Updated site concordance factors minimize effects of homoplasy and taxon sampling.

MOTIVATION: Site concordance factors (sCFs) have become a widely used way to summarize discordance in phylogenomic datasets. However, the original version of sCFs was calculated by sampling a quartet of tip taxa and then applying parsimony-based criteria for discordance. This approach has the potential to be strongly affected by multiple hits at a site (homoplasy), especially when substitution rates are high or taxa are not closely related. RESULTS: Here, we introduce a new method for calculating sCFs. The updated version uses likelihood to generate probability distributions of ancestral states at internal nodes of the phylogeny. By sampling from the states at internal nodes adjacent to a given branch, this approach substantially reduces-but does not abolish-the effects of homoplasy and taxon sampling. AVAILABILITY AND IMPLEMENTATION: Updated sCFs are implemented in IQ-TREE 2.2.2. The software is freely available at https://github.com/iqtree/iqtree2/releases. SUPPLEMENTARY INFORMATION: Supplementary information is available at Bioinformatics online.

Applications of machine learning in phylogenetics.

Machine learning has increasingly been applied to a wide range of questions in phylogenetic inference. Supervised machine learning approaches that rely on simulated training data have been used to infer tree topologies and branch lengths, to select substitution models, and to perform downstream inferences of introgression and diversification. Here, we review how researchers have used several promising machine learning approaches to make phylogenetic inferences. Despite the promise of these methods, several barriers prevent supervised machine learning from reaching its full potential in phylogenetics. We discuss these barriers and potential paths forward. In the future, we expect that the application of careful network designs and data encodings will allow supervised machine learning to accommodate the complex processes that continue to confound traditional phylogenetic methods.

Synergism of non-thermal plasma and low concentration RSL3 triggers ferroptosis via promoting xCT lysosomal degradation through ROS/AMPK/mTOR axis in lung cancer cells.

BACKGROUND: Though (1S, 3R)-RSL3 has been used widely in basic research as a small molecular inducer of ferroptosis, the toxicity on normal cells and poor pharmacokinetic properties of RSL3 limited its clinical application. Here, we investigated the synergism of non-thermal plasma (NTP) and low-concentration RSL3 and attempted to rise the sensitivity of NSCLC cells on RSL3. METHODS: CCK-8 assay was employed to detect the change of cell viability. Microscopy and flowcytometry were applied to identify lipid peroxidation, cell death and reactive oxygen species (ROS) level respectively. The molecular mechanism was inspected with western blot and RT-qPCR. A xenograft mice model was adopted to investigate the effect of NTP and RSL3. RESULTS: We found the synergism of NTP and low-concentration RSL3 triggered severe mitochondria damage, more cell death and rapid ferroptosis occurrence in vitro and in vivo. NTP and RSL3 synergistically induced xCT lysosomal degradation through ROS/AMPK/mTOR signaling. Furthermore, we revealed mitochondrial ROS was the main executor for ferroptosis induced by the combined treatment. CONCLUSION: Our research shows NTP treatment promoted the toxic effect of RSL3 by inducing more ferroptosis rapidly and provided possibility of RSL3 clinical application.

Genome-wide gene expression responses to experimental manipulation of Saccharomyces cerevisiae repressor activator protein 1 (Rap1) expression level.

Precise regulation of transcription in gene expression is critical for all aspects of normal organism form, fitness, and function and even minor alterations in the level, location, and timing of gene expression can result in phenotypic variation within and between species including evolutionary innovations and human disease states. Eukaryotic transcription is regulated by a complex interplay of multiple factors working both at a physical and molecular levels influencing this process. In Saccharomyces cerevisiae, the TF with the greatest number of putative regulatory targets is the essential gene Repressor Activator Protein 1 (RAP1). While much is known about the roles of Rap1 in gene regulation and numerous cellular processes, the response of Rap1 target genes to systematic titration of RAP1 expression level remains unknown. To fill this knowledge gap, we used a strain with a tetracycline-titratable promoter replacing wild-type regulatory sequences of RAP1 to systematically reduce the expression level of RAP1 and followed this with RNA sequencing (RNA-seq) to measure genome-wide gene expression responses. Previous research indicated that Rap1 plays a significant regulatory role in particular groups of genes including telomere-proximal genes, homothallic mating (HM) loci, glycolytic genes, DNA repair genes, and ribosomal protein genes; therefore, we focused our analyses on these groups and downstream targets to determine how they respond to reductions in RAP1 expression level. Overall, despite being known as both an activator and as a repressor of its target genes, we found that Rap1 acts as an activator for more target genes than as a repressor. Additionally, we found that Rap1 functions as an activator of ribosomal protein genes and a repressor for HM loci genes consistent with predictions from the literature. Unexpectedly, we found that Rap1 functions as a repressor of glycolytic enzyme genes contrary to prior reports of it having the opposite effect. We also compared the expression of RAP1 to five different genes related to DNA repair pathway and found that decreasing RAP1 downregulated four of those five genes. Finally, we found no effect of RAP1 depletion on telomere-proximal genes despite its functioning to silence telomeric repeat-containing RNAs. Together our results enrich our understanding of this important transcriptional regulator.

Clinical, Anamnestic, and Demographic Characteristics of Patients with Myocardial Infarction in Russian Federation According to the Russian Registry of Acute Myocardial Infarction - REGION-IM.

AIM: Based on data from the Russian REGION-MI registry, to characterize patients with myocardial infarction (MI) hospitalized in Russian hospitals, describe their historical, demographic, and clinical characteristics, and compare the results with the data of previous Russian and international registries of acute coronary syndrome. MATERIAL AND METHODS: REGION-MI is a multicenter prospective observational study. The follow-up period was divided into three stages: during the hospital stay, at 6 and 12 months after the inclusion in the registry. Demographic and historic data and information about the present case of MI were entered into the patient's individual record card. RESULTS: The median age of all patients was 63 years; 68% of patients were men. The mean age of women was older than that of men. Among all MI cases, 70% were ST-segment elevation myocardial infarction (STEMI). Patients with non-ST-segment elevation myocardial infarction (NSTEMI) were older and had more comorbidities than patients with STEMI. The median time from the first symptoms to ECG recording was two hours, and from the first symptoms to CAG 7 hours. CAG was performed in 91% of patients with STEMI and 84% of patients with NSTEMI. Stenting was performed in 69% of patients. Although many patients had a complicated cardiovascular history, at the time of admission only 31.5% of patients were taking at least one drug from the groups of antiplatelets, oral anticoagulants, statins, and beta-blockers. CONCLUSION: Patients with MI in the Russian Federation are younger than patients with MI in European countries. Among the clinical and historical characteristics, conspicuous is the presence of modifiable risk factors in many patients, as well as the presence of a previous diagnosis of ischemic heart disease. Furthermore, a small proportion of patients took statins, antiplatelet agents or anticoagulants at the outpatient stage, which indicates a great reserve of both primary and secondary prevention of cardiovascular diseases in the Russian Federation. The delayed seeking medical help is also noticeable, which indicates the need for increasing the public awareness of the symptoms of MI and the importance of timely hospitalization.

[Features of the Reperfusion Therapy for ST-Segment Elevation Myocardial Infarction According to the Russian Registry of Acute Myocardial Infarction - REGION-IM].

AIM: Based on data from the Russian REGION-IM registry, to study the features of reperfusion therapy in patients with ST-segment elevation myocardial infarction (STEMI) in real-life clinical practice. MATERIAL AND METHODS: REGION-IM is a multicenter prospective observational study. The observational period is divided into 3 stages: during the stay in the hospital and at 6 and 12 months after inclusion in the registry. The patient's records contain demographic and history data; information about the present case of MI, including the time of the first symptom onset, first contact with medical personnel, and admission to the hospital; coronary angiography (CAG) data, percutaneous coronary intervention (PCI) data, and information about the thrombolytic therapy (TLT). RESULTS: Reperfusion therapy was performed in 88.9 % of patients with STEMI. Primary PCI (pPCI) was performed in 60.6 % of patients. The median time from the onset of symptoms to pPCI was 315 minutes [195; 720]. The median time from ECG to pPCI was 110 minutes [84;150]. Isolated TLT was performed in 7.4 %, pharmaco-invasive treatment tactics were used only in 20.9 % of cases. The median time from ECG to TLT (prehospital and in-hospital) was 30 minutes [10; 59], whereas the median time from ECG to prehospital TLT was 18 minutes [10; 39], and in 63 % of patients, TLT was performed more than 10 minutes after diagnosis. PCI followed TLT in 73 % of patients. CONCLUSION: The frequency of reperfusion therapy for STEMI in the Russian Federation has increased considerably in recent years. The high frequency of pPCI is noteworthy, but the timing of pPCI does not always comply with clinical guidelines. The results of this registry confirm the high demand for pharmaco-invasive strategies in real-life clinical practice. Taking into account geographical and logistical features, implementing timely myocardial reperfusion requires prehospital TLT. However, the TLT frequency in the Russian Federation is still insufficient despite its proven maximum effectiveness in the shortest possible time from the detection of acute MI.

[Non-functioning parathyroid cysts]. / Nefunktsional'nye kisty okoloshchitovidnykh zhelez.

OBJECTIVE: To study the features of clinical course, diagnosis and treatment of true non-functioning parathyroid cysts. MATERIAL AND METHODS: We retrospectively analyzed 18 patients with non-functioning true parathyroid cysts. Inclusion criteria: US-confirmed anechoic lesion of the neck without tissue component, cytological data on cystic lesion, high cystic parathyroid hormone and no laboratory signs of hyperparathyroidism. RESULTS: Non-functioning parathyroid cysts were asymptomatic and diagnosed accidentally after ultrasound of the neck. All patients were women aged 35-77 years. Four patients had cysts near the upper parathyroid glands, 14 patients - near the lower parathyroid glands. Of these, 2 ones had cysts below the level of the clavicle. Cyst volume was 4.3-110.3 cm3 (24.1±26.2 cm3). High cystic parathyroid hormone (2012.5±946.7 pg/ml) was observed in all patients. Simple aspiration was performed in 5 patients, aspiration with sclerotherapy - in 10 patients, cystectomy - in 3 patients. Recurrence was diagnosed in 1 patient after aspiration and 2 patients after sclerotherapy. CONCLUSION: No pathognomonic clinical and ultrasonic symptoms, as well as specific cytological data lead to misdiagnosis. Analysis of PTH in non-functioning parathyroid cysts is essential for diagnosis. Minimally invasive treatment is preferable for true parathyroid cysts. However, these approaches are not radical.

[Pharmacological prevention of fibrosis in dacryosurgery]. / Medikamentoznaya profilaktika fibrotizatsii v dakriokhirurgii.

Chronic inflammatory process in the lacrimal drainage system is the main etiological factor leading to dacryostenosis and consequent obliteration - partial and total nasolacrimal duct obstruction. Prevention of this process is an urgent problem in dacryology. Currently, there is very little research on the development and use of conservative methods for treating dacryostenosis using anti-inflammatory, as well as anti-fibrotic drugs. In this regard, the main method of treating lacrimal drainage obstruction is dacryocystorhinostomy. However, the problem of recurrence after this operation has not been resolved. The causes of recurrence can be cicatricial healing of dacryocystorhinostomy ostium, canalicular obstruction, formation of granulations and synechiae in its area. Surgical methods of recurrence prevention are associated with possible complications, and there is conflicting data on the feasibility of their use. Based on this, the development of pharmacological methods for the prevention of fibrosis in dacryology is promising, among which the antitumor antibiotic Mitomycin C is the most studied. However, there are no specific scientifically substantiated recommendations for the use of this drug, and the data on its effectiveness vary. This has prompted researchers to look for and study alternative anti-fibrotic agents, such as antitumor drugs, glucocorticoids, hyaluronic acid, small molecule, biological, immunological and genetically engineered drugs, as well as nanoparticles. This review presents the current data on the efficacy and prospects of the use of these drugs in dacryology.

Hemin enhances radiosensitivity of lung cancer cells through ferroptosis.

The principle underlying radiotherapy is to kill cancer cells while minimizing the harmful effects on non-cancer cells, which has still remained as a major challenge. In relation, ferroptosis has recently been proposed as a novel mechanism of radiation-induced cell death. In this study, we investigated and demonstrated the role of Hemin as an iron overloading agent in the generation of reactive oxygen species (ROS) induced by ionizing radiation in lung cancer and non-cancer cells. It was found that the presence of Hemin in irradiated lung cancer cells enhanced the productivity of initial ROS, resulting in lipid peroxidation and subsequent ferroptosis. We observed that application of Hemin as a co-treatment increased the activity of GPx4 degradation in both cancer and normal lung cells. Furthermore, Hemin protected normal lung cells against radiation-induced cell death, in that it suppressed ROS after radiation, and boosted the production of bilirubin which was a lipophilic ROS antioxidant. In addition, we demonstrated significant FTH1 expression in normal lung cells when compared to lung cancer cells, which prevented iron from playing a role in increasing IR-induced cell death. Our findings demonstrated that Hemin had a dual function in enhancing the radiosensitivity of ferroptosis in lung cancer cells while promoting cell survival in normal lung cells.

Facilitation of non-indigenous ascidian by marine eco-engineering interventions at an urban site.

Marine artificial structures often support lower native species diversity and more non-indigenous species (NIS), but adding complex habitat and using bioreceptive materials have the potential to mitigate these impacts. Here, the interacting effects of structural complexity (flat, complex with pits) and concrete mixture (standard, or with oyster shell or vermiculite aggregate) on recruitment were assessed at two intertidal levels at an urban site. Complex tiles had less green algal cover, oyster shell mixtures had less brown (Ralfsia sp.) algal cover. At a low tidal elevation, the non-indigenous ascidian Styela plicata dominated complex tiles. Additionally, mixtures with oyster shell supported higher total cover of sessile species, and a higher cover of S. plicata. There were no effects of complexity or mixture on biofilm communities and native and NIS richness. Overall, these results suggest that habitat complexity and some bioreceptive materials may facilitate colonisation by a dominant invertebrate invader on artificial structures.

Ensemble Methods for APS In-Flight Particle Temperature and Velocity Prediction Considering Torch Electrodes Ageing.

The nonlinear relationship between the input process parameters and in-flight particle characteristics of the atmospheric plasma spray (APS) is of paramount importance for coating properties design and quality. It is also known that the ageing of torch electrodes affects this relationship. In recent years, machine learning algorithms have proven to be able to take into account such complex nonlinear interactions. This work illustrates the application of ensemble methods to predict the in-flight particle temperature and velocity during an APS process considering torch electrodes ageing. Experiments were performed to record simultaneously the input process parameters, the in-flight powder particle characteristics and the electrodes usage time. Random Forest (RF) and Gradient Boosting (GB) were used to rank and select the features for the APS process data recorded as the electrodes aged and the corresponding predictive models were compared. The time series aspect of the multivariate APS in-flight particle characteristics data is explored. Two strategies of time series embedding are considered. The first one simply embeds the attributes and the targets from the previous n time segments considered without any modification; whereas the second strategy first performs differencing to make the time series stationary before embedding. For the present application, RF is found to be more suitable than GB since RF can predict both the in-flight particle velocity and temperature simultaneously, properly considering the interactions between the two targets. On the other hand, GB can only predict these two targets one at a time. The superior performance of both embedded predictive models and the feature rankings of them suggest that it is better to consider the APS data as time series for the in-flight particle characteristic prediction. In particular, it is demonstrated that it is advantageous to first make the time series stationary using the traditional differencing technique, even when modeling using RF.

[Predictive value of ultrasound-guided anesthesia injection in arthroscopy for borderline developmental dysplasia of the hip].

Objective: To evaluate the value of ultrasound-guided intra-articular anesthetic injection in predicting postoperative outcomes for borderline developmental hip dysplasia (BDDH). Methods: A follow-up study. The clinical data of 37 BDDH patients who received ultrasound-guided intra-articular anesthetic injection and arthroscopic examination in the Department of Sports Medicine, Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital from May 2018 to February 2021 were retrospectively analyzed. Among them, there were 17 males and 20 females with a mean age of (37.9±12.8) years. All patients underwent ultrasound-guided intra-articular anesthetic injection prior to arthroscopy, and were evaluated with hip physical examination before and after injection, as well as before and after arthroscopy, in order to obtain the visual analog score (VAS) of pain for seven assessments. The total VAS score was calculated based on these evaluations. Follow-up was conducted for at least 12 months. The effective rate of injection referred to the ratio of the improvement of VAS score after anesthetic injection to the total VAS score before injection. Pearson correlation analysis and Bland-Altman analysis were used to test the correlation between modified Harris hip score (mHHS) after ultrasound-guided intra-articular anesthetic injection and mHHS score after arthroscopic surgery. A binary logistic regression model was established to analyze the substantial clinical benefit (SCB) for patients. Following the logistic regression analysis, a receiver operating characteristic (ROC) curve was constructed to evaluate the predictive power of ultrasound-guided intra-articular anesthetic injection in achieving SCB in those patients. The optimal cut-off value for injection efficacy was determined based on the ROC curve when SCB was achieved. Results: The follow-up time for all patients was (26.3±7.6) months. After anesthetic injection for 20 minutes, the total VAS score of pain [M(Q1,Q3)] decreased from 13(8,23) points before injection to 1(0,4) points; and the mHHS score [M(Q1,Q3)] increased from 60(46,70) points before arthroscopy to 90(84,96) points after, with statistically significant differences before and after injection and before and after arthroscopy (both P<0.001). Pearson correlation analysis showed that the mHHS score after intra-articular anesthetic injection was positively correlated with the mHHS score after surgery (r=0.961, P<0.001). The area under the ROC curve for predicting SCB after arthroscopy with ultrasound-guided intra-articular anesthetic injection was 0.769 (95%CI: 0.561-0.976), the Youden index was 0.663, the cut-off value was 0.569 2, the sensitivity was 96.3%, and the specificity was 70.0%. Conclusions: The results of ultrasound-guided intra-articular anesthetic injection before arthroscopy can indicate the presence of intra-articular lesions, and the degree of pain relief after injection is proportional to the functional recovery after arthroscopy. Patients with intra-articular anesthetic injection efficacy>56.92% have better results in hip arthroscopy.

[Clinical efficacy of the treatment of bilateral gluteal muscle contracture by inside-out iliotibial band release under arthroscopy in the supine position].

Objective: To investigate the clinical efficacy of bilateral gluteal muscle contracture treated with inside-out iliotibial band release under arthroscopy in the supine position. Methods: A prospective non-randomized controlled trial. Forty-six patients admitted to the Department of Sports Medicine, Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital from April 2021 to August 2022 for bilateral gluteal muscle contracture and proposed surgical treatment were enrolled. The subjects were divided into two groups according to the preferred surgical protocols of the patients: the supine position group was treated with inside-out iliotibial band release under arthroscopy in the supine position, and the operation in lateral position group was carried out with outside-in iliotibial band release under arthroscopy in the lateral position. The total duration of non-surgical operations and the total duration of surgical operations were recorded for all patients. The gluteal muscle contracture disability scale within 3 days before surgery and at least 2 months after surgery were compared between the two groups, and the occurrence of complications between the two groups was compared too. Results: There were 26 cases in the supine position group, 11 males and 15 females with a mean age of (31.8±7.3) years; and there were 20 cases in the lateral position group, 7 males and 13 females with a mean age of (30.6±6.3) years. The differences in gender, age, body mass index (BMI) and postoperative follow-up time between the two groups were not statistically significant (all P>0.05). The total duration of non-surgical operations was shorter in the supine position group than in the lateral position group [(47.9±10.4) min vs (63.9±7.5) min, P<0.001]. There was no statistically significant difference in the total duration of surgical operations between the supine position group and the lateral position group [31.0(27.0, 43.5) min vs 33.0(24.8, 38.0) min, P>0.05]. The postoperative gluteal muscle contracture disability scales were significantly improved in both the supine position and lateral position groups when compared with those before the operation [93.0 (85.0, 98.0) vs 61.0 (50.5, 66.8), P<0.001 and 88.5±6.9 vs 63.6±9.6, P<0.001, respectively]. There was no statistically significant difference in the gluteal muscle contracture disability scale between the supine position and lateral position groups before and 2 months after surgery [59.3±11.9 vs 63.6±9.6 and 93.0 (85.0, 98.0) vs 89.5(84.0, 94.8), both P>0.05, respectively]. Two patients in each group developed subcutaneous hematoma after surgery, and all of them resolved within 2 weeks after surgery, the difference in complication incidence rate was not statistically significant (P>0.05). No postoperative complications such as fat liquefaction in the operated area, infection, decreased hip abductor muscle strength or nerve injury in the lower extremity were observed in both groups. Conclusion: The treatment of bilateral gluteal muscle contracture by inside-out iliotibial band release under arthroscopy in the supine position can effectively improve clinical efficiency, with definite efficacy, and it is an operative program worth promoting.

[Outcomes of fluoroscopy-free hip arthroscopy technique in the treatment of femoroacetabular impingement syndrome].

Objective: To evaluate the effect of fluoroscopy-free technique in the arthroscopic treatment of femoroacetabular impingement syndrome (FAIS). Methods: A retrospective cohort study. Clinical data of FAI patients treated with hip arthroscopy in the No.4 Medical Center, PLA General Hospital from October 2018 to December 2021 were retrospectively analyzed. The patients were divided into two groups according to the surgical procedure: the fluoroscopy group and the fluoroscopy-free group. The operation time and modified Harris hip score (mHHS), international hip outcome tool (iHOT12) and visual analogue scale (VAS) of hip joint pain before and after the operation were observed and compared between the two groups. And the incidence of surgical complications in the two groups were compared too. Results: A total of 460 patients (213 males and 247 females) [aged (32.6±8.3) years (15-67 years)] with valid follow-up were included in this study. There were 275 cases in the fluoroscopy-free group and 185 cases in the fluoroscopy group. The operation time was shorter in the fluoroscopy-free group when compared with that in the fluoroscopy group, and the difference was statistically significant [(93.36±12.54) min vs (115.62±6.03) min, P<0.001]. In both groups, the VAS scores decreased and the mHHS scores and iHOT12 scores improved significantly at the last follow-up when compared with those before the operation (all P<0.001); however, there was no significant difference in the scores between the two groups (all P>0.05). The complication rate in the fluoroscopy-free group was 10.18% (28/275), and it was 10.81%(20/185) in the fluoroscopy group (P=0.829). Conclusion: Fluoroscopy-free hip arthroscopy technique for FAI can avoid radiation and shorten the operation time, but it does not increase the incidence of complications with reliable clinical outcomes.

Hypotensive Effects of Arginase Inhibition by L-Norvaline in Genetic Models of Normotensive and Hypertensive Rats.

The main effect of arginase inhibition after administration of L-norvaline is a decrease in BP. At the same time, norvaline causes various side effects in normotensive and hypertensive animals. In our experiments, L-norvaline was administered intraperitoneally (30 mg/kg) for 7 days to normotensive WAG rats (Wistar Albino Glaxo) and hypertensive ISIAH rats (Inherited, Stress-Induced Arterial Hypertension). In ISIAH rats, BP decrease was accompanied by an increase in diuresis, while in WAG rats, diuresis remained unchanged or little changed. At the same time, hypertensive rats demonstrated an increase of catecholamine content in the adrenal glands, while in normotensive animals, it was decreased. The differences in the effects of norvaline can be associated with different mechanisms of BP maintenance in normotensive and hypertensive animals. Normally, BP is maintained by the regulatory influences of the nitric oxide system. In hypertension, this system is weakened, and the hypotensive effects are probably achieved via increased diuresis.

[Long-term changes in morphological and functional parameters of the optic nerve in patients with various genetic variants of hereditary optic neuropathies]. / Dolgosrochnaya dinamika morfofunktsional'nykh pokazatelei zritel'nogo nerva u patsientov s razlichnymi geneticheskimi variantami nasledstvennykh opticheskikh neiropatii.

Leber's hereditary optic neuropathy (LHON) and autosomal recessive optic neuropathy (ARON) are degenerative diseases of the optic nerve caused by mutations in nuclear or mitochondrial DNA (nDNA, mtDNA). The clinical picture of these diseases is similar, but there are some differences in how the visual functions change in patients with different molecular genetic variants of hereditary optic neuropathies (HON). PURPOSE: This study evaluates the long-term changes in morphological and functional parameters in patients with different genetic variants of HON. MATERIAL AND METHODS: The study included 84 patients (165 eyes) with a genetically confirmed LHON or ARON diagnosis. The patients underwent best-corrected visual acuity (VA) test, color vision (CV) examination, computerized perimetry using the program for low vision assessment, optical coherence tomography (OCT). RESULTS: Over the course of the follow-up (60 months or longer) HON patients were revealed to have higher VA in c.152A>G and m.14484T>C mutations compared to mutations m.11778G>A and m.3460G>A. The final VA 0.5 or higher in patients with c.152A>G and m.14484T>C mutations in 54 and 71% of cases, and only in 6 and 13% of cases - with m.11778G>A and m.3460G>A mutations. Direct correlation was determined between minimal VA in the first year after disease onset and the final VA (K=0.67; p<0.001). In all patients with the investigated mutations CV recovered slightly quicker than VA. CONCLUSION: HON associated with c.152A>G and m.14484T>C mutations have better prognosis compared to LHON caused by m.11778G>A and m.3460G>A mutations. Vision recovery prognosis is worse in patients who had significant decrease of visual acuity at the disease onset. OCT findings reveal preservation of visual functions in all mutations.

[Rare pathogenic nucleotide variants of mitochondrial DNA associated with Leber's hereditary optic neuropathy]. / Redkie patogennye nukleotidnye varianty mitokhondrial'noi DNK, assotsiirovannye s nasledstvennoi opticheskoi neiropatiei Lebera.

Patients with Leber Hereditary Optic Neuropathy (LHON) in most cases have one of the three most common mutations: m.11778G>A in the ND4 gene, m.3460G>A in the ND1 gene, or m.14484T>C in the ND6 gene. According to the international Mitomap database, in addition to these three most common mutations, there are 16 other primary mutations that are even more rare. There are nucleotide substitutions that are classified as candidate or conditionally pathogenic mutations. Their involvement in the disease development is not proven due to insufficient research. Moreover, in many publications, the authors describe new primary and potential mitochondrial DNA mutations associated with LHON, which are not yet included in the genetic data bases. This makes it possible to expand the diagnostic spectrum during genetic testing in the future. The advancements in genetic diagnostic technologies allow confirmation of the clinical diagnosis of LHON. The importance of genetic verification of the disease is determined by the existing problem of differential diagnosis of hereditary optic neuropathies with optic neuropathies of a different origin.

[Optic neuropathies as an interdisciplinary subject of research]. / Opticheskie neiropatii kak predmet mezhdistsiplinarnogo izucheniya.

Despite the wide range of clinical, instrumental and laboratory methods used in modern ophthalmology, the problem of diagnosing optic neuropathy and identifying its etiology remains relevant. A complex multidisciplinary approach involving various specialists is required in the differential diagnosis of immune-mediated optic neuritis, for example in multiple sclerosis, neuromyelitis optica spectrum disorder, and MOG-associated diseases. Of special interest is differential diagnosis of optic neuropathy in demyelinating diseases of the central nervous system, hereditary optic neuropathies and ischemic optic neuropathy. The article presents a summary of scientific and practical results of differential diagnosis of optic neuropathies with various etiologies. Timely diagnosis and early therapy start reduces the degree of disability in patients with optic neuropathies of different etiologies.

Characterization of rhodanine derivatives as potential disease-modifying drugs for experimental mouse osteoarthritis.

OBJECTIVE: This study was performed to characterize selected rhodanine derivatives as potential preclinical disease-modifying drugs for experimental osteoarthritis (OA) in mice. METHODS: Three rhodanine derivatives, designated rhodanine (R)-501, R-502, and R-503, were selected as candidate OA disease-modifying drugs. Their effects were evaluated by intra-articular (IA) injection in OA mouse models induced by DMM (destabilization of the medial meniscus) or adenoviral overexpression in joint tissues of hypoxia-inducible factor (HIF)-2α or zinc importer ZIP8. The regulatory mechanisms impacted by the rhodanine derivatives were examined in primary-culture chondrocytes and fibroblast-like synoviocytes (FLS). RESULTS: All three rhodanine derivatives inhibited OA development caused by DMM or overexpression of HIF-2α or ZIP8. Compared to vehicle-treated group, for example, IA injection of R-501 in DMM-operated mice reduced median OARSI grade from 3.78 (IQR 3.00-5.00) to 1.89 (IQR 0.94-2.00, P = 0.0001). R-502 and R-503 also reduced from 3.67 (IQR 2.11-4.56) to 2.00 (IQR 1.00-2.00, P = 0.0030) and 2.00 (IQR 1.83-2.67, P = 0.0378), respectively. Mechanistically, the rhodanine derivatives inhibited the nuclear localization and transcriptional activity of HIF-2α in chondrocytes and FLS. They did not bind to Zn2+ or modulate Zn2+ homeostasis in chondrocytes or FLS; instead, they inhibited the nuclear localization and transcriptional activity of the Zn2+-dependent transcription factor, MTF1. HIF-2α, ZIP8, and interleukin-1ß could upregulate matrix-degrading enzymes in chondrocytes and FLS, and the rhodanine derivatives inhibited these effects. CONCLUSION: IA administration of rhodanine derivatives significantly reduced OA pathogenesis in various mouse models, demonstrating that these derivatives have disease-modifying therapeutic potential against OA pathogenesis.

Outcomes during delivery hospitalisations with inflammatory bowel disease.

OBJECTIVE: To characterise inflammatory bowel disease (IBD) trends and associated risk during delivery hospitalisations. DESIGN: Cross-sectional. SETTING: US delivery hospitalisations. POPULATION: Delivery hospitalisations in the 2000-2018 National Inpatient Sample. METHODS: This study analysed a nationally representative hospital discharge database based on the presence of IBD. Temporal trends in IBD were analysed using joinpoint regression to estimate the average annual percent change (AAPC). IBD severity was characterised by the presence of diagnoses such as penetrating and stricturing disease and history of bowel resection. Risks for adverse outcomes were analysed based on presence of IBD. Poisson regression models were performed with unadjusted and adjusted risk ratios (aRR) as measures of effect. MAIN OUTCOME MEASURE: Prevalence of IBD and associated adverse outcomes. RESULTS: Of 73 109 790 delivery hospitalisations, 89 965 had a diagnosis of IBD. IBD rose from 0.06% in 2000 to 0.21% in 2018 (AAPC 7.3%, 95% CI 6.7-7.9%). Among deliveries with IBD, IBD severity diagnoses increased from 4.1% to 8.1% from 2000 to 2018. In adjusted analysis, IBD was associated with increased risk for preterm delivery (aRR 1.50, 95% CI 1.47-1.53), severe maternal morbidity (aRR 1.93, 95% CI 1.83-2.04), venous thrombo-embolism (aRR 2.76, 95% CI 2.39-3.18) and surgical injury during caesarean delivery hospitalisation (aRR 5.03, 95% CI 4.76-5.31). In the presence of a severe IBD diagnosis, risk was further increased for all adverse outcomes. CONCLUSION: IBD is increasing in the obstetric population and is associated with adverse outcomes. Risk is increased in the presence of a severe IBD diagnosis. TWEETABLE ABSTRACT: Deliveries among women with inflammatory bowel disease are increasing. Disease severity is associated with adverse outcomes.