Correction Of Defects Research Articles

Инфузия субанестетических доз кетамина в послеоперационном периоде как средство церебропротекции у детей при хирургической коррекции врожденных пороков сердца: проспективное рандомизированное исследование

INTRODUCTION: The world literature describes the cerebroprotective properties of ketamine when used in minimal doses, which is due to its effect on NMDA receptors and inhibition of damage to the neurovascular unit. However, there is a lack of research on the use of ketamine for cerebroprotection in pediatric populations and cardiac surgery. OBJECTIVES: To establish the safety and effectiveness of ketamine infusion for cerebroprotection in children in the postoperative period during cardiac surgery. MATERIAL AND METHODS: The study included 45 children aged from 1 to 60 months and weighing from 3.5 to 20 kg, who underwent surgical correction of atrial or ventricular septal defect of the heart under artificial circulation. Patients were randomized into a study group or a control group. In the study group, upon completion, patients received a ketamine infusion at a dose of 0.1 mg/kg/hour for 16 h. To establish the effectiveness of cerebroprotection, serum markers of damage to the neurovascular unit were used: protein S100-β, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), occludin, claudin-1. Blood sampling for marker analysis was carried out at three control points: before the start of the operation, immediately after completion of artificial circulation and 16 hours after completion of the operation. RESULTS: Al studied factors in the intra- and postoperative period did not differ significantly between groups. When analyzing markers of damage to a neurovascular unit, their maximum concentration was revealed at the second control point. For the NSE marker, a lower level was found in the group using ketamine — 16.52 [11.61–18.8] and 21.37 [17.78–28.74] ng/ml (p = 0.0019). CONCLUSIONS: The safety of using ketamine infusion in the postoperative period at a dose of 0.1 mg/kg/hour was revealed. Among all markers used, NSE serum concentrations were statistically significantly lower in the ketamine group.

Long-term lineage commitment in hematopoietic stem cell gene therapy.

Hematopoietic Stem Cell (HSC) gene therapy (GT) may provide lifelong reconstitution of the hematopoietic system with gene-corrected cells1. However, the effects of underlying genetic diseases, replication stress, and aging on hematopoietic reconstitution and lineage specification remain unclear. In this study, we analyzed hematopoietic reconstitution in 53 patients treated with lentiviral-HSC-GT for diverse conditions such as metachromatic leukodystrophy2,3 (MLD), Wiskott-Aldrich syndrome4,5 (WAS), and β-thalassemia6 (β-Thal) over a follow-up period of up to 8 years, using vector integration sites as markers of clonal identity. We found that long-term hematopoietic reconstitution was supported by 770 to 35,000 active HSCs. While 50% of transplanted clones demonstrated multilineage potential across all conditions, the remaining clones exhibited a disease-specific preferential lineage output and long-term commitment: myeloid for MLD, lymphoid for WAS, and erythroid for β-Thal, particularly in adult patients. Our results indicate that HSC clonogenic activity, lineage output, long-term lineage commitment, and rates of somatic mutations are influenced by the underlying disease, patient age at the time of therapy, the extent of genetic defect correction, and the hematopoietic stress imposed by the inherited disease. This suggests that HSCs adapt to the pathological condition during hematopoietic reconstitution.

Anesthetic management of laparoscopically assisted fetoscopic surgery to correct spina bifida

Introduction. The growing incidence of intrauterine pathology in the fetus at the present stage dictates the need to develop and improve intrauterine surgical correction of defects in the fetus. Myelomeningocele (SPINA BIFIDA) is the most common and severe neural tube defect in the fetus, the severity of the neurological deficit is determined by the level of location and extent of the anomaly. By uniting doctors of various specialties (obstetricians-gynecologists, neonatologists, surgeons, anesthesiologists-resuscitators), the Clinic of the St. Petersburg State Pediatric Medical University effectively introduces methods of prenatal surgery.The objective was to demonstrate by clinical example the experience of successful fetoscopic correction of myeloneningocele to reduce maternal risks and injuries, to reduce risks aimed at protecting the tissues of the spinal cord of the fetus, as well as to reduce the need for postpartum correction of the defect in the fetus, to improve prognosis and risks of subsequent disability.Materials and methods. The article presents the first successful experience of minimally invasive laparoscopic correction of myelomeningocele in the fetus with the participation of the multidisciplinary team and the features of anesthesiological support of the method.Conclusion. Laparoscopic access, together with the optimal choice of anesthetic management in fetal surgery, allows not only to successfully correct the defect in myelomeningocele in the fetus, but also to significantly minimize and reduce the risks of injury to the mother, and also reduces the need for postpartum surgical treatment and reduce disability. Accumulation and improvement of experience, a multidisciplinary approach is the key to successful correction of intrauterine fetal pathology.

Cerebroprotective properties of nitric oxide in children in cardiac surgery (literature review)

Background. Cardiac surgery in conditions of cardiopulmonary bypass (CPB) in children with congenital heart defects is characterized by a complex of damaging factors (initial immaturity of organs and systems, the fact of non-physiology of cardiopulmonary bypass, frequent use of perfusion and non-perfusion hypothermia, comorbid infection), which dictates the validity of using a number of strategies aimed at protecting vital organs and the brain above all.The objective was to study the effectiveness of the use of nitric oxide to protect the brain in children during surgical correction of congenital heart defects in cardiopulmonary bypass conditions.Materials and methods. A literary search was performed in domestic and international bibliographic databases for keywords: nitric oxide, cerebroprotection, cardiopulmonary bypass, organoprotection, inhalation of nitric oxide, children.Results. The review provides up-to-date information on the effect of nitric oxide on the components of the neurovascular unit: angiogenesis, proliferation and myelination of nerve cells, the role in neuroinflammation and deep hypothermic circulatory arrest.Conclusion. The results of many studies confirm the effectiveness of nitric oxide for neuroprotection. However, there is a deficit of clinical researches in general and in the pediatric patient population, which does not yet allow to definitely state its effectiveness.

The accordion technique did not improve bone healing in a mouse model of distraction osteogenesis.

Distraction osteogenesis (DO) is a valuable surgical method for limb lengthening and bone defect correction, but its lengthy consolidation phase presents challenges. The accordion technique (AT), involving compression and distraction of bone segments, has shown potential for enhancing healing. This study aimed to investigate the effectiveness of the AT conducted at three different time points (distraction phase, early consolidation phase, or late consolidation phase) compared to conventional DO in a mouse osteotomy model. Healing was evaluated using in vivo microCT, histology, and computational modeling. Results showed that bridging frequency, BV, and callus tissue composition were similar between conventional DO and late consolidation AT. In contrast, distraction phase AT led to delayed healing at day 15 with a 72% reduction in BV compared to DO, but no significant differences by the endpoint. Early consolidation AT showed significantly impaired healing compared to DO, with only 29% of mice achieving bony bridging, and significantly reduced bone marrow area of the endpoint callus. In silico modeling was generally predictive of in vivo findings and suggested that application of the AT during early consolidation results in destruction of newly-formed vascular tissue. Overall, no benefit was observed for the AT compared to conventional DO with the parameters employed in this study.

Navicular Drop Height Asymmetry as an Intrinsic Risk Factor for Lower Limb Injury in Male Recreational Athletes

Morphological and functional asymmetry of the lower limbs is a well-recognized factor contributing to musculoskeletal injuries among athletes across different levels. However, limited research exists on evaluating foot mobility asymmetry as a potential predictor of such injuries. This study aimed to (1) assess the frequency of foot mobility asymmetries among amateur athletes, (2) investigate the predictive value of foot mobility asymmetry (measured via navicular height drop) for injury risk, and (3) explore the relationship between foot type and injury occurrence. A cross-sectional sampling method was employed to select 45 physically active male amateur athletes (runners and team sports practitioners) from a university. Injury history was retrospectively recorded, and a modified navicular drop test was conducted to classify foot arch height. The predictive power of navicular height drop asymmetry was analyzed using ROC curves, and the relationship between foot type (neutral and defective combinations—pronated or supinated) and injury occurrence was examined using chi-square tests for independence. Multiple logistic regression was applied to calculate injury risk odds ratios across different foot type subgroups. The results revealed a significant frequency (51.1%) of participants with at least one defective foot, including 31.1% with one neutral and one defective foot and 20% with both feet defective. Navicular height drop asymmetry emerged as a valuable predictor of injuries, with a 36% asymmetry identified as the cut-off for increased injury risk (AUC = 0.832, 95% CI: 0.691–0.973, p < 0.001). A significant relationship was found between foot type and injury occurrence. Only one out of 22 participants with neutral feet (4.55%) experienced an injury, compared to 9 out of 14 (64.29%) with one neutral and one defective foot and 5 out of 9 (55.56%) with both feet defective. These differences were statistically significant (χ2 = 16.24, p < 0.001, Cramer’s V = 0.60). The odds ratio for injury risk was 37.8 (p = 0.016) for those with asymmetry (one neutral and one defective foot) and 26.3 (p = 0.102) for those with both feet defective, compared to participants with both feet neutral. In clinical practice, these findings suggest that routine screenings for physically active individuals should incorporate foot mobility asymmetry assessment. However, it is essential to integrate this factor with other risk indicators. For individuals exhibiting high asymmetry, general foot defect correction programs may be beneficial, but injury prevention strategies should adopt a more comprehensive approach, focusing on overall fitness and tailored interventions for high-risk individuals.

Minimally Modified HIV-1 Infection of Macaques: Development, Utility, and Limitations of Current Models.

Nonhuman primate (NHP) studies that utilize simian immunodeficiency virus (SIV) to model human immunodeficiency virus (HIV-1) infection have proven to be powerful, highly informative research tools. However, there are substantial differences between SIV and HIV-1. Accordingly, there are numerous research questions for which SIV-based models are not well suited, including studies of certain aspects of basic HIV-1 biology, and pre-clinical evaluations of many proposed HIV-1 treatment, prevention, and vaccination strategies. To overcome these limitations of NHP models of HIV-1 infection, several groups have pursued the derivation of a minimally modified HIV-1 (mmHIV-1) capable of establishing pathogenic infection in macaques that authentically recapitulates key features of HIV-1 in humans. These efforts have focused on three complementary objectives: (1) engineering HIV-1 to circumvent species-specific cellular restriction factors that otherwise potently inhibit HIV-1 in macaques, (2) introduction of a C chemokine receptor type 5 (CCR5)-tropic envelope, ideally that can efficiently engage macaque CD4, and (3) correction of gene expression defects inadvertently introduced during viral genome manipulations. While some progress has been made toward development of mmHIV-1 variants for use in each of the three macaque species (pigtail, cynomolgus, and rhesus), model development progress has been most promising in pigtail macaques (PTMs), which do not express an HIV-1-restricting tripartite motif-containing protein 5 α (TRIM5α). In our work, we have derived a CCR5-tropic mmHIV-1 clone designated stHIV-A19 that comprises 94% HIV-1 genome sequence and replicates to high acute-phase titers in PTMs. In animals treated with a cell-depleting CD8α antibody at the time of infection, stHIV-A19 maintains chronically elevated plasma viral loads with progressive CD4+ T-cell loss and the development of acquired immune-deficiency syndrome (AIDS)-defining clinical endpoints. However, in the absence of CD8α+ cell depletion, no mmHIV-1 model has yet displayed high levels of chronic viremia or AIDS-like pathogenesis. Here, we review mmHIV-1 development approaches, the phenotypes, features, limitations, and potential utility of currently available mmHIV-1s, and propose future directions to further advance these models.

Outcomes of Hydroxyapatite Bone Cement for Craniofacial Reconstruction in 1983 Patients.

Hydroxyapatite bone cement (HABC) has evolved to have diverse applications in craniofacial reconstruction. This ranges from filling cranial defects to secondary contouring of residual defects after primary surgeries. This study aims to determine patient outcomes after reconstruction with HABCs. A systematic review and meta-analysis were conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. PubMed, Embase, Web of Science, and Cochrane Library databases were queried. The results were limited to English-language literature with extractable data on HABC for craniofacial reconstruction. A total of 1983 patients were included in the final analysis from 35 studies. HABCs were mostly used for large defect cranioplasty (21.5%), retrosigmoid (44.6%) and translabyrinthine cranioplasty (8.9%), and correction of residual craniofacial defects after congenital craniofacial surgeries (25%). The rates of cerebrospinal fluid (CSF) leak and infection/explantation were 0% and 7.5% [95% CI: 2.4-11.8] for large defect cranioplasty and 0.8% [0.03-2.07] and 1.5% [95% CI: 0.92-3.3] for retrosigmoid cranioplasty, respectively. The infection/explantation rate was 6.2% [95% CI: 2.6-18.7] for HABCs in the correction of residual craniofacial defects after congenital craniofacial surgeries. The total reoperation rates were 20.4% % [95% CI: 4.8-11.8] for large defect cranioplasty and 12% [95% CI: 3.3-15.3] for correction of residual defects after congenital craniofacial surgeries. Aesthetic satisfaction rates were 93.1% [95% CI: 90.3-98.8] for large defect cranioplasty, 99.4% [95% CI 97.2-99.9] for retrosigmoid cranioplasty, and 92.6% [95% CI: 83.3-95.8] for HABC use in the correction of residual craniofacial defects after congenital craniofacial surgeries. HABC is versatile and associated with a high level of patient reported aesthetic satisfaction after cranioplasty and may have a comparably lower complication profile than those of most other alloplastic materials.

TREATMENT OF PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONGENITAL HEART DEFECTS

Patients with pulmonary arterial hypertension, associated with congenital heart disease (PAH-CHD) are a heterogeneous population with a varied course of PH. Improvements in pediatric cardiac surgery have changed the epidemiology and survival rate of patients with CHD, of which 90% reach adulthood. Progress in terms of prognosis has also been observed among patients with PAH-CHD. Better survival was observed in ES compared with PAH after defect correction. Advances in surgical treatment of CHD and an increase in life expectancy have led to the study of PAH-CHD and the need to create recommendations for drug treatment of this category of patients. In most of studies, the evaluation of drug treatment of group 1 PAH was carried out without identifying its subgroups. And thus, according to existing recommendations, treatment algorhithms for patients with PAH-CHD are similar to approaches to other forms of PAH. However, various clinical, functional, physical and hemodynamic characteristics of patients with PAH-CHD call into question of correct risk stratification approaches development. Multicenter randomized clinical trials included predominantly a small number of patients with corrected defects, which does not allow the results to be interpreted for the entire population of patients with PAH-CHD. Data from single-center observational studies, expert opinion, and several randomized trials primarily involving patients with Eisenmenger syndrome (ES) indicate the effectiveness and safety of PAH-specific therapy in patients with PAH-CHD. In this literature review, we examined and showed the results of studies involving patients with PAH-CHD and their response to specific therapy. The results obtained significantly expanded the possibilities of using bosentan, sildenafil, epoprostenol, riociguat, ralinepag, sotatercept as they lead to improvement of functional capacity and hemodynamic parameters in patients with PAH-CHD, and only epoprostenol demonstrated an effect on prognosis. Combination PAH-specific therapy, initial or sequential administration of two or more drugs with different mechanisms of action, is an important treatment strategy for patients with PAH. The role of such therapy has increased in recent years. Based on the results of the AMBITION, SERAPHIN, GRIPHON, COMPASS-2 studies, initial or sequential oral combination PAH-specific therapy is recommended for patients with WHO FC II or III. At the same time, there is little evidence to support the effectiveness of this approach in ES patients. The use of anticoagulants in PAH-CHD remains controversial. Low-flow oxygen therapy should be considered individually and continued when there is a significant predominance of subjective or objective benefit. Iron deficiency is associated with poor survival in ES. It is important to note that microcytosis is rare in patients with iron deficiency cyanosis and a normal mean red cell volume does not indicate the absence of anemia. In cases of intolerance to oral iron, intravenous drugs should be used. Currently, based on existing guidelines, most centers follow a consistent symptom-based approach in the treatment of patients with PAH-CHD. Therapy begins with oral ERAs or PDE-5 inhibitors and is escalated if symptoms persist or clinical worsening occurs. If there is no effect of oral PAH-specific therapy, it is recommended to consider parenteral drugs.

Assessing the Feasibility of a Cancer Biomarker Testing Navigator in the Laboratory

Abstract Introduction/Objective Cancer biomarker testing is a crucial component of precision oncology, as it can guide medical treatment decisions with targeted therapies and immune checkpoint inhibitors. However, complex, fragmented, and inefficient operational processes involved in biomarker testing lead to delays, errors, and variability in testing. One potential solution is to introduce a novel role in the pathology laboratory: the cancer biomarker testing navigator (BTN). Methods/Case Report The American Society for Clinical Pathology (ASCP) conducted a mixed-methods project to assess the current state of biomarker testing operations and explore how a BTN may improve biomarker testing processes. ASCP conducted an online survey, focus groups, and worked with two hospital-based cancer centers on a feasibility pilot. Results (if a Case Study enter NA) Survey and focus group insights reveal several operational challenges around the biomarker testing process. 47 completed the survey and 16 participated in the focus groups. Participants report that biomarker test orders may be incorrect or incomplete. 37% of survey respondents experience delays preparing tissue samples for send-out cancer biomarker testing. 42% of survey respondents are unable to track the processing status of send-out tests. Excessive time is required to coordinate and facilitate send-out tests, especially when multiple reference laboratories are used since each has its own portal, requisition form, specimen requirements, etc. 87% agree they would benefit significantly from having a dedicated person to coordinate and manage cancer biomarker tests. The cancer centers that piloted this role found that they could catch and correct defects such as incorrect test ordered, incorrect specimen types marked on the test order, outdated requisition used, etc. The BTN also found instances where the test report was incomplete or had not been uploaded into the EHR. The BTN role could be justified by evaluating metrics such as task efficiency, workplace satisfaction in the lab, and levels of service satisfaction from oncologists. Patient care can be improved by reducing delays in testing and by reviewing other metrics of quality care delivery. Conclusion The BTN role in the laboratory is a novel solution for ensuring the proper collection and triage of pathology samples for biomarker testing. This role could serve as a liaison between the laboratory and ordering clinicians, provide collection and testing guidance, and help with benchmarking and quality measurement initiatives.

Post-Treating Grain Boundaries and Surface Defects by Long-Chain Polymer for Highly Efficient and Stable Perovskite Solar Cells.

Grain boundaries (GBs) and surface defects within perovskite films are inherent challenges that affect the photovoltaic performance of perovskite solar cells (PSCs. In this work, Nylon 11 (N11) is utilized, a long-chain polymer, for post-treating the GBs and surface defects within FAPbI3 films. The multifunctional groups of N11 exhibit unique passivation abilities, enabling self-regulation and selective correction of reverse-charged defects. Post-treating with N11 results in high-quality FAPbI3 films characterized by tight GBs and low surface defect density. Despite fabrication under full open-air conditions, the N11 post-treatment significantly enhances the power conversion efficiency (PCE) value of FAPbI3 PSCs, increasing it from the reference value of 21.89% to 23.54%. Importantly, the long alkyl chain present in N11 significantly enhances the humidity stability of the PSCs. Unencapsulated PSCs treated with N11 maintain 89% of their initial PCE after exposure to air with 30% relative humidity (RH) for 1000h, demonstrating resilience to elevated humidity levels. This work highlights the substantial improvement in the photovoltaic performance of PSCs achieved through the post-treatment with N11.

Impact of Intraoperative Blood Transfusion on Cerebral Injury in Pediatric Patients Undergoing Congenital Septal Heart Defect Surgery

Background: The components of donor blood themselves have the potential to initiate a systemic inflammatory response and exacerbate neuroinflammation, resulting in subsequent cerebral injury. The aim of this study was to establish the role of transfusion in the development of cerebral injury during the correction of congenital heart defects in children. Material and Methods: A total of 78 patients aged from 1 to 78 months, with body weights ranging from 3.3 to 21.5 kg, were investigated. Biomarkers of cerebral injury and systemic inflammatory response were studied at three time points. First: prior to the surgical intervention. Second: after the completion of cardiopulmonary bypass. Third: 16 h after the conclusion of the surgery. Results: The strongest correlation was found for S-100-β protein with the volume of transfusion at the second (Rho = 0.48, p = 0.00065) and third time points (Rho = 0.36, p = 0.01330). Neuron-specific enolase demonstrated a similar trend: Rho = 0.41 and p = 0.00421 after the completion of cardiopulmonary bypass. Conclusions: The use of red blood cell suspension and its dosage per kilogram of body weight correlated with the biomarkers of cerebral injury and systemic inflammatory response with moderate to significant strength.

Energy balance and scale truncation of the approximate deconvolution with correction

We present the similarity theory of Approximate Deconvolution with Correction (ADC) - a member of the recently proposed family of turbulence models called LES-C. This model stems from a combination of a well-known Approximate Deconvolution Model (ADM) with a defect correction procedure. We derive the energy equality for the ADC in a way that highlights the enhanced accuracy of the ADC, as compared to the ADM. Using the proposed definitions of the ADC energy and dissipation rates, we investigate the energy cascade of the ADC; we show that it correctly predicts the energy cascade in the inertial range, and acts to dissipate the small scales at a higher rate than the ADM. The micro-scale of the ADC is then found; we prove it to be larger than the micro-scale of the ADM, which also explains the previously established efficiency of the ADC.

Molecular Phenotypes Segregate Missense Mutations in SLC13A5 Epilepsy

The sodium-coupled citrate transporter (NaCT, SLC13A5) mediates citrate uptake across the plasma membrane via an inward Na+ gradient. Mutations in SLC13A5 cause early infantile epileptic encephalopathy type-25 (EIEE25, SLC13A5 Epilepsy) due to impaired citrate uptake in neurons and astrocytes. Despite clinical identification of disease-causing mutations, underlying mechanisms and cures remain elusive. Here we mechanistically classify six frequent SLC13A5 mutations by phenotyping their protein cell surface expression and citrate transport functions. Mutants C50R, T142M, and T227M exhibit impaired citrate transport despite normal expression at the cell surface. In contrast, mutations G219R, S427L, and L488P show low total protein expression levels, absence of mature, glycosylated proteins at the cell surface, retention of the proteins in the endoplasmic reticulum, and diminished transport activity. This mechanistic classification divides SLC13A5 mutants into two groups, Class I (C50R, T142M, and T227M) and Class II (G219R, S427L, and L488P). Importantly, mutants’ mRNA levels resemble wildtype, suggesting post-translational defects. Class II mutations display immature core-glycosylation and shortened half-lives, indicating protein folding defects. Together, these experiments provide a comprehensive understanding of the disease-causing mutation’s defects in SLC13A5 Epilepsy at the biochemical and molecular level and shed light into the trafficking pathway(s) of NaCT. The two classes of mutations will require fundamentally different approaches for treatment to either restore transport function of the mutant protein that is capable of reaching the cell surface (Class I), or therapies that enable the correction of protein folding defects to enable escape to the cell surface where it may restore transport function (Class II).

EAR LOBULOPLASTY: INDICATIONS AND SURGICAL TECHNIQUES — LITERATURE REVIEW

Introduction: Lobuloplasty alone or associated with otoplasty is among the most commonly performed aesthetic procedures on the face. Despite being a small appendage of approximately 2.0 cm with no function in the physiology of the external ear, it plays an important aesthetic role in the harmony of the face, motivating children, adults, men and women to seek surgeons qualified to work in the area to correct defects and improves aesthetics. Objective: The objective of this study was to systematize the main changes in the earlobe and the respective surgical technique most indicated in the...

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.