Correction Of Defects Research Articles

Neuroimaging Applications for the Delivery and Monitoring of Gene Therapy for Central Nervous System Diseases.

Neurological disease due to single gene defects represents a targetable entity for adeno-associated virus (AAV) mediated gene therapy. The delivery of AAV-mediated gene therapy to the brain is challenging, owing to the presence of the blood-brain barrier. Techniques in gene transfer, such as convection-enhanced intraparenchymal delivery and image-guided delivery to the cerebrospinal fluid (CSF) spaces of the brain has led the field into highly accurate delivery techniques, which provide correction of genetic defects in specific brain regions or more broadly. These techniques commonly use magnetic resonance imaging (MRI), computed tomography (CT), and fluoroscopic guidance. Even more, the neuroimaging changes evaluated by MRI, MR spectroscopy (MRS), diffusion tensor imaging (DTI), and functional MRI (fMRI) can serve as important biomarkers of therapy effect and overall disease progression. Here, we discuss the role of neuroimaging in delivering AAV vectors and monitoring the effect of gene therapy.

Lipopeptide-mediated Cas9 RNP delivery: A promising broad therapeutic strategy for safely removing deep-intronic variants in ABCA4

Deep-intronic (DI) variants represent approximately 10-12% of disease-causing genetic defects in ABCA4-associated Stargardt disease (STGD1). Although many of these DI variants are amenable to antisense oligonucleotide-based splicing modulation therapy, no treatment is currently available. These molecules are mostly variant-specific, limiting their applicability to a broader patient population. In this study, we investigated the therapeutic potential of the CRISPR-Cas9 system combined with the amphipathic lipopeptide C18:1-LAH5 for intracellular delivery to correct splicing defects caused by different DI variants within the same intron. The combination of these components facilitated efficient editing of two target introns (introns 30 and 36) of ABCA4 in which several recurrent DI variants are found. The partial removal of these introns did not affect ABCA4 splicing or its expression levels when assessed in two different human cellular models: fibroblasts and induced pluripotent stem cell-derived photoreceptor precursor cells (PPCs). Furthermore, the DNA editing in STGD1 patient-derived PPCs led to a ∼50% reduction of the pseudoexon-containing transcripts resulting from the c.4539+2001G>A variant in intron 30. Overall, we provide proof-of-concept evidence of the use of C18:1-LAH5 as a delivery system for therapeutic genome editing for ABCA4-associated DI variants, offering new opportunities for clinical translation.

Long-term functional results of reconstructive plastic surgery on the pelvic floor

Background. With all the variety of treatment methods for pelvic organ prolapse (POP), the criteria for cure are reduced to the absence of anatomical defects of the pelvic floor. At the same time, the complete restoration of the physical, psycho-emotional and social components of a woman’s life is practically not taken into account. Studying the quality of life, as well as the sexual function of patients with POP will help to clarify the effectiveness of the synergy of surgical treatment and hardware rehabilitation methods.The purpose of the study is to assess the quality of life and sexual function of women of reproductive age after reconstructive plastic surgery on the pelvic floor in combination with radiofrequency exposure.Material and methods. An open prospective longitudinal study was conducted on 60 patients of reproductive age with stage II-III genital prolapse according to the POP-Q classification. The women were divided into two groups: group 1 — patients who underwent vaginal plastic surgery with their own tissues (n=30); group 2 — patients who, after reconstructive plastic interventions, underwent postoperative rehabilitation using dynamic quadripolar radiofrequency (n=30). Before surgery, 1 month and 1 year after treatment, a survey was conducted to determine the quality of life using the Short Form-36 questionnaire and sexual function using the Female Sexual Function Index and Female Sexual Distress Scale.Research results. The combination of surgical correction of pelvic organ prolapse with subsequent radio wave therapy makes it possible to correct anatomical defects, and at the same time statistically significantly increases the index of quality of life and female sexual function, reducing a woman’s experiences associated with problems in her sexual life.Conclusion. The synergy of surgical methods of correction and postoperative rehabilitation with the use of DCRF contributes to the long-term preservation of the functional results of treatment of pelvic floor incompetence during reproductive age.

Von Willebrand Factor Antigen, Biomarkers of Inflammation, and Microvascular Flap Thrombosis in Reconstructive Surgery.

Background: Microvascular flap surgery has become a routine option for defect correction. The role of von Willebrand factor antigen (VWF:Ag) in the pathophysiology of flap complications is not fully understood. We aim to investigate the predictive value of VWF:Ag for microvascular flap complications and explore the relationship between chronic inflammation and VWF:Ag. Methods: This prospective cohort study included 88 adult patients undergoing elective microvascular flap surgery. Preoperative blood draws were collected on the day of surgery before initiation of crystalloids. The plasma concentration of VWF:Ag as well as albumin, neutrophil-to-lymphocyte ratio (NLR), interleukin-6, and fibrinogen were determined. Results: The overall complication rate was 27.3%, and true flap loss occurred in 11.4%. VWF:Ag levels were higher in true flap loss when compared to patients without complications (217.94 IU/dL [137.27-298.45] vs. 114.14 [95.67-132.71], p = 0.001). Regression analysis revealed the association between VWF:Ag and true flap loss at the cutoff of 163.73 IU/dL (OR 70.22 [10.74-485.28], p = 0.043). Increased VWF:Ag concentrations were linked to increases in plasma fibrinogen (p < 0.001), C-reactive protein (p < 0.001), interleukin-6 (p = 0.032), and NLR (p = 0.019). Conclusions: Preoperative plasma VWF:Ag concentration is linked to biomarkers of inflammation and may be valuable in predicting complications in microvascular flap surgery.

Disruption of Mitochondrial Quality Control in Inherited Metabolic Disorders.

Inherited metabolic disorders (IMDs) are genetic disorders often characterized by the accumulation of toxic metabolites in patient tissues and bodily fluids. Although the pathophysiologic effect of these metabolites and their direct effect on cellular function is not yet established for many of these disorders, animal and cellular studies have shown that mitochondrial bioenergetic dysfunction with impairment of citric acid cycle activity and respiratory chain, along with secondary damage induced by oxidative stress are prominent in some. Mitochondrial quality control, requiring the coordination of multiple mechanisms such as mitochondrial biogenesis, dynamics, and mitophagy, is responsible for the correction of such defects. For inborn errors of enzymes located in the mitochondria, secondary abnormalities in quality control this organelle could play a role in their pathophysiology. This review summarizes preclinical data (animal models and patient-derived cells) on mitochondrial quality control disturbances in selected IMDs.

Percutaneous correction of structural congenital heart diseases during the early puerperium. Experience of a center

Congenital heart diseases (CHD) can be found in pregnant women. Although cardiac interventions in the catheterization laboratory are considered safe and effective, it is preferable to wait 3-6 months after delivery to correct simple, uncomplicated CHD; however, this may result in follow-up losses. The objective is to present our experience in correcting CHD during the early puerperium (EP). All cases of pregnant women with CHD, including atrial septal defect (ASD), patent ductus arteriosus (PDA), and aortic coarctation (CoA) between 2017-2023, who underwent percutaneous defect correction during the EP were collected. Fifteen pregnant women were included, diagnosed with ASD (5), PDA (6), and CoA (4). Five patients (33.3%) were classified as WHO risk class IV; the procedure was successful in 80% of the cases, and only 1 patient presented complications. In our experience, the closure of uncomplicated congenital defects during the EP did not present major complications and could be a treatment strategy to prevent follow-up losses after delivery in pregnant women with CHD.

Nonsurgical Rhinoplasty after Rhinoplasty: A Systematic Review of the Technique, Results, and Complications.

Introduction: Surgical rhinoplasty is a complex procedure with a high revision rate. Nonsurgical rhinoplasty (NSR) could avoid secondary rhinoplasty allowing the correction of postsurgical defects. A systematic review has been performed among adult patients who had previously undergone surgical rhinoplasty and now presenting for NSR with filler, demonstrated most common indications, fillers, and complications in this technique. Materials and Methods: A systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) system guidelines. Primary outcomes included indications for NSR in patients with prior rhinoplasty and complication rate. Secondary outcomes included filler material and degree of patient satisfaction. Results: Twenty articles met the inclusion criteria, obtaining 2,048 patients analyzed in the review. Hyaluronic acid was the most used filler, found in 67% of patients. Indications were highly variable, considering deformities of the middle third of the nose the most remarkable. A high degree of satisfaction was found in the analyzed studies and the rate of major complications was low. Discussion and Conclusions: NSR in patients with prior rhinoplasty is a useful option for correcting a range from subtle aesthetic defects to severe nasal deformities. However, this technique is not exempt from complications, since an increased risk of skin necrosis has been observed.

Disorders of word formation in adolescents under operation for congenital heart defects

Literary data on the speech status of children with congenital heart defects are presented. The results of a study of word-formation function in adolescents after radial correction of septal congenital heart defects are described. Purpose. To assess the speech status of adolescents operated on for congenital heart defects using the example of word formation. Material and methods. A prospective study of the word-formation function of 37 adolescents in the early postoperative period after radical correction of septal heart defects under artificial circulation was conducted at the Research Institute of Complex Problems of Cardiovascular Diseases. Results. The most difficult task was the formation of diminutive nouns. The respondents completed this task with a score of 55.31 %. Teenagers coped better with tasks on the formation of different categories of adjectives. Score of the task of forming relative adjectives — 60.54 %. The children coped with the task of forming possessive adjectives even more successfully — by 63.24 %. The respondents were most successful in completing the task of forming qualitative adjectives — by 81.44 %. Conclusion. Despite successful cardiac surgery, patients require interdisciplinary monitoring in the postoperative period.

A Novel View on Dental Service Management Optimization Using Markov Processes

To develop a mathematical model for managing dental services as a Markov random process based on the state graph of the process of providing dental care to the population. Markov chains, limiting probabilities of states and equations of A.N. Kolmogorov, and a graph of possible states of the dental care provision process, enabling to mathematically describe and optimize the process of managing dental services using a Markov random process in Moscow. With a full return of patients for correction of defects in the same dental medical organization where the poor-quality service was provided and a maximum warranty period of 5 years, the average financial result (gross profit) of the considered dental medical organization and the relative average increase in the financial result are maximum and equal to Rub 5,018,18 and 64.42%, respectively. It is shown that with a slight increase in the warranty period from one to three years, the financial result (gross profit) grows faster than with a warranty period of 3 to 5 years. To achieve a relative average increase in financial results by a factor of 1.5, the warranty period for dental services provided should be 3.13 years. Doi: 10.28991/HEF-2024-05-03-05 Full Text: PDF

Ablation of Akt2 rescues chronic caloric restriction-provoked myocardial remodeling and dysfunction through a CDK1-mediated regulation of mitophagy

Chronic caloric restriction triggers unfavorable alterations in cardiac function albeit responsible scenarios remain unclear. This work evaluated the possible involvement of Akt2 in caloric restriction-evoked cardiac geometric and functional changes and responsible processes focusing on autophagy and mitophagy. Akt2 knockout and WT mice were subjected to caloric restriction for 30 weeks prior to assessment of myocardial homeostasis. Caloric restriction compromised echocardiographic parameters (decreased LV wall thickness, LVEDD, stroke volume, cardiac output, ejection fraction, fractional shortening, and LV mass), cardiomyocyte contractile and intracellular Ca2+ capacity, myocardial atrophy, interstitial fibrosis and mitochondrial injury associated with elevated blood glucocorticoids, autophagy (LC3B, p62, Atg7, Beclin-1), and mitophagy (Pink1, Parkin, TOM20), dampened cardiac ATP levels, mitochondrial protein PGC1α and UCP2, anti-apoptotic protein Bcl2, intracellular Ca2+ governing components Na+-Ca2+ exchanger, phosphorylation of SERCA2a, mTOR (Ser2481) and ULK1 (Ser757), and upregulated Bax, phospholamban, phosphorylation of Akt2, AMPK, and ULK1 (Ser555), the responses except autophagy markers (Beclin-1, Atg7), phosphorylation of AMPK, mTOR and ULK1 were negated by Akt2 ablation. Levels of CDK1 and DRP1 phosphorylation were overtly upregulated with caloric restriction, the response was reversed by Akt2 knockout. Caloric restriction-evoked changes in cardiac remodeling and cardiomyocyte function were alleviated by glucocorticoid receptor antagonism, Parkin ablation and Mdivi-1. In vitro experiment indicated that serum deprivation or glucocorticoids evoked GFP-LC3B accumulation and cardiomyocyte dysfunction, which was negated by inhibition of Akt2, CDK1 or DRP1, whereas mitophagy induction reversed Akt2 ablation-evoked cardioprotection. These observations favor a protective role of Akt2 ablation in sustained caloric restriction-evoked cardiac pathological changes via correction of glucocorticoid-induced mitophagy defect in a CDK1-DRP1-dependent manner.

MORPHOMETRIC CHARACTERISTICS OF NECK PARAMETERS IN THE PERINATAL PERIOD OF ONTOGENESIS

This study aims – to establish the normative morphometric parameters of the neckcircumference, anterior- posterior diameter, height, and width during the perinatal periodof ontogenesis, after which the parameters will be used to construct anatomical models. Material and Methods. The study was conducted on 63 human fetuses aged 4 to10 months and 7 newborns (including 5 isolated organ systems). To create anatomicalmodels, the well-known dimensions of the neck in all age groups were determined usinga centimeter tape and a caliper. The neck circumference was measured at the level of thehyoid bone. The anteroposterior neck diameter was defined as the distance between thebody of the hyoid bone and the VII spinous process of the cervical vertebra. Neck heightwas measured from the upper to the lower neck borders. Neck width was determined inthe frontal plane at the level of the hyoid bone between the lateral edges of the neck.Statistical analysis of the data was performed using the licensed program RStudio.Results. A morphometric analysis of the average values of the well-known neck parameters,namely its circumference, anterior- posterior diameter, height, and width, was conductedin the perinatal period of ontogenesis. The analysis revealed that these parameters exhibitnon-synchronous growth throughout the studied period of the development, with periodsof intensive and relative growth. A correlation analysis was conducted between allmorphometric parameters of the neck of fetuses and newborns. The results demonstratedthat the correlation coefficients between the values of all paired correlation coefficientswere positive and close to 1 (≥0.90), indicating a strong positive correlation between allstudied parameters. A statistical analysis of the data from the Conover- Iman test indicatesthat the median values of the morphometric parameters of the neck cannot be consideredreliable for the pairs «9 months – 10 months» and «10 months – Newborns». This isjustified by the fact that individual anatomical variability is inherent in each individual,and these periods of the development are critical for the neck area. The constructedstandard anatomical models of the morphometric parameters of the neck will serve asa norm for the subsequent determination of certain morphological deviations, which willthen be used to establish variants of the structure and developmental defects of the neck.Conclusions. 1. During the perinatal period of the development, the well-known parametersof the neck, namely its circumference, anterior- posterior diameter, height and width,increase asynchronously. 2. The average values of the morphometric parameters of the neckcircumference and anterior- posterior diameter during the perinatal period of ontogenesisindicate that one period of accelerated development is evident, occurring between the 7thand 9th month of intrauterine development for the neck circumference and between the 6thand 9th month of development for the anterior- posterior diameter of the neck. Two periods ofaccelerated development are observed for the parameters of neck height and width. For neckheight, these periods are from the 5th to the 7th month of development and from the 8th to the9th month of development. For neck width, the periods are from the 4th to the 5th month ofthe development and from the 7th to the 9th month of intrauterine development. In all otherperiods of development, the morphometric parameters of the neck exhibit a slight increase. 3.Based on the arithmetic mean data of the circumference, anterior- posterior diameter, height,and width of the neck, models for predicting the normative morphometric parameters of fetusesand newborns were constructed. The systematized data on the peculiarities of spatial andtemporal transformations of the morphometric parameters of the neck circumference, anteriorposterior diameter, neck height and width, followed by their construction of mathematicalmodels, will contribute to the individualization of the norm, improvement of early diagnosticmethods and development of new methods of surgical correction of congenital neck defects.

Algorithm for the Treatment ofTip Malformation Combining a Clinical Qualitative Assessment and Specific Closed-Rhinoplasty Techniques Based on Retrospective Analysis of Pellegrini's Fellows 40 Years' Experience.

The aesthetic importance of nasal tip and the complexity of its surgical correction make the surgery of this area one of the most fascinating facial surgical procedures. Despite description of different sculpturing techniques to correct nasal tip defects, this surgery remains one of the most discussed and challenging aesthetic procedures. The objective of this study was to define an algorithm of treatment for nasal tip surgery based on 40-year experience on Caucasian patients evaluated by our proposed clinical qualitative assessment, who were treated by closed rhinoplasty. We retrospectively reviewed 19,643 Caucasian patients (15,266 females and 4,377 males) who underwent primary closed rhinoplasty from 1979 to 2019 due to different tip defects. The patients were evaluated by volume projection rotation (VPR) assessment. The surgical indications options, long-term aesthetic results and complications were analysed. 22% patients with minimal nasal defects were treated by non-delivery approach and 78% patients with important tip malformation by delivery approach. In all cases, the surgery was performed to reduce tip volume and modify tip projection and rotation based on the specific nasal defects. 67% patients, who needed important reduction of tip projection, were treated by tip-interrupting techniques. 88.7% patientsdeclared full satisfaction after surgery,and only 12.3% needed a requiring minor revision surgery during the 20 years follow-up. The proposed algorithm may be a useful tool to plan surgery. The use of an adequate technique depending on the evaluation of volume, projection and rotation may guarantee higher patients satisfaction and a stable long-term aesthetic result. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Pharmacological and pre-clinical safety profile of rSIV.F/HN, a hybrid lentiviral vector for cystic fibrosis gene therapy.

Cystic fibrosis (CF) is caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators offer significant improvements, but approximately 10% of patients remain nonresponsive or are intolerant. This study provides an analysis of rSIV.F/HN, a lentiviral vector optimized for lung delivery, including CFTR protein expression, functional correction of CFTR defects and genomic integration site analysis in preparation for a first-in-human clinical trial. Air-liquid interface cultures of primary human bronchial epithelial cells (HBEC) from CF patients (F508del/F508del), as well as a CFTR-deficient immortalized human lung epithelial cell line mimicking Class I (CFTR-null) homozygous mutations, were used to assess transduction efficiency. Quantification methods included a novel proximity ligation assay (PLA) for CFTR protein expression. For assessment of CFTR channel activity, Ussing chamber studies were conducted. The safety profile was assessed using integration site analysis and in vitro insertional mutagenesis studies. rSIV.F/HN expressed CFTR and restored CFTR-mediated chloride currents to physiological levels in primary F508del/F508del HBECs as well as in a Class I cells. In contrast, the latter could not be achieved by small-molecule CFTR modulators, underscoring the potential of gene therapy for this mutation class. Combination of rSIV.F/HN-CFTR with the potentiator ivacaftor showed a greater than additive effect. The genomic integration pattern showed no site predominance (frequency of occurrence ≤10%), and a low risk of insertional mutagenesis was observed in an in vitro immortalization assay. The results underscore rSIV.F/HN as a promising gene therapy vector for CF, providing a mutation-agnostic treatment option.

Real-time visual intelligence for defect detection in pharmaceutical packaging

Defect detection in pharmaceutical blister packages is the most challenging task to get an accurate result in detecting defects that arise in tablets while manufacturing. Conventional defect detection methods include human intervention to check the quality of tablets within the blister packages, which is inefficient, time-consuming, and increases labor costs. To mitigate this issue, the YOLO family is primarily used in many industries for real-time defect detection in continuous production. To enhance the feature extraction capability and reduce the computational overhead in a real-time environment, the CBS-YOLOv8 is proposed by enhancing the YOLOv8 model. In the proposed CBS-YOLOv8, coordinate attention is introduced to improve the feature extraction capability by capturing the spatial and cross-channel information and also maintaining the long-range dependencies. The BiFPN (weighted bi-directional feature pyramid network) is also introduced in YOLOv8 to enhance the feature fusion at each convolution layer to avoid more precise information loss. The model's efficiency is enhanced through the implementation of SimSPPF (simple spatial pyramid pooling fast), which reduces computational demands and model complexity, resulting in improved speed. A custom dataset containing defective tablet images is used to train the proposed model. The performance of the CBS-YOLOv8 model is then evaluated by comparing it with various other models. Experimental results on the custom dataset reveal that the CBS-YOLOv8 model achieves a mAP of 97.4% and an inference speed of 79.25 FPS, outperforming other models. The proposed model is also evaluated on SESOVERA-ST saline bottle fill level monitoring dataset achieved the mAP50 of 99.3%. This demonstrates that CBS-YOLOv8 provides an optimized inspection process, enabling prompt detection and correction of defects, thus bolstering quality assurance practices in manufacturing settings.

ENDOTHELIAL-DEPENDENT VASCULAR REACTIVITY AFTER CARDIOPULMONARY BYPASS IS ASSOCIATED WITH UNIQUE METABOLOMIC SIGNATURES.

Cardiopulmonary bypass (CPB), an extracorporeal method necessary for the surgical correction of complex congenital heart defects, incites significant inflammation that affects vascular function. These changes are associated with alterations in cellular metabolism that promote energy production to deal with this stress. Utilizing laser Doppler perfusion monitoring coupled with iontophoresis in patients undergoing corrective heart surgery, we hypothesized that temporal, untargeted metabolomics could be performed to assess the link between metabolism and vascular function. Globally, we found 2,404 unique features in the plasma of patients undergoing CPB. Metabolites related to arginine biosynthesis were the most altered by CPB. Correlation of metabolic profiles with endothelial-dependent (acetylcholine [ACh]) or endothelial-independent (sodium nitroprusside [SNP]) vascular reactivity identified purine metabolism being most consistently associated with either vascular response. Concerning ACh-mediated responses, acetylcarnitine levels were most strongly associated, while glutamine levels were associated with both ACh and SNP responsiveness. These data provide insight into the metabolic landscape of children undergoing CPB for corrective heart surgery and provide detail into how these metabolites relate to physiological aberrations in vascular function.

Research and application of the flatness target curve discrete dynamic programming based on two-dimensional decision making

The flatness target curve (FTC) is a fundamental process model in cold rolling flatness control, which directly affects the quality control effect of the strip. The accurate and efficient setting of the flatness target curve is the key to ensuring continuous rolling and is a common problem faced by various production companies. This paper establishes a discrete dynamic planning (DDP) setting method for FTC with two-dimensional decision-making. To quantitatively analyze the roles of the coefficients in the FTC, the preprocessing process is established using standardized processing methods and statistical analysis methods. The flatness target curve discrete dynamic programming (FTC-DDP) is based on Bellman optimization theory with a dual structure of local and system decision-making. The decision-making functions are established based on the effect of each coefficient on FTC geometric characteristics. The concepts of “curvature factor” and “wedge factor” are innovatively proposed to obtain the decision-making value functions. The regression analysis establishes the solution equations of even number coefficients, odd number coefficients, and gain coefficients, respectively. Roll bending and tilting roll analyze the FTC’s ability to correct flatness defects. Meanwhile, utilizing a 1450 mm five-stand six-roll cold rolling mill, it is verified that FTC-DDP can quickly and accurately set the FTC, which provides an effective solution for obtaining high-precision and high-quality cold-rolled strips. Application results show that FTC-DDP can reduce the difficulty of setting up FTC by more than 70 %, reduce the setup time to milliseconds, and improve the setup accuracy by more than 50 %.

Photocontrolled Reversible Solid-Fluid Transitions of Azopolymer Nanocomposites for Intelligent Nanomaterials.

Intelligent polymer nanocomposites are multicomponent and multifunctional materials that show immense potential across diverse applications. However, to exhibit intelligent traits such as adaptability, reconfigurability and dynamic properties, these materials often require a solvent or heating environment to facilitate the mobility of polymer chains and nanoparticles, rendering their applications in everyday settings impractical. Here intelligent azopolymer nanocomposites that function effectively in a solvent-free, room-temperature environment based on photocontrolled reversible solid-fluid transitions via switching flow temperatures (Tfs) are shown. A range of nanocomposites is synthesized through the grafting of Au nanoparticles, Au nanorods, quantum dots, or superparamagnetic nanoparticles with photoresponsive azopolymers. Leveraging the reversible cis-trans photoisomerization of azo groups, the azopolymer nanocomposites transition between solid (Tf above room temperature) and fluid (Tf below room temperature) states. Such photocontrolled reversible solid-fluid transitions empower the rewriting of nanopatterns, correction of nanoscale defects, reconfiguration of complex multiscale structures, and design of intelligent optical devices. These findings highlight Tf-switchable polymer nanocomposites as promising candidates for the development of intelligent nanomaterials operative in solvent-free, room-temperature conditions.

Exploring Novel Treatment Modalities for Type 1 Diabetes Mellitus: Potential and Prospects.

Despite the effectiveness of insulin injections in managing hyperglycemia in type 1 diabetes mellitus (T1DM), they fall short in addressing autoimmunity and regenerating damaged islets. This review aims to explore the potential and prospects of emerging treatment modalities for T1DM, including mesenchymal stem cells (MSCs), MSC-derived exosomes, gene therapy, islet allotransplantation, pancreatic islet cell transplantation, and teplizumab. We review emerging treatment modalities for T1DM, highlighting several promising strategies with varied mechanisms and outcomes. Mesenchymal stem cells demonstrate potential in modulating the immune response and preserving or restoring beta-cell function, although variability in sources and administration routes necessitates further standardization. Similarly, MSC-derived exosomes show promise in promoting beta-cell regeneration and immune regulation, supported by early-stage studies showing improved glucose homeostasis in animal models, albeit with limited clinical data. Gene therapy, utilizing techniques like CRISPR-Cas9, offers targeted correction of genetic defects and immune modulation; however, challenges in precise delivery and ensuring long-term safety persist. Islet allotransplantation and pancreatic islet cell transplantation have achieved some success in restoring insulin independence, yet challenges such as donor scarcity and immunosuppression-related complications remain significant. Teplizumab, an anti-CD3 monoclonal antibody, has demonstrated potential in delaying T1DM onset by modulating immune responses and preserving beta-cell function, with clinical trials indicating prolonged insulin production capability. Despite significant progress, standardization, long-term efficacy, and safety continue to pose challenges across these modalities. Conclusion: While these therapies demonstrate significant potential, challenges persist. Future research should prioritize optimizing these treatments and validating them through extensive clinical trials to enhance T1DM management and improve patient outcomes.

Gene Therapy for Retinitis Pigmentosa: Current Challenges and New Progress.

Retinitis pigmentosa (RP) poses a significant threat to eye health worldwide, with prevalence rates of 1 in 5000 worldwide. This genetically diverse retinopathy is characterized by the loss of photoreceptor cells and atrophy of the retinal pigment epithelium. Despite the involvement of more than 3000 mutations across approximately 90 genes in its onset, finding an effective treatment has been challenging for a considerable time. However, advancements in scientific research, especially in gene therapy, are significantly expanding treatment options for this most prevalent inherited eye disease, with the discovery of new compounds, gene-editing techniques, and gene loci offering hope for more effective treatments. Gene therapy, a promising technology, utilizes viral or non-viral vectors to correct genetic defects by either replacing or silencing disease-causing genes, potentially leading to complete recovery. In this review, we primarily focus on the latest applications of gene editing research in RP. We delve into the most prevalent genes associated with RP and discuss advancements in genome-editing strategies currently employed to correct various disease-causing mutations.

A Posteriori Error Analysis of Defect Correction Method for Singular Perturbation Problems With Discontinuous Coefficient and Point Source

Abstract The paper presents a defect correction method to solve singularly perturbed problems with discontinuous coefficient and point source. The method combines an inexpensive, lower-order stable, upwind difference scheme and a higher-order, less stable central difference scheme over a layer-adapted mesh. The mesh is designed so that most mesh points remain in the regions with rapid transitions. A posteriori error analysis is presented. The proposed numerical method is analyzed for consistency, stability, and convergence. The error estimates of the proposed numerical method satisfy parameter-uniform second-order convergence on the layer-adapted grid. The convergence obtained is optimal because it is free from any logarithmic term. The numerical analysis confirms the theoretical error analysis.