The clinical significance of long non-coding RNAs MALAT1 and CASC2 in the diagnosis of HCV-related hepatocellular carcinoma.

BACKGROUND: Globally, hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death due to a lack of early predictive and/or diagnostic tools. Thus, research for a new biomarker is important. LncRNAs play a functional role in target gene regulation and their deregulation is associated with several pathological conditions including HCC. OBJECTIVE: This study aimed to explore the diagnostic potential of two LncRNAs MALAT1 and CASC2 in HCC compared to the routinely used diagnostic biomarker. MATERIALS AND METHODS: The current study is a case-control study carried out at Fayoum University Hospital and conducted on 89 individuals. The study included three groups of 36 HCC patients on top of HCV(HCC/HCV), 33 HCV patients, and 20 healthy volunteers as a control group. All study subjects were subjected to radiological examinations. The determination of CBC was performed by the automated counter and liver function tests by the enzymatic method were performed. In addition, HCV RNA quantification and the expression level of two LncRNAs (MALAT1 and CASC2) were performed by qRT-PCR. RESULTS: The results revealed a statistically significant difference between study groups regarding liver function tests with a higher mean in HCC/HCV group. Also, serum MALAT1 significantly up-regulated in HCV (11.2±2.8) and HCC/HCV (4.56±1.4) compared to the control group. Besides, serum CASC2 levels in the HCV group were significantly upregulated (14.9±3.6), while, downregulated in the HCC group (0.16± 0.03). Furthermore, The ROC analysis for diagnostic efficacy parameters indicated that CASC2 has higher accuracy (94.6%) and sensitivity (97.2%) for HCC diagnosis than AFP with an accuracy of (90.9%), sensitivity (69.4%), and MALAT1 showed an accuracy of (56.9%), sensitivity (72.2%). CONCLUSION: Our study results indicated that CASC2 is a promising biomarker and is considered better and could help in HCC diagnosis on top of HCV than MALAT1 and the routine biomarker AFP.

Retrieval of a Missing Translocated Intrauterine Contraceptive Device Using Combined Laparoscopic and Cystoscopic Techniques.

Background: Intrauterine contraceptive devices (IUCDs) are considered to be an effective way of preventing unwanted pregnancies. However, one significant complication associated with IUCDs is uterine perforation especially at the time of insertion and could reach the peritoneal cavity and the viscus of the adjacent organs. Intravesical migration is extremely rare. Case Presentation. We report a 41-year-old woman who was diagnosed with IUCD intravesical migration after she presented to our hospital complaining of persistent lower urinary tract symptoms. Laparoscopic removal was done after the failure of cystoscopic extraction. Conclusion: The IUCD must be monitored continuously by the gynaecologist, and suspicions of intravesical migration must be considered in those presenting with persistent, unexplained lower urinary tract symptoms.

The Use of Thoracic Segmental Spinal Anaesthesia for Thoracoscopic Diaphragmatic Hernia Repair in an Adult With Cardiac Compromise.

Morgagni hernias are uncommon diaphragmatic defects and are commonly found incidentally as a congenital defect. Acquired Morgagni hernias have been documented in the pediatric population, making them extremely uncommon. Thoracic segmental spinal anesthesia (TSSA) may be used as a successful substitute for general anesthesia, especially in cardiovascularly compromised patients like our patient who had heart failure with reduced ejection fraction (HFrEF), and this is one of the very few documented cases of acquired Morgagni hernia laparoscopic repair surgery done by this anesthesia method. An 80-year-old woman presented with a complaint of left lower chest and left upper quadrant pain. Acute coronary artery syndrome was ruled out. She underwent a coronary artery bypass graft in 2009, complicated two months later by mediastinitis, which is believed to be the cause of the acquired diaphragmatic defect in our patient. Chest and abdominal CT showed a large anterior Morgagni-type diaphragmatic hernia, in which the left hemithorax and anterior mediastinum were both occupied by a herniated transverse colon. Under regional anesthesia, which was done by injecting anesthesia in the spinal space between thoracic spinal vertebrae T8 and T9 and second injections in the epidural space at the level between thoracic epidural T9 and T10, which is neuraxial anesthesia. The repair of the diaphragmatic hernia was done by suturing the mesh into the proper position. We report the first known case of laparoscopic repair of a Morgagni hernia in an adult patient with HFrEF and other comorbidities.

Mid-infrared Imaging Using Strain-Relaxed Ge1-xSnx Alloys Grown on 20 nm Ge Nanowires.

Germanium-tin (Ge1-xSnx) semiconductors are a front-runner platform for compact mid-infrared devices due to their tunable narrow bandgap and compatibility with silicon processing. However, their large lattice parameter has been a major hurdle, limiting the quality of epitaxial layers grown on silicon or germanium substrates. Herein, we demonstrate that 20 nm Ge nanowires (NWs) act as effective compliant substrates to grow extended defect-free Ge1-xSnx alloys with a composition uniformity over several micrometers along the NW growth axis without significant buildup of the compressive strain. Ge/Ge1-xSnx core/shell NWs with Sn content spanning the 6-18 at. % range are achieved and processed into photoconductors exhibiting a high signal-to-noise ratio at room temperature with a cutoff wavelength in the 2.0-3.9 µm range. The processed NW devices are integrated in an uncooled imaging setup enabling the acquisition of high-quality images under both broadband and laser illuminations at 1550 and 2330 nm without the lock-in amplifier technique.

Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

Assessment of long noncoding RNA CCAT1 using real time-polymerase chain reaction in colorectal cancer patients.

Colorectal cancer (CRC) is linked to high mortality, mainly when discovered in its advanced stages. Several studies have pointed to the role of epigenetic factors in CRC and other cancers. Long non-coding RNAs (lncRNAs) are involved in the initiation, progression, metastasis, and modulation of the response to chemotherapeutic modalities of CRC as vital contributors to epigenetic mechanisms. Colon cancer-associated transcript-1 (CCAT1) is one of the lncRNAs that have been dysregulated in serum samples, providing a non-invasive route for diagnosing CRC patients. This study aimed to determine the role of CCAT1 expression as diagnostic and prognostic markers. We tested the associations of CCAT1 expression with serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). The study included three groups: 41 patients with colorectal cancer, 39 patients with precancerous benign colorectal diseases, and 20 normal control individuals. CEA and CA 19-9 were measured by an immunoassay automated system. The expression level of CCAT1 was assessed by a real-time polymerase chain reaction. There was a statistically significant elevation of serum CEA levels in patients with CRC compared to patients with precancerous benign colorectal diseases. Furthermore, there was no statistically significant difference in serum CA 19-9 levels between all groups (p = 0.102). Interestingly, CCAT1 expression was significantly upregulated in the blood of CRC patients compared to the precancerous benign colorectal diseases group (p = 0.009) and the control group (p <0.001). Also, expression of CCAT1 was significantly elevated in patients with precancerous benign colorectal diseases compared to the control group (p=0.004). In conclusion, measuring the expression level of CCAT1 is more advised than assessment of CEA and CA 19-9 for the early diagnosis and prognosis of colorectal cancer.

Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder resulting from pathogenic variants in three distinct genes, with most of the variants occurring in the electron transfer flavoprotein-ubiquinone oxidoreductase gene (ETFDH). Recent evidence of potential founder variants for MADD in the South African (SA) population, initiated this extensive investigation. As part of the International Centre for Genomic Medicine in Neuromuscular Diseases study, we recruited a cohort of patients diagnosed with MADD from academic medical centres across SA over a three-year period. The aim was to extensively profile the clinical, biochemical, and genomic characteristics of MADD in this understudied population. METHODS: Clinical evaluations and whole exome sequencing were conducted on each patient. Metabolic profiling was performed before and after treatment, where possible. The recessive inheritance and phase of the variants were established via segregation analyses using Sanger sequencing. Lastly, the haplotype and allele frequencies were determined for the two main variants in the four largest SA populations. RESULTS: Twelve unrelated families (ten of White SA and two of mixed ethnicity) with clinically heterogeneous presentations in 14 affected individuals were observed, and five pathogenic ETFDH variants were identified. Based on disease severity and treatment response, three distinct groups emerged. The most severe and fatal presentations were associated with the homozygous c.[1067G > A];c.[1067G > A] and compound heterozygous c.[976G > C];c.[1067G > A] genotypes, causing MADD types I and I/II, respectively. These, along with three less severe compound heterozygous genotypes (c.[1067G > A];c.[1448C > T], c.[740G > T];c.[1448C > T], and c.[287dupA*];c.[1448C > T]), resulting in MADD types II/III, presented before the age of five years, depending on the time and maintenance of intervention. By contrast, the homozygous c.[1448C > T];c.[1448C > T] genotype, which causes MADD type III, presented later in life. Except for the type I, I/II and II cases, urinary metabolic markers for MADD improved/normalised following treatment with riboflavin and L-carnitine. Furthermore, genetic analyses of the most frequent variants (c.[1067G > A] and c.[1448C > T]) revealed a shared haplotype in the region of ETFDH, with SA population-specific allele frequencies of < 0.00067-0.00084%. CONCLUSIONS: This study reveals the first extensive genotype-phenotype profile of a MADD patient cohort from the diverse and understudied SA population. The pathogenic variants and associated variable phenotypes were characterised, which will enable early screening, genetic counselling, and patient-specific treatment of MADD in this population.

A new (T-X[Formula: see text]) family of distributions: properties, discretization and estimation with applications.

In this paper, a new class of distributions called the T-X[Formula: see text] family of distributions for bounded-(0,1)-and unbounded-[Formula: see text]-supported random variables is suggested. Some special sub-models of the proposed family are utilized. A new sub-model is selected to be studied in details. The statistical properties of the suggested family including quantile function, moments, moment generating function, order statistics and Rényi entropy are discussed. The maximum likelihood method is provided to estimate the parameters of the distribution and a Monte Carlo simulation study is used. The discretized T-X[Formula: see text] family provided many sub-families and sub-models. In addition, eight real data sets are utilized to demonstrate the flexibility of the proposed continuous and discrete family's multiple sub models.

Possible Role of Netrin-1/Deleted in Colorectal Cancer/Vascular Endothelial Growth Factor Signaling Pathway in the Pathogenesis of Placenta Accreta Spectrum: A Case-control Study.

SUMMARY: Netrin-1, an epithelial-secreted protein, plays a key role in placental formation through the promotion of cytotrophoblast proliferation and placental vascular development. These effects are mediated through several receptors, including the deleted in colorectal cancer (DCC) receptor. Placenta accreta spectrum (PAS) is an exaggerated trophoblastic invasion into the uterine myometrium. The exact etiology is unknown, but it is believed that increased trophoblastic invasion, defect decidualization, and/or abnormal angiogenesis might play a role. Our study aimed to investigate the suggested role of macrophage-induced netrin-1/DCC/vascular endothelial growth factor (VEGF) signaling in PAS pathogenesis. A total of 29 women with PAS (as cases) and 29 women with normal pregnancies (as controls) were enrolled in the study. At delivery, placental tissues of both groups were collected and processed for the evaluation of placental netrin-1 level by enzyme-linked immunoassay technique and immunohistochemical analysis of tissue DCC receptor. Placental tissue netrin-1 level of PAS cases showed a statistically significantly higher value than those in the normal group. Significant overexpression of DCC receptors, VEGF, and enhanced macrophage recruitment was noted in PAS cases in comparison to the normal placenta. Macrophage-induced netrin-1/DCC/VEGF signaling might be involved in PAS pathogenesis through the enhancement of trophoblastic angiogenesis.

Extrinsic Calibration of Thermal Camera and 3D LiDAR Sensor via Human Matching in Both Modalities during Sensor Setup Movement.

LiDAR sensors, pivotal in various fields like agriculture and robotics for tasks such as 3D object detection and map creation, are increasingly coupled with thermal cameras to harness heat information. This combination proves particularly effective in adverse conditions like darkness and rain. Ensuring seamless fusion between the sensors necessitates precise extrinsic calibration. Our innovative calibration method leverages human presence during sensor setup movements, eliminating the reliance on dedicated calibration targets. It optimizes extrinsic parameters by employing a novel evolutionary algorithm on a specifically designed loss function that measures human alignment across modalities. Our approach showcases a notable 4.43% improvement in the loss over extrinsic parameters obtained from target-based calibration in the FieldSAFE dataset. This advancement reduces costs related to target creation, saves time in diverse pose collection, mitigates repetitive calibration efforts amid sensor drift or setting changes, and broadens accessibility by obviating the need for specific targets. The adaptability of our method in various environments, like urban streets or expansive farm fields, stems from leveraging the ubiquitous presence of humans. Our method presents an efficient, cost-effective, and readily applicable means of extrinsic calibration, enhancing sensor fusion capabilities in the critical fields reliant on precise and robust data acquisition.

Antimicrobial therapy in the management of odontogenic infections: the penicillin-allergic patient.

This retrospective analysis was performed to investigate whether clindamycin remains the preferred antibiotic for penicillin-allergic patients with odontogenic infections. The medical records of 311 patients admitted to the study department with odontogenic infections between 2018 and 2022 and treated with either intravenous amoxicillin-clavulanic acid (Augmentin) or intravenous clindamycin were analyzed. The Augmentin-treated group included 268 patients (86.2%) and the clindamycin-treated group included 43 patients (13.8%). Severity parameters did not differ significantly between the two groups, except for a higher prevalence of abscesses in the clindamycin-treated group (58.1% vs 41.0% in the Augmentin-treated group; P = 0.035). The clindamycin-treated group required a longer duration of intravenous antibiotics (P = 0.001) and had a higher rate of treatment failure (14.0% vs 2.2%; P = 0.002) when compared to the Augmentin-treated group, with a seven-fold increased risk of treatment failure. Moreover, significantly more isolated organisms in the clindamycin-treated group were resistant to clindamycin (P = 0.015); these were all Streptococcus anginosus group. Given the higher risk of treatment failure with clindamycin, it is necessary to choose the antibiotic treatment for penicillin-allergic patients carefully. A detailed history and allergy testing followed by combination therapy is recommended, especially in severe cases.

Adiponectin rs1501299 and chemerin rs17173608 gene polymorphism in children with type 1 diabetes mellitus: relation with macroangiopathy and peripheral artery disease.

AIM: Although macrovascular complications represent the leading cause of mortality in type 1 diabetes mellitus (T1DM), the prevalence of subtle macrovascular affection including peripheral artery disease (PAD) among children with T1DM and its genetic predictors remains to be unraveled. Increasing evidence suggests a link between adiponectin rs1501299 and chemerin rs17173608 gene polymorphism and atherogenesis, and insulin resistance. Hence, this study assess the prevalence of these variants among children with T1DM in comparison to healthy controls and their association with macrovascular complications, namely PAD and hyperlipidemia. METHODS: Fifty children with T1DM and 50 matched controls underwent a thorough assessment including adiponectin rs1501299 and chemerin rs17173608 gene polymorphisms, fasting lipids, glycated hemoglobin (HbA1c), and ankle-brachial index (ABI). Cochran-Armitage trend test was used to decide the risk allele and evaluate the association between the candidate variant and PAD using a case-control design. RESULTS: Children with T1DM were found to have significantly higher ABI (p = 0.011) than controls. Chemerin gene polymorphism was detected in 41 children with T1DM (82.0%), while adiponectin gene polymorphism was detected in 19 children (38.0%). Children with T1DM having GG chemerin variant and those having TT adiponectin variant had significantly higher cholesterol with significantly lower HDL-C and ABI than those having the other two variants (p < 0.005). Children with T1DM having abnormal ABI had significantly higher chemerin G (p = 0.017) and adiponectin T (p = 0.022) alleles than those with normal ABI. Cholesterol and ABI were independently associated with chemerin and adiponectin gene polymorphism by multivariable regression analysis. CONCLUSION: Children with T1DM having chemerin and adiponectin gene polymorphisms have significantly higher cholesterol and ABI than those without these polymorphisms and controls. TRIAL REGISTRATION: The Research Ethics Committee of Ain Shams University, approval number R 31/2021.

The Ideal Interval Between Repeated Shockwaves Lithotripsy Sessions for Renal Stones: A Randomized Controlled Trial.

Objectives: To assess the ideal interval between repeated extracorporeal shockwave lithotripsy (SWL) for renal stones. Patient and Methods: Eligible patients with a single renal stone ≤20 mm who required SWL were randomly assigned to one of three groups based on intervals between first and second sessions. Patients underwent the second session after 3, 7, and 14 days in Groups 1, 2, and 3, respectively. Tubular functions were assessed through comparisons of urinary execration of kidney injury molecule-1 (KIM-1), neutrophil gelatinase associated lipocalin (NGAL), and interleukin-18 (IL-18) with pre-SWL values, whereas glomerular function was assessed by comparisons of protein/creatinine ratio with pre-SWL and changes in ipsilateral renal function on isotope scans. Treatment success was assessed by noncontrast CT after 3 months. Results: All demographics of the 166 patients included in the study were comparable between the three groups. There were significant elevations of tubular biomarkers and protein/creatinine ratio after first and second SWL sessions compared with pre-SWL values (p < 0.0001). All tubular biomarkers returned to pre-SWL values at 7 and 14 days after second session, whereas they remained significantly elevated 3 days after second session (p = 0.027, < 0.001 and <0.001 for KIM-1, NGAL, and IL-18, respectively). SWL success was 73.6% in Group 1, 83.7% in Group 2, and 81% in Group 3. A significant decrease in ipsilateral renal split function was observed in Group 1 at the 3-month follow-up. Conclusions: An interval of 7 days is required between SWL sessions when treating renal stones to allow for complete recovery of kidney functions. Clinical Trial Registration: ID: NCT04575480.

Dorsal inlay inner preputial graft repair versus ventral-only preputial graft repair in primary distal penile hypospadias with narrow urethral plate.

Background: Tubularized incised plate (TIP) is the most common technique used for distal hypospadias repair with good outcome but with a high rate of urethral stricture. Inner preputial-free graft can be used as an inlay graft in the incised area of the narrow urethral plate, also can be used as an onlay graft for urethroplasty in hypospadias repair to avoid this complication. Patients and Methods: A comparative prospective randomized study was conducted on two groups of hypospadias patients with narrow urethral plate. Group A: dorsal inlay inner preputial graft repair was performed (grafted TIP [G-TIP]) and Group B: ventral onlay preputial graft repair was performed. The assessment of outcome and hypospadias objective scoring evaluation (HOSE) score was done at 2 weeks and 6 months. Results: Group A included 55 patients for whom dorsal inlay inner preputial graft repair was performed (G-TIP), and Group B which was planned to be conducted on 55 patients using onlay preputial graft (onlay graft) but was terminated after 15 cases due to high failure rate (33%). Group A showed better success rate 96% and better HOSE score (score 16) at 2 months and 6 months 83.6% and 88.2% versus 26.7% and 33.3% in Group B. Postoperative complications showed a statistically significant difference; glans dehiscence (3.6% vs. 40%), wound infection (1.8% vs. 33.3%), and skin sloughing (3.6% vs. 26.7%) in Groups A and B, respectively. Conclusion: G-TIP is a good technique for the management of distal hypospadias with narrow urethral plate with good success rate, cosmetic outcome, and with less complications compared to onlay graft.

Body metrics are associated with clinical, free-living, and self-report measures of mobility in a cohort of adults with obesity and multiple sclerosis.

BACKGROUND: Obesity is associated with multiple sclerosis (MS) onset and may contribute to more rapid disability accumulation. Whether obesity impacts mobility in MS is uncertain. Some studies find that obesity in MS is associated with poorer mobility; other studies find no relationship. Discrepant findings may be due to differences in measurement and methodology. In the present study, we employ a comprehensive battery of anthropometric and mobility measures in a sample of people with MS and obesity. METHODS: Participants with MS (N = 74) completed a battery of adiposity measurements (weight, height, waist circumference, and full body dual-energy x-ray absorptiometry [DXA] scans). They also completed validated clinical, free-living (accelerometry), and self-report measures of mobility. Spearman's Rho correlations were used to examine the associations between mobility and obesity measures with Benjamini and Hochberg correction for multiple comparisons. Multiple linear regression was used to examine if adiposity predicted mobility outcomes in people with MS when controlling for age and disease duration. RESULTS: The majority of participants (n = 70) were diagnosed with relapsing-remitting MS and reported mild MS-related disability on the Patient Determined Disease Steps (M = 0.77, SD = 1.1). Median BMI was 35.8 (SD = 5.4). Higher percentage body fat (measured via DXA) was associated with poorer self-reported physical functioning (rs = -0.52, p <0.001), less moderate-to-vigorous physical activity (rs = -0.24, p = 0.04), and worse performance on the Six Minute Walk Test (6MWT; rs = -0.44, p <0.001), the Timed 25 Foot Walk (T25FW; rs = 0.45, p <0.001), and the Timed Up and Go test (TUG; rs = 0.35, p = .003). Higher BMI and waist-to-height ratio (WtHR) were associated with worse outcomes on the 6MWT (BMI; rs = -0.35, p <0.01, WtHR; rs = -0.43, p <0.001), T25FW (BMI; rs = 0.32, p <0.01, WtHR; rs = 0.38, p <0.001), and the SF-36 (BMI; rs = -0.29, p <0.005, WtHR; rs = -0.31, p <0.05). Percentage body fat accounted for an additional 17 % of the variance in the T25FW and 6MWT performance, after controlling for age and disease duration. CONCLUSION: Higher BMI, WtHR, and percentage body fat were associated with lower levels of mobility (T25FW and 6MWT) in people with MS who have class I, class II, and class III obesity. Higher percentage body fat was associated with significantly worse performance on clinical, free-living, and self-report measures of mobility in people with MS even when accounting for participant age and disease duration. These findings suggest that people with MS and obesity may show improved mobility with weight loss.

Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused by IFT74 mutations.

Ciliopathies are inherited disorders caused by defective cilia. Mutations affecting motile cilia usually cause the chronic muco-obstructive sinopulmonary disease primary ciliary dyskinesia (PCD) and are associated with laterality defects, while a broad spectrum of early developmental as well as degenerative syndromes arise from mutations affecting signalling of primary (non-motile) cilia. Cilia assembly and functioning requires intraflagellar transport (IFT) of cargos assisted by IFT-B and IFT-A adaptor complexes. Within IFT-B, the N-termini of partner proteins IFT74 and IFT81 govern tubulin transport to build the ciliary microtubular cytoskeleton. We detected a homozygous 3-kb intragenic IFT74 deletion removing the exon 2 initiation codon and 40 N-terminal amino acids in two affected siblings. Both had clinical features of PCD with bronchiectasis, but no laterality defects. They also had retinal dysplasia and abnormal bone growth, with a narrowed thorax and short ribs, shortened long bones and digits, and abnormal skull shape. This resembles short-rib thoracic dysplasia, a skeletal ciliopathy previously linked to IFT defects in primary cilia, not motile cilia. Ciliated nasal epithelial cells collected from affected individuals had reduced numbers of shortened motile cilia with disarranged microtubules, some misorientation of the basal feet, and disrupted cilia structural and IFT protein distributions. No full-length IFT74 was expressed, only truncated forms that were consistent with N-terminal deletion and inframe translation from downstream initiation codons. In affinity purification mass spectrometry, exon 2-deleted IFT74 initiated from the nearest inframe downstream methionine 41 still interacts as part of the IFT-B complex, but only with reduced interaction levels and not with all its usual IFT-B partners. We propose that this is a hypomorphic mutation with some residual protein function retained, which gives rise to a primary skeletal ciliopathy combined with defective motile cilia and PCD.

Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Synergistic Effects of Kaolin and Silicon Nanoparticles for Ameliorating Deficit Irrigation Stress in Maize Plants by Upregulating Antioxidant Defense Systems.

Water deficit is a significant environmental stress that has a negative impact on plant growth and yield. In this research, the positive significance of kaolin and SiO2 nanoparticles in moderating the detrimental effects of water deficit on maize plant growth and yield is investigated. The foliar application of kaolin (3 and 6%) and SiO2 NPs (1.5 and 3 mM) solutions increased the growth and yield variables of maize plants grown under normal conditions (100% available water) and drought stress conditions (80 and 60% available water (AW)). In addition, plants treated with SiO2 NPs (3 mM) demonstrated increased levels of important osmolytes, such as proline and phenol, and maintained more of their photosynthetic pigments (net photosynthetic rate (PN), stomatal conductance (gs), intercellular CO2 concentration (Ci), and transpiration rate (E)) than with other applied treatments under either stress or non-stress conditions. Furthermore, the exogenous foliar application of kaolin and SiO2 NPs also reduced the amounts of hydroxyl radicals (OH), superoxide anions (O2), hydrogen peroxide (H2O2), and lipid peroxidation in maize plants experiencing a water deficit. In contrast, the treatments led to an increase in the activity of antioxidant enzymes such as peroxidase (POX), ascorbate peroxidase (APX), glutathione peroxidase (GR), catalase (CAT), and superoxide dismutase (SOD). Overall, our findings indicate the beneficial impact of the application of kaolin and silicon NPs, particularly the impact of SiO2 NPs (3 mM) on managing the negative, harmful impacts of soil water deficit stress in maize plants.