Integrative Drug Screening and Multiomic Characterization of Patient-derived Bladder Cancer Organoids Reveal Novel Molecular Correlates of Gemcitabine Response.

BACKGROUND AND OBJECTIVE: Predicting response to therapy for each patient's tumor is critical to improving long-term outcomes for muscle-invasive bladder cancer. This study aims to establish ex vivo bladder cancer patient-derived organoid (PDO) models that are representative of patients' tumors and determine the potential efficacy of standard of care and curated experimental therapies. METHODS: Tumor material was collected prospectively from consented bladder cancer patients to generate short-term PDO models, which were screened against a panel of clinically relevant drugs in ex vivo three-dimensional culture. Multiomic profiling was utilized to validate the PDO models, establish the molecular characteristics of each tumor, and identify potential biomarkers of drug response. Gene expression (GEX) patterns between paired primary tissue and PDO samples were assessed using Spearman's rank correlation coefficients. Molecular correlates of therapy response were identified using Pearson correlation coefficients and Kruskal-Wallis tests with Dunn's post hoc pairwise comparison testing. KEY FINDINGS AND LIMITATIONS: A total of 106 tumors were collected from 97 patients, with 65 samples yielding sufficient material for complete multiomic molecular characterization and PDO screening with six to 32 drugs/combinations. Short-term PDOs faithfully represent the tumor molecular characteristics, maintain diverse cell types, and avoid shifts in GEX-based subtyping that accompany long-term PDO cultures. Utilizing an integrative approach, novel correlations between ex vivo drug responses and genomic alterations, GEX, and protein expression were identified, including a multiomic signature of gemcitabine response. The positive predictive value of ex vivo drug responses and the novel multiomic gemcitabine response signature need to be validated in future studies. CONCLUSIONS AND CLINICAL IMPLICATIONS: Short-term PDO cultures retain the molecular characteristics of tumor tissue and avoid shifts in expression-based subtyping that have plagued long-term cultures. Integration of multiomic profiling and ex vivo drug screening data identifies potential predictive biomarkers, including a novel signature of gemcitabine response. PATIENT SUMMARY: Better models are needed to predict patient response to therapy in bladder cancer. We developed a platform that uses short-term culture to best mimic each patient's tumor and assess potential sensitivity to therapeutics.

Spectral and conductivity measurements insights on loading mechanisms of DMSO/water-kaolin complexes.

Kaolin, a naturally occurring clay mineral renowned for its distinctive properties, holds significant importance across various industries. The integration of dimethyl sulfoxide (DMSO) into kaolin matrices, both in the presence and absence of water, has been extensively explored for its potential to enhance material characteristics. Addressing debates surrounding the proposed adsorption mechanism for the type I structure of DMSO, this study undertook a comprehensive physicochemical characterization of DMSO-kaolin complexes (DMSO-KCs) derived from untreated (UnK) and HCl-treated (HK) Egyptian ore, with a focus on elucidating the loading mechanism facilitated by water. Key insights gleaned from electrical conductivity, dielectric constant, and Fine Testing Technology - Fourier-transform infrared (FTT-FTIR) measurements, shedding light on the bonding nature of DMSO-KCs. FTT-FTIR analysis revealed two stages of water departure at 180 °C, with the final stage coinciding with the release of pyrolysis gases, confirming the catalytic degradation of DMSO. Through X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA), two distinct bonding types of DMSO molecules with kaolinite were identified: amorphous adsorbed (type I) and lattice-oriented intercalated (type II). Electrical characteristic evaluations within the temperature range of room temperature (RT) to 260 °C and frequency range of 42 Hz-1 MHz revealed that DMSO intercalation enhances the electrical properties of kaolin. Hydrated DMSO-KCs exhibited higher values of σac and ɛ' compared to non-hydrated samples. The activation energy (Ea) values for HCl-treated samples were smaller than those of untreated ones. Alternating current (AC) conductivity analysis indicated predominantly ionic behavior with frequency and temperature dependency in both HCl-treated and untreated kaolin. Our findings substantiate the adsorption mechanism of Type I DMSO, highlighting its amorphous nature, instability, and catalytic degradation over time, in contrast to the intercalated type II. This elucidation is pivotal for understanding the behavior of DMSO-KCs across diverse applications, including electronics, ceramics, and materialsscience.

Distinct inflammatory markers in primary and secondary dengue infection: can cytokines CXCL5, CXCL9, and CCL17 act as surrogate markers?

Dengue fever poses a significant global health threat, with symptoms including dengue hemorrhagic fever and dengue shock syndrome. Each year, India experiences fatal dengue outbreaks with severe manifestations. The primary cause of severe inflammatory responses in dengue is a cytokine storm. Individuals with a secondary dengue infection of a different serotype face an increased risk of complications due to antibody-dependent enhancement. Therefore, it is crucial to identify potential risk factors and biomarkers for effective disease management. In the current study, we assessed the prevalence of dengue infection in and around Aligarh, India, and explored the role of cytokines, including CXCL5, CXCL9, and CCL17, in primary and secondary dengue infections, correlating them with various clinical indices. Among 1,500 suspected cases, 367 tested positive for dengue using Real-Time PCR and ELISA. In secondary dengue infections, the serum levels of CXCL5, CXCL9, and CCL17 were significantly higher than in primary infections (P < 0.05). Dengue virus (DENV)-2 showed the highest concentrations of CXCL5 and CCL17, whereas DENV-1 showed the highest concentrations of CXCL9. Early detection of these cytokines could serve as potential biomarkers for diagnosing severe dengue, and downregulation of these cytokines may prove beneficial for the treatment of severe dengue infections.

Apigenin: A Bioflavonoid with a Promising Role in Disease Prevention and Treatment.

Apigenin is a powerful flavone compound found in numerous fruits and vegetables, and it offers numerous health-promoting benefits. Many studies have evidenced that this compound has a potential role as an anti-inflammatory and antioxidant compound, making it a promising candidate for reducing the risk of pathogenesis. It has also been found to positively affect various systems in the body, such as the respiratory, digestive, immune, and reproductive systems. Apigenin is effective in treating liver, lung, heart, kidney, neurological diseases, diabetes, and maintaining good oral and skin health. Multiple studies have reported that this compound is capable of suppressing various types of cancer through the induction of apoptosis and cell-cycle arrest, suppressing cell migration and invasion, reduction of inflammation, and inhibiting angiogenesis. When used in combination with other drugs, apigenin increases their efficacy, reduces the risk of side effects, and improves the response to chemotherapy. This review broadly analyzes apigenin's potential in disease management by modulating various biological activities. In addition, this review also described apigenin's interaction with other compounds or drugs and the potential role of nanoformulation in different pathogeneses. Further extensive research is needed to explore the mechanism of action, safety, and efficacy of this compound in disease prevention and treatment.

MolDy: molecular dynamics simulation made easy.

MOTIVATION: Molecular dynamics (MD) is a computational experiment that is crucial for understanding the structure of biological macro and micro molecules, their folding, and the inter-molecular interactions. Accurate knowledge of these structural features is the cornerstone in drug development and elucidating macromolecules functions. The open-source GROMACS biomolecular MD simulation program is recognized as a reliable and frequently used simulation program for its precision. However, the user requires expertise, and scripting skills to carrying out MD simulations. RESULTS: We have developed an end-to-end interactive MD simulation application, MolDy for Gromacs. This front-end application provides a customizable user interface integrated with the Python and Perl-based logical backend connecting the Linux shell and Gromacs software. The tool performs analysis and provides the user with simulation trajectories and graphical representations of relevant biophysical parameters. The advantages of MolDy are (i) user-friendly, does not requiring the researcher to have prior knowledge of Linux; (ii) easy installation by a single command; (iii) freely available for academic research; (iv) can run with minimum configuration of operating systems; (v) has valid default prefilled parameters for beginners, and at the same time provides scope for modifications for expert users. AVAILABILITY AND IMPLEMENTATION: MolDy is available freely as compressed source code files with user manual for installation and operation on GitHub: https://github.com/AIBResearchMolDy/Moldyv01.git and on https://aibresearch.com/innovations.

Recent Updates of the CRISPR/Cas9 Genome Editing System: Novel Approaches to Regulate Its Spatiotemporal Control by Genetic and Physicochemical Strategies.

The genome editing approach by clustered regularly interspaced short palindromic repeats (CRISPR)/associated protein 9 (CRISPR/Cas9) is a revolutionary advancement in genetic engineering. Owing to its simple design and powerful genome-editing capability, it offers a promising strategy for the treatment of different infectious, metabolic, and genetic diseases. The crystal structure of Streptococcus pyogenes Cas9 (SpCas9) in complex with sgRNA and its target DNA at 2.5 Å resolution reveals a groove accommodating sgRNA:DNA heteroduplex within a bilobate architecture with target recognition (REC) and nuclease (NUC) domains. The presence of a PAM is significantly required for target recognition, R-loop formation, and strand scission. Recently, the spatiotemporal control of CRISPR/Cas9 genome editing has been considerably improved by genetic, chemical, and physical regulatory strategies. The use of genetic modifiers anti-CRISPR proteins, cell-specific promoters, and histone acetyl transferases has uplifted the application of CRISPR/Cas9 as a future-generation genome editing tool. In addition, interventions by chemical control, small-molecule activators, oligonucleotide conjugates and bioresponsive delivery carriers have improved its application in other areas of biological fields. Furthermore, the intermediation of physical control by using heat-, light-, magnetism-, and ultrasound-responsive elements attached to this molecular tool has revolutionized genome editing further. These strategies significantly reduce CRISPR/Cas9's undesirable off-target effects. However, other undesirable effects still offer some challenges for comprehensive clinical translation using this genome-editing approach. In this review, we summarize recent advances in CRISPR/Cas9 structure, mechanistic action, and the role of small-molecule activators, inhibitors, promoters, and physical approaches. Finally, off-target measurement approaches, challenges, future prospects, and clinical applications are discussed.

Ondansetron or beta-sitosterol antagonizes inflammatory responses in liver, kidney, lung and heart tissues of irradiated arthritic rats model.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder mainly affecting joints, yet the systemic inflammation can influence other organs and tissues. The objective of this study was to unravel the ameliorative capability of Ondansetron (O) or ß-sitosterol (BS) against inflammatory reactions and oxidative stress that complicates Extra-articular manifestations (EAM) in liver, kidney, lung, and heart of arthritic and arthritic irradiated rats. METHODS: This was accomplished by exposing adjuvant-induced arthritis (AIA) rats to successive weekly fractions of total body γ-irradiation (2 Gray (Gy)/fraction once per week for four weeks, up to a total dose of 8 Gy). Arthritic and/or arthritic irradiated rats were either treated with BS (40 mg/kg b.wt. /day, orally) or O (2 mg/kg) was given ip) or were kept untreated as model groups. RESULTS: Body weight changes, paw circumference, oxidative stress indices, inflammatory response biomarkers, expression of Janus kinase-2 (JAK-2), Signal transducer and activator of transcription 3 (STAT3), high mobility group box1 (HMGB1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), as well as pro- and anti-inflammatory mediators in the target organs, besides histopathological examination of ankle joints and extra-articular tissues. Treatment of arthritic and/or arthritic irradiated rats with BS or O powerfully alleviated changes in body weight gain, paw swelling, oxidative stress, inflammatory reactions, and histopathological degenerative alterations in articular and non-articular tissues. CONCLUSION: The obtained data imply that BS or O improved the articular and EAM by regulating oxidative and inflammatory indices in arthritic and arthritic irradiated rats.

Prevalence and Risk Factors of Cardiovascular Disease in Chronic Kidney Disease Patients at King Abdulaziz University Hospital (KAUH).

BACKGROUND: Chronic kidney disease (CKD) has emerged as a significant global health concern, with its incidence doubling over the past three decades. Cardiovascular diseases (CVD) pose a major threat to CKD patients, surpassing the risk of progressing to end-stage renal disease. While previous studies worldwide have shed light on this association, limited research has been conducted in Saudi Arabia regarding this burden. This study aims to fill this gap by identifying the prevalence and risk factors of CVD in CKD patients at King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia, between 2017 and 2022. METHODS: A six-year retrospective review of medical records at KAUH was conducted, including 465 non-end-stage CKD patients aged 30 to 79. Data, including demographics, clinical information, and laboratory results, were collected and statistically analyzed to investigate the association between variables. RESULTS: Out of 465 CKD patients, 262 (56.3%) were diagnosed with CVD, with congestive heart failure and ischemic heart disease being the most common types. The majority were male 259 (55.7%), non-Saudi 278 (59.8%), and aged 60 years and older 291 (62.6%). Hypertension 394 (84.7%) and diabetes mellitus 336 (72.3%) were prevalent comorbidities. Severely reduced left ventricular ejection fraction, proteinuria, diabetes mellitus, and higher BMI were identified as significant risk factors for CVD in CKD patients. CONCLUSION: This research contributes valuable insights into the prevalence and risk factors of CVD in CKD patients in Saudi Arabia, emphasizing the need for early detection and intervention. The identified risk factors provide a basis for developing targeted preventive strategies to mitigate this population's CVD burden.

Pathological Extramural Venous Invasion in High-stage Urothelial Carcinoma of the Bladder has Shorter Locoregional Recurrence-free Survival.

Extramural venous invasion is an independent prognostic factor in colorectal cancers; the pathological identification of extramural venous invasion in bladder cancer remains unclear. By focusing on high-stage urothelial carcinoma of the bladder, we provide insights into the pathological identification of extramural venous invasion in this particular clinical context. Clinical and demographic details and pathological reports were extracted from electronic medical records. Histological sections were reviewed for the pathological identification of extramural venous invasion. Statistical analysis was done using SPSS version 23 software. Survival analysis was done using Kaplan-Meier method. In patients with available follow-up data, 62% (n = 21) exhibited pathologically evidenced extramural venous invasion, whereas 38% (n = 13) did not. The extramural venous invasion positive group showed trends toward more advanced and pathological staging and a higher occurrence of extra-nodal extension. Positive margins were more frequent in the extramural venous invasion positive group (33%) compared to the extramural venous invasion negative group (8%). However, these differences were not statistically significant. Notably, all instances of recurrence were in the extramural venous invasion positive group of patients. The extramural venous invasion positive group of patients showed a significantly shorter locoregional recurrence-free survival (P-value of 0.045). However, extramural venous invasion did not emerge as a significant factor in univariate analyses for recurrence-free survival. These findings highlight the potential role of extramural venous invasion as a prognostic factor in bladder cancer but underscore the need for further research with larger cohorts to confirm its significance.

Cupping Therapy as a Potential Complimentary Treatment for Meniere's Disease: A Case Report.

Meniere's disease is defined by the presence of three essential symptoms: episodic vertigo, tinnitus, and sensorineural hearing loss. The mainstay of its management constitutes lifestyle modification and medical and surgical therapies. Cupping therapy is an ancient treatment that is still widely used especially in the Middle East, Africa, and the United Kingdom. This study portraits the case of a 54-year-old patient suffering from long-standing Meniere's disease. The patient was treated with the routine treatment that was to no avail. It was decided that the patient undergoes cupping therapy. Over two years of monthly cupping therapy sessions, the patient reported a decrease in intensity and frequency of symptoms until its disappearance. Cupping therapy has shown a positive outcome on the patient. According to our search, there is a previous case report published in 2020 that shares multiple similarities with our case. Further studies on cupping therapy and its efficacy, mechanism of action, and complications on a larger scale are advised.

A Retrospective Review of Seasonal Patterns of Idiopathic Facial Nerve Paralysis in a Tertiary Care Center.

Background The objective of this retrospective study was to investigate the seasonal patterns of idiopathic facial nerve paralysis, specifically Bell's palsy, in Riyadh, Saudi Arabia. The study aimed to determine if there is a correlation between cold weather and the incidence of Bell's palsy, as well as to examine the relationship between age, gender, comorbidities, and the development of the disease. Methodology Data were collected from King Abdulaziz Medical City in Riyadh, Saudi Arabia, between 2016 and 2021. Electronic medical records of adult patients diagnosed with idiopathic facial paralysis were reviewed. Patients with facial paralysis caused by known illnesses were excluded. Demographic information, clinical characteristics, and the course of the disease were analyzed using SPSS version 25 (IBM Corp., Armonk, NY, USA). Results The study included 136 Bell's palsy patients, with a mean age of 39.9 years. Males represented 58.1% (79) of the sample, and the right side of the face was more commonly affected in 71 (52.2%) patients. The majority of patients had House-Brackmann grade III (51, 37.5%). The monthly distribution showed a higher number of Bell's palsy cases during the winter months, particularly December, October, and November, but the seasonal distribution did not yield a statistically significant difference in incidence. Conclusions While this study observed a higher incidence of Bell's palsy during the winter months, it did not establish a statistically significant correlation between cold temperatures and the onset of Bell's palsy in Riyadh, Saudi Arabia. Furthermore, the study found that Bell's palsy predominantly affects middle-aged males, and comorbidities did not appear to be significant risk factors for the development of the disease. This research lays the groundwork for future investigations into the relationship between weather and the pathogenesis of Bell's palsy in the region.

Prediction of cardiovascular risk factors and metabolic syndrome in adults from Saudi Arabia using the logarithm of triglyceride/HDL-cholesterol ratio.

Objective: Cardiovascular diseases (CVD) are the leading cause of death globally. Metabolic syndrome (MtS) is a risk factor that increases the likelihood of CVD. The atherogenic index (AIP), calculated as the logarithm of the ratio of triglycerides (TG) to high-density lipoprotein cholesterol (HDL) cholesterol in plasma, is a valuable marker for highly atherogenic small dense low-density lipoprotein cholesterol particles. This study aimed to explore MtS prevalence and investigate the potential of using the AIP as a predictor for CVD risk factors in adults from the Qassim region of Saudi Arabia. Methods: The cross-sectional study enrolled 589 participants from public hospitals in nine major cities who completed a detailed questionnaire on health, diet, and lifestyle. Anthropometric measurements and some clinical parameters were measured. Results: The findings indicated a significant prevalence of MtS (37.5%) among participants from the Qassim Area, which was higher in males (39.9%) than females (34.9%). Nevertheless, a significant prevalence was shown for CVD risk factors among participants, with hyperglycemia (78.1%), hypertriglyceridemia (39.0%), hypo-HDL-cholesterolemia (38.9%), and hypertension (21.6%) being common. The AIP's performance in identifying CVD risk factors showed a receiver operating characteristic value of 0.909 (P < 0.001). The optimal cutoff value for the AIP was determined to be 0.468, demonstrating high sensitivity (84.8%) and specificity (78.6%). Conclusion: Incorporating AIP into clinical practice could enhance CVD risk prediction compared to using lipid profiles alone. These findings suggest that there is a high prevalence of MtS among adults in the Qassim region of Saudi Arabia. Further longitudinal studies are needed to recommend AIP as a robust tool for predicting CVD in clinical settings.

A M1 muscarinic acetylcholine receptor-specific positive allosteric modulator VU0486846 reduces neurogliosis in female Alzheimer's mice.

Alzheimer's disease (AD) is the most prevalent type of dementia, disproportionately affecting females, who make up nearly 60% of diagnosed cases. In AD patients, the accumulation of beta-amyloid (Aß) in the brain triggers a neuroinflammatory response driven by neuroglia, worsening the condition. We have previously demonstrated that VU0486846, an orally available positive allosteric modulator (PAM) targeting M1 muscarinic acetylcholine receptors, enhances cognitive function and reduces Aß pathology in female APPswe/PSEN1ΔE9 (APP/PS1) mice. However, it remained unclear whether these improvements were linked to a decrease in neuroglial activation. To investigate, we treated nine-month-old APP/PS1 and wildtype mice with VU0486846 for 8 weeks and analyzed brain slices for markers of microglial activation (ionized calcium binding adaptor molecule 1, Iba1) and astrocyte activation (Glial fibrillary acidic protein, GFAP). We find that VU0486846 reduces the presence of Iba1-positive microglia and GFAP-positive astrocytes in the hippocampus of female APP/PS1 mice and limits the recruitment of these cells to remaining Aß plaques. This study sheds light on an additional mechanism through which novel M1 mAChR PAMs exhibit disease-modifying effects by reducing neuroglial activation and underscore the potential of these ligands for the treatment of AD, especially in females.

Removal Efficiency and Effectiveness of Four Different Fiber Posts Using Five Different Drill Systems in Multirooted Teeth.

AIM: In comparing the effectiveness and efficiency of different types of post removal systems in removing different types of fiber posts (FPs), this study aims to shed light on the success of removal by currently available drill systems. MATERIALS AND METHODS: A total of 200 maxillary first molars, were root canal treated and prepared to receive posts. The molars were divided into four groups corresponding to four different FPs: Group RX, Radix FP; Group RF, Reforpost Glass Fiber; Group HI; Hi-Rem Endodontic Post; and Group DT, D.T. Light-Post Illusion X-RO. Fiber posts were done with luting by Gradia Core (GC America, Inc.). Groups were again divided into five subgroups corresponding to the technique by which the FP was removed into as follows: Subgroup P, PD-25-1.1 Drill; subgroup G, GC FP Drill; subgroup E, EasyPost Precision Drill; subgroup R, Reaccess Carbide Double Taper Kit; and subgroup H; H-Endodontic Drill. After posts were removed, effectiveness and efficiency were documented. Data were tabulated and statistically analyzed. RESULTS: Strong significant differences regarding efficiency among groups (FP type) and subgroups (drills used) (p = 0.00) were shown by the one-way analysis of variance (ANOVA) test. Subgroup DT-G scored the longest mean removal time (20.9 minutes) while Subgroup RX-R scored the shortest mean removal time (1.4 minutes) Regarding effectiveness, strong significant differences among groups (p = 0.00) and subgroups (p = 0.00) were shown by one-way ANOVA. Subgroup RF-G scored the highest scale (5.2) whereas subgroup HI-R scored the lowest mean scale (1.2). CONCLUSION: The difference was strongly significant between tested post-removal kits and between tested FPs. Re-access Carbide Double Taper Kit performed superiorly in both effectiveness and efficiency, followed by PD-25-1.1 Drill. Hi-Rem post showed the best retrieving results among other FPs. CLINICAL SIGNIFICANCE: Knowing the best technique and tools for post removal could spare the practitioner any unwanted complications during post removal. How to cite this article: Sayed M, Alahmad AM, Alhajji KS, et al. Removal Efficiency and Effectiveness of Four Different Fiber Posts Using Five Different Drill Systems in Multirooted Teeth. J Contemp Dent Pract 2024;25(1):72-78.

Anterior segment migration of intravitreal dexamethasone implant in a patient with scleral fixation intraocular lens implant: a case report.

Corticosteroids are crucial for treating inflammatory ocular conditions. The development of dexamethasone revolutionized targeted ocular therapy. Ozurdex, a dexamethasone implant, effectively treats various eye conditions but carries risks such as implant migration. This is a case of anterior segment migration of intravitreal dexamethasone implant, Ozurdex, in a patient with scleral fixation intraocular lens implant in whom conservative management with supine positioning and pharmacologic pupil dilation can help retain the implant back in the vitreous. Patients at high risk of Ozurdex migration should avoid its use. Educate patients on the risk of implant migration and signs of migration to present immediately to an ophthalmology emergency department to avoid corneal damage. It is essential to identify high-risk patients before considering Ozurdex migration. In some cases, conservative management can be initiated while preparing for surgical removal.

Modified versus Classical Tubularised Incised Plate Urethroplasty in Hypospadias: A Comparative Study.

BACKGROUND: Hypospadias is a wide-world congenital malformation that accounts for 1 of 300 live male births. Many procedures were considered for its management. As the tubularised incised plate (TIP) urethroplasty, the most prevalent technique, caused many complications, several modifications were applied to the original operation to improve the outcomes and alleviate complications. The aim of this study was to compare the outcome of the ordinary TIP urethroplasty with the technique modified without dissection of the glans penis. MATERIALS AND METHODS: A total of 82 patients with a mean age of 18.8 (±14.8) months, were randomly assigned to undergo TIP with either complete glans wings mobilisation (Group A, n = 42 patients) or without glans dissection (Group B, n = 40 patients). To evaluate the effect of modified TIP urethroplasty without glanular dissection for treatment of distal hypospadias in contrast to classical TIP repair. RESULTS: Both techniques showed similar outcomes regarding functional repair, with good to excellent results between 88% and 90% after 6 months of follow-up. Most confronted post-operative complications were wound infection, oedema, urethrocutaneous fistulas and meatal stenosis. Less frequently haematoma, post-operative bleeding and glans dehiscence were encountered. The differences in complication rates between the two studied groups were statistically insignificant except for oedema (P = 0.04), and need for urethral dilatation (P = 0.002) that were more prevalent among patients who were treated with classic TIP repair with complete glans wings mobilisation. CONCLUSION: From our point of view, it seems that TIP without glanular dissection technique does not outweigh TIP with complete glans wings mobilisation regarding functional outcomes and post-operative complications.

Reducing Time to Diagnosis of Autism Spectrum Disorder Using an Integrated Community Specialty Care Model: A Retrospective Study.

OBJECTIVE: To evaluate a fast-track triage model in an integrated community specialty clinic to reduce the age of diagnosis for patients with autism spectrum disorder (ASD). STUDY DESIGN: A retrospective chart review was performed for patients seen in an integrated community specialty pediatric practice using a fast-track screening and triage model. The percentage of ASD diagnoses, age at diagnosis, and time from referral to diagnosis were evaluated. The fast-track triage model was compared with national and statewide estimates of median age of first evaluation and diagnosis. RESULTS: From January 1, 2020, through December 31, 2021, 189 children with a mean (SD) age of 32.2 (12.4) months were screened in the integrated community specialty. Of these, 82 (43.4%) children were referred through the fast-track triage for further evaluation in the developmental and behavioral pediatrics (DBP) department, where 62 (75.6%) were given a primary diagnosis of ASD. Average wait time from referral to diagnosis using the fast-track triage model was 6 months. Mean (SD) age at diagnosis was 37.7 (13.5) months. The median age of diagnosis by the fast-track triage model was 33 months compared with the national and state median ages of diagnosis at 49 and 59 months, respectively. CONCLUSIONS: With the known workforce shortage in fellowship-trained developmental behavioral pediatricians, the fast-track triage model is feasible and maintains quality of care while resulting in more timely diagnosis, and reducing burden on DBP by screening out cases who did not require further multidisciplinary DBP evaluation as they were appropriately managed by other areas.

Recent Advances in Understanding the Molecular Mechanisms of Multidrug Resistance and Novel Approaches of CRISPR/Cas9-Based Genome-Editing to Combat This Health Emergency.

The rapid spread of multidrug resistance (MDR), due to abusive use of antibiotics has led to global health emergency, causing substantial morbidity and mortality. Bacteria attain MDR by different means such as antibiotic modification/degradation, target protection/modification/bypass, and enhanced efflux mechanisms. The classical approaches of counteracting MDR bacteria are expensive and time-consuming, thus, it is highly significant to understand the molecular mechanisms of this resistance to curb the problem from core level. The revolutionary approach of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated sequence 9 (CRISPR/Cas9), considered as a next-generation genome-editing tool presents an innovative opportunity to precisely target and edit bacterial genome to alter their MDR strategy. Different bacteria possessing antibiotic resistance genes such as mecA, ermB, ramR, tetA, mqrB and blaKPC that have been targeted by CRISPR/Cas9 to re-sensitize these pathogens against antibiotics, such as methicillin, erythromycin, tigecycline, colistin and carbapenem, respectively. The CRISPR/Cas9 from S. pyogenes is the most widely studied genome-editing tool, consisting of a Cas9 DNA endonuclease associated with tracrRNA and crRNA, which can be systematically coupled as sgRNA. The targeting strategies of CRISPR/Cas9 to bacterial cells is mediated through phage, plasmids, vesicles and nanoparticles. However, the targeting approaches of this genome-editing tool to specific bacteria is a challenging task and still remains at a very preliminary stage due to numerous obstacles awaiting to be solved. This review elaborates some recent updates about the molecular mechanisms of antibiotic resistance and the innovative role of CRISPR/Cas9 system in modulating these resistance mechanisms. Furthermore, the delivery approaches of this genome-editing system in bacterial cells are discussed. In addition, some challenges and future prospects are also described.

Insight into land cover dynamics and water challenges under anthropogenic and climatic changes in the eastern Nile Delta: Inference from remote sensing and GIS data.

The destabilization of delta's worldwide due to climate change and human activities presents challenges in meeting the growing demands for freshwater and food. The Nile Delta in Egypt is a prime example of a vulnerable region facing various stressors. In order to preserve land and water resources, it is crucial to monitor the spatial and temporal changes in Land Use/Land Cover (LULC), shoreline, and Terrestrial Water Storage (TWS) in these vulnerable regions This study comprehensively investigates the dynamic changes in LULC and their associated water and soil responses in the Eastern Nile Delta under these combined impacts. To achieve this goal, a combination of remote sensing techniques utilizing Landsat (5, 8, and 9), and GRACE datasets, along with field observations and Geographic Information System (GIS) tools, was employed. Accordingly, shoreline changes show coastal erosion rates ranging from 5.28 to 34.92 m/year due to climate change-induced SLR, with continued inland movement predicted for the next 20 years. Moreover, the dynamic changes in urbanization and alterations in agricultural cover have considerable penalties for water demand. Analysis of GRACE data indicates a notable reduction in average TWS by 77.89 mm between 2002 and 2017, with an annual rate, estimated at -5.821 mm/year. Soil sampling in highly vulnerable areas confirms agricultural degradation attributed to elevated salinity levels, with EC values ranging from 3.60 to 190 ds/m. These finds provide valuable insights for stakeholders and policymakers, to make reliable strategies regarding water allocation, land use regulations, and climate change adaptation in the worldwide vulnerable deltas.