expression of Oxr1, suggesting that the phenotype is driven by the cell-intrinsic defects of neuronal cells lacking the gene. Next, we generate a ubiquitous, adult inducible knockout of Oxr1 that surprisingly displays rapid-onset ataxia and cerebellar neurodegeneration, establishing for the first time that the distinctive pathology associated with the loss of Oxr1 occurs irrespective of developmental stage. Finally, we describe two new homozygous human pathogenic variants in OXR1 that cause neurodevelopmental delay, including a novel stop-gain mutation. We also compare functionally two missense human pathogenic mutations in OXR1, including one newly described here, that cause different clinical phenotypes but demonstrate partially retained neuroprotective activity against oxidative stress. Together, these data highlight the essential role of Oxr1 in modulating neuroinflammatory and lysosomal pathways in the mammalian brain and support the hypothesis that OXR1 protein dosage may be critical for pathological outcomes in disease.

Three Cd 2+ resistant bacterium's minimal inhibition concentrations were assessed and their percentages of Cd 2+ accumulation were determined by measurements using an atomic absorption spectrophotometer (AAS). The results revealed that two isolates Bacillus paramycoides (PM51) and Bacillus tequilensis (PM52), identified by 16S rDNA gene sequencing, showed a higher percentage of Cd 2+ accumulation i.e., 83.78% and 81.79%, respectively. Moreover, both novel strains can tolerate Cd 2+ levels up to 2000 mg/L isolated from district Chakwal. Amplification of the czcD, nifH, and acdS genes was also performed. Batch bio-sorption studies revealed that at pH 7.0, 1 g/L of biomass, and an initial 150 mg/L Cd 2+ concentration were the ideal bio-sorption conditions for Bacillus paramycoides (PM51) and Bacillus tequilensis (PM52). The experimental data were fit to Langmuir isotherm measurements and Freundlich isotherm model R 2 values of 0.999 for each of these strains. Bio sorption processes showed pseudo-second-order kinetics. The intra-diffusion model showed X i values for Bacillus paramycoides (PM51) and Bacillus tequilensis (PM52) of 2.26 and 2.23, respectively. Different surface ligands, was investigated through Fourier-transformation infrared spectroscopy (FTIR). The scanning electron microscope SEM images revealed that after Cd 2+ adsorption, the cells of both strains became thick, adherent, and deformed. Additionally, both enhanced Linum usitatissimum plant seed germination under varied concentrations of Cd 2+ (0 mg/L, 250 mg/L,350 mg/L, and 500 mg/L). Current findings suggest that the selected strains can be used as a sustainable part of bioremediation techniques., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr.Hassan Javed Chaudhary reports equipment, drugs, or supplies was provided by Quaid-i-Azam University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

In in-process quality monitoring for Continuous Manufacturing (CM) and Critical Quality Attributes (CQA) assessment for Real-time Release (RTR) testing, ultrasonic characterization is a critical technology for its direct, non-invasive, rapid, and cost-effective nature. In quality evaluation with ultrasound, relating a pharmaceutical tablet's ultrasonic response to its defect state and quality parameters is essential. However, ultrasonic CQA characterization requires a robust mathematical model, which cannot be obtained with traditional first principles-based modeling approaches. Machine Learning (ML) using experimental data is emerging as a critical analytical tool for overcoming such modeling challenges. In this work, a novel Deep Neural Network-based ML-driven Non-Destructive Evaluation (ML-NDE) modeling framework is developed, and its effectiveness for extracting and predicting three CQAs, namely defect states, compression force levels, and amounts of disintegrant, is demonstrated. Using a robotic tablet handling experimental rig, each attribute's distinct waveform dataset was acquired and utilized for training, validating, and testing the respective ML models. This study details an advanced algorithmic quality assessment framework for pharmaceutical CM in which automated RTR testing is expected to be critical in developing cost-effective in-process real-time monitoring systems. The presented ML-NDE approach has demonstrated its effectiveness through evaluations with separate (unused) test datasets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study investigated the association between apolipoprotein E ( APOE ) gene polymorphisms (rs429358 and rs7412) and primary angle-closure glaucoma (PACG) and pseudoexfoliation glaucoma (PXG) in a Saudi cohort. Genotyping of 437 DNA samples (251 controls, 92 PACG, 94 PXG) was conducted using PCR-based Sanger sequencing. The results showed no significant differences in the allele and genotype frequencies of rs429358 and rs7412 between the PACG/PXG cases and controls. Haplotype analysis revealed ε3 as predominant, followed by ε4 and ε2 alleles, with no significant variance in PACG/PXG. However, APOE genotype analysis indicated a significant association between ε2-carriers and PACG (odds ratio = 4.82, 95% CI 1.52-15.26, p = 0.007), whereas no notable association was observed with PXG. Logistic regression confirmed ε2-carriers as a significant predictor for PACG ( p = 0.008), while age emerged as significant for PXG ( p < 0.001). These findings suggest a potential role of ε2-carriers in PACG risk within the Saudi cohort. Further validation and larger-scale investigations are essential to elucidate the precise role of APOE in PACG pathogenesis and progression.

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Hair and scalp disorders present a significant challenge in dermatology due to their clinical diversity and overlapping symptoms, often leading to misdiagnoses. Traditional diagnostic methods rely heavily on clinical expertise and are limited by subjectivity and accessibility, necessitating more advanced and accessible diagnostic tools. Artificial intelligence (AI) and deep learning offer a promising solution for more accurate and efficient diagnosis., Methods: The research employs a modified Xception model incorporating ReLU activation, dense layers, global average pooling, regularization and dropout layers. This deep learning approach is evaluated against existing models like VGG19, Inception, ResNet, and DenseNet for its efficacy in accurately diagnosing various hair and scalp disorders., Results: The model achieved a 92% accuracy rate, significantly outperforming the comparative models, with accuracies ranging from 50% to 80%. Explainable AI techniques like Gradient-weighted Class Activation Mapping (Grad-CAM) and Saliency Map provided deeper insights into the model's decision-making process., Conclusion: This study emphasizes the potential of AI in dermatology, particularly in accurately diagnosing hair and scalp disorders. The superior accuracy and interpretability of the model represents a significant advancement in dermatological diagnostics, promising more reliable and accessible diagnostic methods., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: The VPS13 family of proteins has been implicated in lipid transport and trafficking between endoplasmic reticulum and organelles, to maintain homeostasis of subcellular membranes. Recently, pathogenic variants in each human VPS13S gene, have been linked to distinct human neurodevelopmental or neurodegenerative disorders. Within the VPS13 family of genes, VPS13D is known to be implicated in mitochondria homeostasis and function., Methods: We investigated a Pakistani sibship affected with neurodevelopmental impairment and severe hyperkinetic (choreoathetoid) movements. Whole exome sequencing (WES) and Sanger sequencing were performed to identify potential candidate variants segregating in the family. We described clinical phenotypes and natural history of the disease during a 3-year clinical follow-up and summarized literature data related to previously identified patients with VPS13D-related neurological disorders., Results: We identified by WES an homozygous non-synonymous variant in VPS13D (c.5723 T > C; p.Ile1908Thr) as the potential underlying cause of the disease in our family. Two young siblings developed an early-onset neurological impairment characterized by global developmental delay, with impaired speech and motor milestones, associated to hyperkinetic movement disorders as well as progressive and non-progressive neurological abnormalities., Conclusion: In this study we delineated the heterogeneity of VPS13D-related clinical phenotypes and described a novel VPS13D homozygous variant associated with severe neurological impairment. Further studies will be pivotal to understand the exact VPS13D function and its impact on mitochondria homeostasis, brain development and regulation of movements, to further clarify genotype-phenotype correlations and provide crucial prognostic information and potential therapeutic implications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Non-line-of-sight (NLOS) imaging systems involve the measurement of an optical signal at a diffuse surface. A forward model encodes the physics of these measurements mathematically and can be inverted to generate a reconstruction of the hidden scene. Some existing NLOS imaging techniques rely on illuminating the diffuse surface and measuring the photon time of flight (ToF) of multi-bounce light paths. Alternatively, some methods depend on measuring high-frequency variations caused by shadows cast by occluders in the hidden scene. While forward models for ToF-NLOS and Shadow-NLOS have been developed separately, there has been limited work on unifying these two imaging modalities. Dove et al introduced a unified mathematical framework capable of modeling both imaging techniques [Opt. Express27, 18016 (2019)10.1364/OE.27.018016]. The authors utilize this general forward model, known as the two frequency spatial Wigner distribution (TFSWD), to discuss the implications of reconstruction resolution for combining the two modalities but only when the occluder geometry is known a priori. In this work, we develop a graphical representation of the TFSWD forward model and apply it to novel experimental setups with potential applications in NLOS imaging. Furthermore, we use this unified framework to explore the potential of combining these two imaging modalities in situations where the occluder geometry is not known in advance.

Adult-onset glaucoma, an age-related neurodegenerative disease, is very prevalent among the elderly Arabs of Saudi origin. This study investigated the association between apolipoprotein E ( APOE ) gene variants (rs429358 and rs7412) and primary open-angle glaucoma (POAG) in Arabs of Saudi origin. A case-control genetic association study involving 179 POAG patients and 251 controls utilized Sanger sequencing to genotype APOE gene variants. The allele frequencies and genotype distributions for rs429358 and rs7412 did not show significant associations with POAG. The haplotype analysis revealed apoε3 (87.6% and 87.4%) as the most prevalent, followed by ε4 (2.8% and 3.6%) and ε2 (9.6% and 8.9%) in the controls and POAG patients, respectively. Although the ε2/ε3 genotype and ε2-carriers displayed a more than two-fold increased risk, statistical significance was not reached. Notably, these polymorphisms did not affect clinical markers, such as intraocular pressure and cup/disc ratio. The logistic regression analysis demonstrated no significant influence of age, sex, rs429358, or rs7412 polymorphisms on POAG. In conclusion, within the Saudi cohort, APOE variants (rs429358 and rs7412) do not appear to be associated with POAG and are not substantial risk factors for its development. However, additional population-based studies are required to validate these findings.

Background: The geo-strategic position of Pakistan on the world map is incredibly important and idyllic as the country is considered the gateway to central Asia. Pakistan has faced political instability for the last three decades, causing a brain drain and adversely affecting socioeconomic growth. This study aims to investigate the impact of an unstable environment on the brain drain of highly skilled professionals, healthcare workers, researchers, and research productivity in Pakistan from January 2000 to December 2022., Material and Methods: The data were recorded from the World Bank, the Higher Education Commission (HEC) Pakistan, the Pakistan Medical and Dental Council (PMDC), the Bureau of Emigration and Overseas Employment (BEOS), Pakistan, Academic Ranking of World Universities (ARWU), and Web of Science Clarivate Analytics. Initially, 32 documents were selected in this study, and finally, eight fact sheets, official government websites, and international organizations were included., Results: The result revealed that due to political instability, in 2022 about 832,339 highly qualified and accomplished experts headed abroad, among them 17976 (2.15%) were highly qualified and 20865 (2.50%) were highly competent professionals. These include accountants 7197 (0.86%), engineers 6,093 (0.73%), agricultural experts 3,110 (0.37%), doctors 2,464 (0.29%), computer experts 2,147 (0.25%), nurses and paramedics 1768 (0.21%), technicians 23347 (2.80%), electricians 20322 (2.44%), and schools and university faculty 1004 (0.12%). Pakistan has a total of 380 Higher Education Commission-indexed academic journals, among them 11 (2.89%) academic journals were indexed in the Web of Science and 23 journals were placed in the Web of Science emerging indexing. Among these journals, only one journal surpassed the impact factor of more than 2.0. The quartile ranking of Pakistani journals is 01 journal in Q2; 02 in Q3; and the remaining 08 journals in Q4. From August 1947 to December 2022, Pakistan produced a total of 259249 research articles, and from January 2000 to December 2022, the number of articles published was 248457 (95.83%). Since the last 22 years, the trend of research publications was continuously increased; however, the rising trend decreased in 2022 with a declined rate of 1263 (3.42%)., Conclusion: The unstable sociopolitical environment in Pakistan caused a brain drain of highly qualified and skilled professionals and impaired the global standing of universities, academic journals, and research productivity in Pakistan. Pakistan must resolve the instability and establish sustainable policies to minimize the brain drain of highly qualified and skilled experts and convalesce their academic institutes and their research productivity for the development of the nation., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Saudi Journal of Anesthesia.)

The genetic etiology of Keratoconus (KC) in Middle Eastern Arabs of Saudi origin is still unclear. A recent genome-wide study identified two significant loci in the region of PNPLA2 (rs61876744) and CSNK1E (rs138380) for KC that may be associated with KC in the Saudi population. In addition, polymorphisms in the apolipoprotein E ( APOE ) gene, namely, rs429358 and rs7412, responsible for APOE allelic variants ε2, ε3, and ε4, may influence KC via oxidative stress mechanism(s). Thus, we investigated the possible association of polymorphisms rs61876744, rs138380, rs429358, rs7412, and APOE genotypes in KC patients of the Saudi population. This study included 98 KC cases and 167 controls. Polymorphisms rs6187644 and rs138380 were genotyped using TaqMan assays, and rs429358 and rs7412 were genotyped via Sanger sequencing. Although the allele frequency of rs61876744(T) in PNPLA2 was a protective effect against KC (odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.44-0.93), the p -value ( p = 0.020) was not significant for multiple testing correction ( p = 0.05/4 = 0.015). However, rs6187644 genotype showed a modestly significant protective effect in the dominant model (OR = 0.53, 95% CI = 0.32-0.88, p = 0.013). Polymorphisms rs138380, rs429358, and rs7412 showed no significant allelic or genotype association with KC. However, the ε2-carriers (ε2/ε2 and ε2/ε3 genotypes) exhibited a greater than 5-fold increased risk of KC, albeit non-significantly ( p = 0.055). Regression analysis showed no significant effect of age, gender, and the four polymorphisms on KC. Our results suggest that polymorphism rs6187644 in PNPLA2 might be associated with KC in the Middle Eastern Arabs of Saudi origin but warrant a large-scale association analysis at this locus.

Different drying techniques may alter the chemical composition of plant extracts and consequently affect their bioactivity potential. The current study was designed to reveal the effect of four different drying methods on the phytochemical composition and antioxidant activity of hydrodistilled essential oil (HD-EO) and methanolic (APM) extract obtained from the aerial part of Anthemis palestina from Jordan. Aerial parts of A. palestina in their fresh (FR) form and after drying in shade (ShD), sun (SD), oven at 40 °C (O40D) and 60 °C (O60D), in addition to microwave (MWD), were used to extract their essential oils by hydrodistillation and to prepare the different methanolic extracts (APM). GC/MS analysis of the different HD-EOs revealed qualitative and quantitative differences among the different samples. While FR, O40D, O60D, and MWD EO samples contained mainly sesquiterpene hydrocarbons (35.43%, 29.04%, 53.69%, and 59.38%, respectively), ShD sample was rich in oxygenated monoterpenes (33.57%), and SD-EO contained mainly oxygenated sesquiterpenes (40.36%). Principal component analysis (PCA) and Cluster analysis (CA) grouped the different drying methods based on their impact on the concentration of chemical constituents. SD-EO demonstrated high DPPH and ABTS antioxidant activity (1.31 ± 0.03) × 10 -2 ; (1.66 ± 0.06) × 10 -2 μg/mL, respectively). Furthermore, A. paleistina methanolic extracts (APM) obtained after subjecting the plant to different drying methods showed interesting patterns in terms of their TPC, TFC, antioxidant activity, and phytochemical profiling. Of all extracts, SD-APM extract had the highest TPC (105.37 ± 0.19 mg GA/g DE), highest TFC (305.16 ± 3.93 mg Q/g DE) and demonstrated the highest DPPH and ABTS scavenging activities ((4.42 ± 0.02) × 10 -2 ; (3.87 ± 0.02) × 10 -2 mg/mL, respectively); all were supported by correlation studies. LC-MS/MS analysis of the different extracts revealed the richness of the SD-APM extract in phenolic acids and flavonoids.

A compressed pharmaceutical oral solid dosage (OSD) form is a strongly micro-viscoelastic material composite arranged as a network of agglomerated particles due to its constituent powders and their bonding and fractural mechanical properties. An OSD product's Critical Quality Attributes, such as disintegration, drug release (dissolution) profile, and structural strength ("hardness"), are influenced by its micro-scale properties. Ultrasonic evaluation is direct, non-destructive, rapid, and cost-effective. However, for practical process control applications, the simultaneous extraction of the micro-viscoelastic and scattering properties from a tablet's ultrasonic response requires a unique solution to a challenging inverse mathematical wave propagation problem. While the spatial progression of a pulse traveling in a composite medium with known micro-scale properties is a straightforward computational task when its dispersion relation is known, extracting such properties from the experimentally acquired waveforms is often non-trivial. In this work, a novel Machine Learning (ML)-based micro-property extraction technique directly from waveforms, based on Multi-Output Regression models and Neural Networks, is introduced and demonstrated. Synthetic waveforms with a given set of micro-properties of virtual tablets are computationally generated to train, validate, and test the developed ML models for their effectiveness in the inverse problem of recovering specified micro-scale properties. The effectiveness of these ML models is then tested and demonstrated for a set of physical OSD tablets. The micro-viscoelastic and micro-structural properties of physical tablets with known properties have been extracted through experimentally acquired waveforms to exhibit their consistency with the generated ML-based attenuation results., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Neurodevelopmental disorders (NDD) are a diverse group of disorders that affect the development of the nervous system. Epilepsy is a common phenotypic aspect of NDD., Methods: We recruited eight consanguineous families from Pakistan which segregated recessively inherited NDD with epilepsy. Magnetic Resonance imaging (MRI) and Electroencephalogram (EEG) were completed. Exome sequencing was carried out for selected participants from each family. The exome data were analyzed for exonic and splice-site variants that had allele frequencies of less than 0.01 in public databases., Results: Clinical investigations determined that developmental delay, intellectual disability and seizures were manifested by most patients in early childhood. EEG findings were abnormal in the participants of four families. MRI revealed demyelination orcerebral atrophic changes in multiple participants. We identified four novel homozygous variants including nonsense andmissense variants in OCLN, ALDH7A1, IQSEC2 and COL3A1, segregating with the phenotypes in the participants of four families. Previously reported homozygous variants of CNTNAP2, TRIT1 and NARS1 were found in individuals from three families. Clinical utility was observed in directing treatment in case of patients with an ALDH7A1 variant which included pyridoxine administration and enabling accurate counseling about the natural history and recurrence risk., Conclusion: Our results add to the clinical and molecular delineation of very rare NDD with epilepsy. The high success rate of exome sequencing is likely attributable to the expectation of homozygous variants in patients of consanguineous families, and in one case, the availability of positional mapping data that greatly aided the variant prioritization., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Go Hun Seo reports financial support was provided by 3billion, Inc.]., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The literature on the impact of temporomandibular disorders (TMDs) on orthodontic management or vice versa lacks clarity. This study presents a review that aims to evaluate the influence of TMDs on orthodontic management and explore the association between TMDs and various aspects of orthodontic treatment. A systematic search was conducted across multiple databases to identify relevant articles documenting the correlation between TMD incidence and orthodontic treatment to achieve the objectives. The selection process followed predefined criteria, and the selected studies underwent bias assessment using the AXIS tool and Cochrane risk of bias (RoB) tool. Among the articles identified, nine studies were deemed suitable for inclusion in the review. The findings from the subsequent meta-analysis indicated a significant overall effect, suggesting that orthodontic treatment may increase the risk of developing TMD. Furthermore, the analysis revealed that patients with TMD had higher odds of experiencing orthodontic issues than those without TMD. Subgroup analysis further demonstrated that orthodontic treatment could have a negative impact on the psychological well-being of TMD patients, while its effect on TMD incidence was found to be negligible. The results highlight the need for additional research to gain a better understanding of the underlying mechanisms and develop appropriate interventions aimed at minimizing the risk of TMD in patients undergoing orthodontic treatment. Clinicians should be aware of TMD as a potential complication of orthodontic treatment and implement appropriate monitoring strategies., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Alam et al.)

LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy and nonspecific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK -related disorder. Exome or genome sequencing was carried out in 11 families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified 12 distinct homozygous loss-of-function variants in 16 individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor ('ear-of-the-lynx' sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK -related disorder and expand the list of neurological disorders presenting with the 'ear-of-the-lynx' sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction., Competing Interests: The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: The objective of this study was to evaluate the effectiveness of preoperative analgesics on inferior alveolar nerve blocks (IANB) during root canal treatment in patients with symptomatic irreversible pulpitis of the mandibular molars., Methods: This study was a randomized, double-blinded, superiority trial with a parallel study design. A total of 120 subjects with symptomatic irreversible pulpitis were randomly assigned to one of four groups: group A (con- trol, Vitamin E, Evion 400 mg), group B (Diclofenac sodium, Voltral SR100 100 mg), group C (Piroxicam, Feldene 20 mg), and group D (Tramadol, Tramal 50 mg). The patients recorded preoperative pain levels, and after admin- istration of local anaesthesia intraoperative pain levels using the Heft-Parker visual analogue scale before and after the oral administration of the analgesics. Statistical analysis was performed using the Kruskal-Wallis test., Results: All the analgesic groups showed a significant effect on the efficacy of the inferior alveolar nerve block in contrast to the control group (p<0.05). However, no significant difference was found between the drug groups on the effectiveness of the inferior alveolar nerve block (p>0.05). No side effects were reported in the present study., Conclusion: Preoperative analgesics significantly increase the effectiveness of inferior alveolar nerve block in patients with symptomatic irreversible pulpitis. Therefore, preoperative analgesics should be considered to increase the effectiveness of inferior alveolar nerve block in patients with symptomatic irreversible pulpitis on the mandibular molars. (EEJ-2023-02-033).

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability., Methods: By international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro., Results: In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well., Conclusion: By identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders., Competing Interests: Conflict of Interest Jeffrey B. Ratliff serves on the editorial board for the journal Neurology and has received consulting fees from Supernus Pharmaceuticals. All other authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Quality issues related to compressed oral solid dosage (OSD) forms, such as tablets, arise during the design, development, and production stages, despite established processes and robust production tools. One of the primary quality concerns is the disintegration properties and drug release profile of immediate-release OSD products, which depend on their micro-texture and micro-viscoelastic properties at the grain level. These properties are influenced by the composition of the formulation, particularly the disintegrant level in the tablet matrix and the porosity of the matrix. In this study, a novel, rapid, non-destructive ultrasonic characterization technique was proposed to correlate the sensitivity of propagating elastic wave speeds, physical/mechanical properties, and the dispersion profile of the OSD material with the disintegrant level (% w/w) in the formulation and the compression force applied during tableting. The proposed characterization framework involves transmitting pressure (longitudinal) and shear (transverse) waves through the OSDs to calculate the speed of sound, which in turn provides information on the apparent Young's and shear moduli. In addition, the attenuation profile of the propagating wave is obtained through dispersion analysis. To investigate the impact of disintegrants and compression force on ultrasonic wave propagation in OSDs, we incorporated seven levels of a frequently used disintegrant. In each formulation, OSDs are compacted in five compaction forces. The sensitivity of wave speeds, physical/mechanical properties, and attenuation profile was observed with each disintegrant and compression force level. The utilization of ultrasonic techniques may present a viable solution for rapid, non-destructive, non-invasive, and cost-effective testing methods required in continuous manufacturing (CM) and real-time release testing (RTRT), and its practical utility in pharmaceutical manufacturing is also discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Since the creation of Pakistan in August 1947, political instability has been a persistent issue in the country, causing a migration of highly qualified, skilled people, and healthcare professionals. From 1971 to 2022 the total number of highly qualified and skilled people including healthcare professionals who migrated from the country is 60,19,888. Among them, 251677 (4.18%), were highly qualified, 455097 (7.55%) were highly skilled, and 5313114 (88.27%) were skilled professionals. Moreover, 50110 (0.83%) were healthcare professionals including doctors 31418 (62.69%), nurses 12853 (25.64%), and pharmacists 5839 (11.65%). The unsustainable political environment, lack of advanced technology-based institutes, poor healthcare infrastructure, low job opportunities and salary benefits in Pakistan caused the brain drain of highly qualified people including healthcare professionals. It adversely affected the academic institutes, the healthcare system, socio-economic growth, research productivity, and the development of the nation. The government of Pakistan must establish sustainable policies to minimize the brain drain of highly qualified people, and healthcare professionals, and recuperate the prosperity of their academic institutes and healthcare system for better healthcare services, and the advancement and sustainable development of the nation., (Copyright: © Pakistan Journal of Medical Sciences.)

The genus Scrophularia is one of the largest genera belonging to the Scrophulariaceae family. Different members of the genus exhibit an interesting, wide spectrum of bioactivities. Accordingly, the current study aimed to investigate, for the first time, the chemical composition of the essential oil of Scrophularia peyronii Post. from Jordan. Additionally, extracts obtained from the aerial parts with solvents of different polarities were assayed for their phytochemical constituents and in vitro antioxidant activities. The major constituents detected in the essential oil, as revealed by GC/MS analysis, contained mainly Z , Z -farnesyl acetone (11.04%), β-elemene (6.36%), n -octanal (5.98%), and spathulenol (4.58%). Each of the aqueous methanol (Sp-M) and butanol (Sp-B) extracts contained flavonoids, saponins, anthraquinone, and glycosides. Both extracts were evaluated for their total phenolic content (TPC), total flavonoid content (TFC), and their in vitro antioxidant activity, which were assayed using the DPPH radical scavenging activity and ABTS radical scavenging methods. Additionally, the two extracts were then subjected to LC-ESI-MS/MS for the qualitative determination of their secondary metabolite content, especially in flavonoids and phenolic compounds. The results showed that the Sp-B extract of S. peyronii had the highest contents of both phenolic compounds and flavonoids and showed high radical scavenging activity, as determined by the two assay methods, when compared with the Sp-M extract. The LC-ESI-MS/MS analysis resulted in the detection of 21 compounds, including 8 flavonoids, 6 phenolic acids, 6 iridoids, and 2 acids. Although the majority of compounds were detected in both extracts, it was noticed that scropolioside B, 6'-O-cinnamoylharpagide, isoferulic acid, and 6-O-methylcatapol were only detected in the Sp-M fraction.

Objectives: To investigate if chronic pain in children with cerebral palsy is undertreated with the current pharmacological/non-pharmacological interventions using a pain management index., Methods: Parents of 120 children with cerebral palsy between the ages of 2-19 years from our region in Denmark answered a questionnaire about whether their child had everyday pain. When answering in pain, we inquired about pain status and pharmacological/non-pharmacological pain coping interventions. Everyday pain was viewed as chronic pain with acute exacerbations. Pain experienced was divided into worst pain (highest moments of pain intensity) and least pain (lowest moments of pain intensity). To describe and evaluate the effectiveness of pain interventions used, a pain management index was utilized. Everyday pain was assessed using a logistical regression by adjusting for age, sex, and gross motor function classification system level., Results: 59/115 (0.51) of parents answering the questionnaire reported everyday pain. Of those, the median age was 10 years. For pain alleviation, massage was reported by parents as being used by 29/59 (0.49) children and paracetamol by 21/59 (0.36). Pain affected daily life in 44/59 (0.75). By our evaluation 44/59 (0.75) were inadequately treated for their pain. Our evaluation also revealed that 19/59 (0.32) of children in pain had inadequately treated pain combined with an undesirable intensity of least pain., Conclusions: Half of the children with cerebral palsy experienced chronic pain according to our pain questionnaire answered by parents. Among these children three-quarters were insufficiently treated for their pain. In the same group, one-third were impacted by pain felt at both its highest and lowest moments of intensity. Massage therapy and paracetamol were the most frequently utilized pain-alleviating interventions. In our cohort, pain was undertreated and likely underdiagnose (Protocol number H-17008823)., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Aim: In a retrospective and exploratory case-control study, we examined the genetic association of two common polymorphisms in the 3' untranslated region (UTR) of DICER1 (rs3742330) and DROSHA (rs10719) genes in primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), and its related clinical phenotypes in a Saudi cohort., Methods: DNA genotyping was performed using TaqMan real-time PCR assays in 500 participants, including 152 POAG, 102 PACG, and 246 non-glaucomatous controls. Statistical analyses were performed to examine the association(s)., Results: Allele and genotype frequency of rs3742330 and rs10719 did not vary significantly in POAG and PACG compared to controls. No significant deviation was observed from Hardy-Weinberg Equilibrium (p > 0.05). Gender stratification revealed no significant allelic/genotype association with glaucoma types. Also, these polymorphisms showed no significant genotype effect on clinical markers such as intraocular pressure, cup/disc ratio, and the number of antiglaucoma medications. Logistic regression showed no effect of age, sex, rs3742330, and rs10719 genotypes on the risk of disease outcome. We also examined a combined allelic effect of rs3742330 (A>G) and rs10719 (A>G). However, none of the allelic combinations significantly affected POAG and PACG., Conclusions: The 3' UTR polymorphisms rs3742330 and rs10719 of DICER1 and DROSHA genes are not associated with POAG and PACG or its related glaucoma indices in this Middle-Eastern cohort of Saudi Arab ethnicity. However, there is a need to validate the results on a broader population and other ethnicities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kondkar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Child abuse is a significant issue across many countries. Despite the situation's innate understanding, many children are not reported to authorities and continue to experience abuse, sometimes even death. Healthcare professionals must be alert for abuse in any child who appears with injuries that are out of the ordinary because it is easy for indicators of child abuse to go unnoticed in a busy emergency department. The current study aims to evaluate and detect the challenges in diagnosing and reporting cases of child abuse among healthcare practitioners in emergency, pediatrics, and family medicine., Methods: A self-administered online disseminated questionnaire was used for data collection during the period from October 1 to December 30, 2022. A cross-sectional study was conducted on emergency, pediatrics, and family medicine healthcare practitioners working in hospitals in healthcare centers in Riyadh, Saudi Arabia. All data were collected, tabulated, and statistically analyzed using SPSS 23.0 for (IBM Corp., Armonk, NY) Windows., Results: The study sample constituted 200 physicians working in the front lines of healthcare like emergency, pediatrics, and family medicine primary care services, 50.5% were males and 49.5% were females. 36.5% of participants were 31-39 years old. 42% were family medicine physicians, 36.5% were pediatricians, and 21.5% were emergency medicine. About 43% of participants attended an educational workshop on child abuse. Nineteen percent of participants are very familiar with the diagnosis of child abuse and 36% of participants reported one to three cases of child abuse in the emergency department in the last year, 5% reported four to six cases and 56.5% reported none. Forty-seven percent of participants reported diagnosing one to five cases of child abuse throughout their whole career, 13% reported 11-15 cases, 6.5% reported six to 10 cases and 28.5% reported none. Causes of underdiagnosis of child abuse by healthcare providers were reported as 63% inexperience, 59% inadequate time for physical examination, 59% lack of diagnosis protocol, 51% lack of confidence in communicating with parents, 36% physicians' cultural background, and 38% lack of confidence in the diagnosis. 93.5% of participants think that healthcare practices need further education for child abuse., Conclusion: In conclusion, physicians in Saudi Arabia who participated in the study had good knowledge to diagnose a case of child abuse. Inexperience, inadequate time for physical examination, lack of diagnosis protocol, lack of confidence in communicating with parents, and physicians' cultural background were the main identified challenges for diagnosing child abuse. Familiarity with cases of child abuse was significantly associated with physicians' age, specialty, and level of training., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, AlShalhoub et al.)

In the pharmaceutical manufacturing industry, real-time in situ quality monitoring for detecting defects at an early stage is a desirable ability, especially in high-rate production, to minimize downstream quality-related issues, financial losses, and timeline risks. In this study, we focus on the early detection of crack formation in compressed oral solid dosage (OSD) forms at its onset before complete delamination and/or capping in downstream processing. The detection of internal tablet cracks related to local micro-stress/strain states, internal granularity (texture), and micro-structure failures is rather unlikely by traditional testing methods, such as the USP reference standards for friability, fracturing, or hardness testing. In addition, these tests do not permit the objective and quantitative evaluation of the influence of formulation and process parameters, which are critical for the development of high-quality drug products manufactured at high rates on a large scale. Internal cracks (potentially resulting in 'capping' and/or 'lamination') under high-strain compaction of highly visco-elastic powder materials are a common failure mode. In the current study, two approaches are introduced and utilized for non-destructively detecting and evaluating hidden cracks in pharmaceutical compacts based on (i) varying axial load-displacement measurements and (ii) ultrasonic reflection ray tracing. The reflection ray tracing technique is a non-destructive, inexpensive, rapid, and material-sparing approach, which makes it advantageous for real-time quality monitoring and defect characterization applications. The varying axial load-displacement technique is more suitable for analytical studies, especially in the design and development phases of compressed OSD products. In this study, as a model application, utilizing these two approaches, it is demonstrated how internal and external cracks can be detected, localized, characterized, and analyzed as a function of disintegrant ratio and main compression force. Various uses of these two techniques in practice, such as in Continuous Manufacturing (CM) and Real-Time Release Testing (RTRT), are also discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Polymorphisms rs2472493 near ABCA1 , rs7636836 in FNDC3B , and rs61275591 near the ANKRD55-MAP3K1 genes were previously reported to exhibit genome-wide significance in primary open-angle glaucoma (POAG). Since these polymorphisms have not been investigated in the Arab population of Saudi Arabia, we examined their association with POAG in a Saudi cohort. Genotyping was performed in 152 POAG cases and 246 controls using Taqman real-time assays and their associations with POAG and clinical markers, such as intraocular pressure, cup/disc ratio, and the number of antiglaucoma medications, were tested by statistical methods. There was no association observed between POAG and the minor allele frequencies of rs2472493[G], rs7636836[T], or rs61275591[A]. None of the genetic models such as co-dominant, dominant, recessive, over-dominant, and log-additive demonstrated any genotype link. The Rs2472493 genotype showed a modest association ( p = 0.044) with the number of antiglaucoma medications in the POAG group, but no significant genotype effect on post hoc analysis. In addition, a G-T allelic haplotype of rs2472493 ( ABCA1 ) and rs7636836 ( FNDC3B ) did show an over two-fold increased risk of POAG (odds ratio = 2.18), albeit non-significantly ( p = 0.092). Similarly, no other allelic haplotype of the three variants showed any significant association with POAG. Our study did not replicate the genetic association of rs2472493 ( ABCA1 ), rs763683 ( FNDC3B ), and rs61275591 ( ANKRD55 - MAP3K1 ) in POAG and related clinical phenotypes, suggesting that these polymorphisms are not associated with POAG in a Saudi cohort of Arab ethnicity. However, large population-based multicenter studies are needed to validate these results.

Introduction Chlorophylls are natural pigments in our everyday diet, especially with customers' rising preference for more natural and healthful habits. The antioxidant capabilities of both classes of lipophilic substances have been researched since disrupting antioxidant equilibrium appears to be linked to the development of several diseases. Methods This research aimed to evaluate the effect of injection with chlorophyll (30 and 60 mg/ml) on enhancing the blood parameters of rats. Twenty-one white male rats were included in this study and divided into three groups: control, 30 mg/ml, and 60 mg/ml.  Results Treatment with liquid chlorophyll significantly increased white blood cells (WBCs), red blood cells (RBCs), granulocytes, lymphocytes, hemoglobin (Hgb), hematocrit (Hct), mean corpuscular Hgb concentration (MCHC), and platelets. However, it nonsignificantly increased mean corpuscular volume (MCV). These results confirm a great increase in important hematological parameters in response to exogenous injectable chlorophyll with concentrations of 30 and 60 mg/ml and at two different time points, 14 and 28 days after injection. The platelet count was significantly (p<0.001) increased after 30 mg/ml and 60 mg/ml. Conclusion These results show a significant increase in important hematological parameters in response to exogenous injectable chlorophyll. The liquid chlorophyll is recommended to increase blood parameters and improve blood characteristics avoiding anemia., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Tagauov et al.)

The finding that some mAbs are antifungal suggests that antibody immunity may play a key role in the defense of the host against mycotic infections. The discovery of antibodies that guard against fungi is a significant advancement because it gives rise to the possibility of developing vaccinations that trigger protective antibody immunity. These vaccines might work by inducing antibody opsonins that improve the function of non-specific (such as neutrophils, macrophages, and NK cells) and specific (such as lymphocyte) cell-mediated immunity and stop or aid in eradicating fungus infections. The ability of antibodies to defend against fungi has been demonstrated by using monoclonal antibody technology to reconsider the function of antibody immunity. The next step is to develop vaccines that induce protective antibody immunity and to comprehend the mechanisms through which antibodies mediate protective effects against fungus.

Objectives: The purposes of this study were to determine the prevalence and cost of absenteeism in nurses as well as the factors that affect absenteeism., Methods: This is a cross sectional study where a self-administered questionnaire response were obtained from 442 nurses for the previous working in 4 hospitals and 3 primary health care centers in Saudi Arabia. Analyses compared those with zero absences with those with one or more absences per month. Attributable risk was calculated as the difference in the absence percentages among nurses with high-risk exposure and low risk exposure., Results: The average absence of nurses is 0.62 days per month. This results in an annual loss of around $4 million. The greatest absence frequency was significantly associated with work psychosocial factors. The modifiable factors included the clarity of work responsibilities, rating of managers, work facilities, work environment, transportation difficulties, and work satisfaction. Cost-effectiveness modules for absence intervention programs were built for these factors., Conclusions: This study demonstrated that nurse absenteeism is a costly issue related to work and psychosocial factors. Preventive programs to improve the quality of work life are likely to be cost effective., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Al Ismail, Herzallah and Al-Otaibi.)

The current research was conducted at Vermi-tech Unit, Muzaffarabad in 2018 to evaluate the efficacy of cow dung and vermicompost on seed sprouting, seedlings, and vegetative developmental parameters of Viola x wittrokiana (pansy). In the current study, vermicompost was produced using Eisenia fetida. Physicochemical parameters of vermicompost and organic manure were recorded before each experimentation. The potting experiment was designed and comprised of eight germination mediums containing different combinations of soil, sand, cow dung, and various concentrations of vermicompost such as 10% VC, 15% VC, 20% VC, 25% VC, 30% VC, and 35% VC. Seed sprouting and seedling developmental parameters were observed for 28 days while vegetative plant growth parameters were recorded after 10 weeks of transplantation in various vermicompost amended germination media. Pre and post-physicochemical analysis of germination media were also recorded to check their quality and permanency. The current findings showed that 30% VC germination media was an effective dose for early seed germination initiation and all seed germination parameters. However, the significant vegetative plant growth and flowering parameters of pansy occurred at 35% VC. Findings revealed that vermicompost not only enhanced the seed germination and growth of pansy but also improved soil health. These results indicate that vermicompost can be exploited as a potent bio-fertilizer for ornamental plant production., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Shafique et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: There is dearth of information on the spectrum of neurological disorders among children less than 18 years of age. The aim of this study is to identify the commonly presenting neurological disorders among children aged ≤ 18 years in Pakistan., Methods: We conducted a cross-sectional study at three tertiary care hospitals in Pakistan., Results: A total of 17,176 children were included in our study; 61.8% were boys and 38.2% females. The most commonly presenting neurological disorder was epilepsy (36%), followed by behavior disorders (16%) and cerebral palsy (10.5%). There was significant difference between children less than 5 years and greater than 5 years age groups, with less than 5 years age group showing higher prevalence for behavioral disorders (P < 0.001), cerebral palsy (P < 0.001), infections (P = 0.014), sequalae (P < 0.001), and developmental disorders (P < 0.001). Gender-wise distribution showed epilepsy to be the most common neurological disorder among both genders, with a significant difference being reported between gender and epilepsy (P = 0.009), headache disorders (P < 0.001), neuroinflammatory disorders (P = 0.025), neurocutaneous syndromes (P < 0.001), behavioral diseases (P < 0.001), cerebral palsy (P = 0.009), and movement disorders (P < 0.001)., Conclusions: The result of this analysis helps to assess the commonly presenting neurological disorders in children. This study will help health care workers in resource-poor settings within Pakistan to be mindful of the common neurological disorders while diagnosing a child with neurological symptoms in an outpatient setting. Health care providers need to be trained to identify and treat these common conditions; however, there is still a dire need for more trained neurologists across the country., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Due to their constituent powders, the materials of advanced compressed oral solid dosage (OSD) forms are micro-composites and strongly visco-elastic at macro- and micro-length scales. The disintegration, drug release, and mechanical strength of OSD forms depend on its micro-texture (such as porosity) and micro-scale physical/mechanical properties. In the current work, an algorithmic ultrasonic characterization framework for extracting the micro-visco-elastic properties of OSD materials is presented, and its applicability is demonstrated with a model material. The proposed approach is based on the effect of visco-elasticity and granularity on the frequency-dependent attenuation of an ultrasonic wave pulse in a composite (granular) and viscous medium. In modeling the material, a two-parameter Zener model for visco-elasticity and a scattering attenuation mechanism based on Rayleigh scattering for long-wave approximation are employed. A novel linear technique for de-coupling the effects of micro-visco-elasticity and scattering on attenuation and dispersion is developed and demonstrated. The apparent Young's modulus, stress, and strain relaxation time constants of the medium at micro-scale are extracted and reported. Based on this modeling and analysis framework, a set of computational algorithms has been developed and demonstrated with experimental data, and its practical utility in pharmaceutical manufacturing and real-time release testing of tablets is discussed., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Objectives: The aim of this study was to determine the hematological changes associated with heat exposure in a population of bakers., Materials and Methods: Personal information was collected using a questionnaire, and a venous blood sample was drawn at the end of a work shift from the bakers and from a control group. The average wet-bulb globe temperature (WBGT) index was measured in the workplaces of both the bakers and the controls., Results: This cross-sectional study involved 137 bakers working in 20 bakeries and 107 controls who were comparable in terms of likely confounding factors. Hemoglobin and platelet values were abnormal among the bakers and statistically significantly different to the control group (P = 0.026, and P = 0.016 respectively). The average WBGT index in the bakeries was 37.4°C, while the average WBGT in the workplaces of the controls was 25.5°C, (P<0.0001)., Conclusions: The changes in the bakers' hematological parameters were found to be associated with exposure to high environmental heat at bakeries, as measured by the WBGT index. Preventive measures should be introduced to reduce the adverse effect of heat exposure among bakers and directed toward the worker-equipment-environment triad., Competing Interests: The authors have declared that no competing interests exist.

(1) Background: The monkeypox virus (MPV) is a double-stranded DNA virus belonging to the Poxviridae family, Chordopoxvirinae subfamily, and Orthopoxvirus genus. It was called monkeypox because it was first discovered in monkeys, in a Danish laboratory, in 1958. However, the actual reservoir for MPV is still unknown. (2) Methods and Results: We have reviewed the existing literature on the options for Monkeypox virus. There are three available vaccines for orthopoxviruses-ACAM2000, JYNNEOS, and LC16-with the first being a replicating vaccine and the latter being non- or minimally replicating. (3) Conclusions: Smallpox vaccinations previously provided coincidental immunity to MPV. ACAM2000 (a live-attenuated replicating vaccine) and JYNNEOS (a live-attenuated, nonreplicating vaccine) are two US FDA-approved vaccines that can prevent monkeypox. However, ACAM2000 may cause serious side effects, including cardiac problems, whereas JYNNEOS is associated with fewer complications. The recent outbreaks across the globe have once again highlighted the need for constant monitoring and the development of novel prophylactic and therapeutic modalities. Based on available data, there is still a need to develop an effective and safe new generation of vaccines specific for monkeypox that are killed or developed into a mRNA vaccine before monkeypox is declared a pandemic.

Despite a well-established process understanding, quality issues for compressed oral solid dosage forms are frequently encountered during various drug product development and production stages. In the current work, a non-destructive contact ultrasonic experimental rig integrated with a collaborative robot arm and an advanced vision system is presented and employed to quantify the effect of the shape of a compressed tablet on its mechanical properties. It is observed that these properties are affected by the tablet geometric shapes and found to be linearly sensitive to the compaction pressures. It is demonstrated that the presented approach significantly improves the repeatability of the experimental waveform acquisition. In addition, with the increased confidence levels in waveform acquisition accuracy and corresponding pressure and shear wave speeds due to improved measurement repeatability, we conclude that pharmaceutical compact materials can indeed have a negative Poisson's ratio, therefore can be auxetic. The presented technique and instrument could find critical applications in continuous tablet manufacturing, and its real-time quality monitoring as measurement repeatability has been significantly improved, minimizing product quality variations., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Musculoskeletal disorders (MSDs) affecting healthcare workers (HCWs) must be considered and addressed as a serious issue. Thus, it is important to incorporate ergonomics into clinical practice to prevent MSDs. The objectives of this study were to investigate HCWs' knowledge, attitudes, and practices regarding ergonomics in a large governmental healthcare facility., Methods: A cross-sectional study was conducted in which the participants were interviewed to complete a validated four-section questionnaire (demographic data, knowledge, attitudes, and practice information related to ergonomics). The questionnaire was newly self-developed based on a literature review and was pilot tested after development., Results: This study included 273 HCWs. Their average knowledge score regarding ergonomics was 2.6, or "fair to good." Overall, the participants reported good attitude scores, with a total average score of 1 and 2, or "agree to strongly agree." The findings also indicated that appropriate ergonomics practices were often not implemented, as the average practice score was 1 to 2, or "always to sometimes engaging in bad practice." The risk factors of being Saudi, being a woman, and having low academic achievement were associated with poor knowledge, attitudes, and practices related to ergonomics among HCWs., Conclusion: This study showed that the majority of the participants had fair knowledge and good attitudes toward ergonomics at work while practicing. However, the practice of ergonomics at work was not implemented. It is important to apply ergonomics at work to prevent MSDs; therefore, ergonomic principles should be included in the undergraduate health curriculum for all HCWs, with emphasis on practicing ergonomics in their routine clinical work., Competing Interests: The authors report no conflicts of interest in relation to this work., (© 2022 ALHazim et al.)