Diagnostic Value of Dynamic Magnetic Resonance Imaging (dMRI) of the Pelvic Floor in Genital Prolapses.

Pelvic organ prolapse is a chronic disease resulting from a weakening of the musculoskeletal apparatus of the pelvic organs. For the diagnosis of this pathology, it is insufficient to conduct only a clinical examination. An effective diagnostic tool is the method of dynamic magnetic resonance imaging (MRI) of the pelvic floor, which allows a comprehensive assessment of the anatomical and functional characteristics of the walls of the pelvis and pelvic organs. The aim of the study was to analyze the literature data on the possibilities and limitations of using dynamic MRI in pelvic organ prolapse. The widespread use of the dynamic MRI method is due to the high quality of the resulting image, good reproducibility, and the maximum ability to display the characteristics of the pelvic floor. Dynamic MRI of the small pelvis allows a comprehensive assessment of the anatomical and functional features of the pelvis, excluding the effect of ionizing radiation on the body. The method is characterized by good visualization with high resolution and excellent soft tissue contrast. The method allows for assessing the state of the evacuation function of visualized structures in dynamics. Simultaneous imaging of all three parts of the pelvic floor using dynamic MRI makes it possible to assess multicompartment disorders. The anatomical characteristics of the state of the pelvic organs in the norm and in the event of prolapse are considered. The technique for performing the method and the procedure for analyzing the resulting images are described. The possibilities of diagnosing a multicomponent lesion are considered, while it is noted that dynamic MRI of the pelvic organs provides visualization and functional analysis of all three parts of the pelvis and often allows the choice and correction of tactics for the surgical treatment of pelvic organ prolapse. It is noted that dynamic MRI is characterized by a high resolution of the obtained images, and the advantage of the method is the ability to detect functional changes accompanying the pathology of the pelvic floor.

Genetic landscape in Russian patients with familial left ventricular noncompaction.

Background: Left ventricular noncompaction (LVNC) cardiomyopathy is a disorder that can be complicated by heart failure, arrhythmias, thromboembolism, and sudden cardiac death. The aim of this study is to clarify the genetic landscape of LVNC in a large cohort of well-phenotyped Russian patients with LVNC, including 48 families (n=214). Methods: All index patients underwent clinical examination and genetic analysis, as well as family members who agreed to participate in the clinical study and/or in the genetic testing. The genetic testing included next generation sequencing and genetic classification according to ACMG guidelines. Results: A total of 55 alleles of 54 pathogenic and likely pathogenic variants in 24 genes were identified, with the largest number in the MYH7 and TTN genes. A significant proportion of variants -8 of 54 (14.8%) -have not been described earlier in other populations and may be specific to LVNC patients in Russia. In LVNC patients, the presence of each subsequent variant is associated with increased odds of having more severe LVNC subtypes than isolated LVNC with preserved ejection fraction. The corresponding odds ratio is 2.77 (1.37 -7.37; p <0.001) per variant after adjustment for sex, age, and family. Conclusion: Overall, the genetic analysis of LVNC patients, accompanied by cardiomyopathy-related family history analysis, resulted in a high diagnostic yield of 89.6%. These results suggest that genetic screening should be applied to the diagnosis and prognosis of LVNC patients.

The Association of PLAUR Genotype and Soluble suPAR Serum Level with COVID-19-Related Lung Damage Severity.

Uncovering the risk factors for acute respiratory disease coronavirus 2019 (COVID-19) severity may help to provide a valuable tool for early patient stratification and proper treatment implementation, improving the patient outcome and lowering the burden on the healthcare system. Here we report the results of a single-center retrospective cohort study on 151 severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected symptomatic hospitalized adult patients. We assessed the association of several blood test measurements, soluble urokinase receptor (uPAR) serum level and specific single nucleotide polymorphisms of ACE (I/D), NOS3 (rs2070744, rs1799983), SERPINE1 (rs1799768), PLAU (rs2227564) and PLAUR (rs344781, rs2302524) genes, with the disease severity classified by the percentage of lung involvement on computerized tomography scans. Our findings reveal that the T/C genotype of PLAUR rs2302524 was independently associated with a less severe lung damage (odds ratio 0.258 [0.071-0.811]). Along with high C-reactive protein, fibrinogen and soluble uPAR serum levels turned out to be independently associated with more severe lung damage in COVID-19 patients. The identified factors may be further employed as predictors of a possibly severe COVID-19 clinical course.

A Splice Variant of the MYH7 Gene Is Causative in a Family with Isolated Left Ventricular Noncompaction Cardiomyopathy.

Variants of the MYH7 gene have been associated with a number of primary cardiac conditions, including left ventricular noncompaction cardiomyopathy (LVNC). Most cases of MYH7-related diseases are associated with such variant types as missense substitutions and in-frame indels. Thus, truncating variants in MYH7 (MYH7tv) and associated mechanism of haploinsufficiency are usually considered not pathogenic in these disorders. However, recent large-scale studies demonstrated evidence of the significance of MYH7tv for LVNC and gave rise to an assumption that haploinsufficiency may be the causal mechanism for LVNC. In this article, we present a family with isolated LVNC and a heterozygous splice variant of the MYH7 gene, analyze possible consequences of this variant and conclude that not all variants that are predicted truncating really act through haploinsufficiency. This study can highlight the importance of a precise assessment of MYH7 splicing variants and their participation in the development of LVNC.

A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene.

Left ventricular noncompaction (LVNC) is a highly heterogeneous primary disorder of the myocardium. Its clinical features and genetic spectrum strongly overlap with other types of primary cardiomyopathies, in particular, hypertrophic cardiomyopathy. Study and the accumulation of genotype-phenotype correlations are the way to improve the precision of our diagnostics. We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene. This is the first description of FHOD3-dependent LVNC to our knowledge. We also revise the assumed mechanism of pathogenesis in the case of FHOD3 splicing alterations.

Regional pericarditis following uncomplicated catheter ablation procedure: a case report.

BACKGROUND: Acute post-ablation pericarditis is the most common complication of epicardial ablation of ventricular arrhythmias, while regional pericarditis following an initially uneventful endocardial catheter ablation (CA) procedure is a rare and elusive diagnosis. CASE SUMMARY: We report a case of a 66-year-old Russian female who developed chest pain accompanied by electrocardiogram (ECG) changes-biphasic T waves in V1-V4 leads after an initially uncomplicated premature ventricular complex CA procedure. After examination and investigations, including transthoracic echocardiography (TTE), cardiac magnetic resonance imaging (CMR) and cardiac computed tomography (CCT), she was diagnosed with regional pericarditis, which occurred even though the ablation was uneventful with the limited number of radiofrequency applications. Furthermore, the diagnosis was difficult due to normal body temperature and the absence of pericardial effusion and myocardial abnormalities on TTE, findings that are not characteristic of pericarditis. The patient's last office visit was in 6 months after the procedure. Neither patient had any complaintsnor there were any changes on ECG and TTE. DISCUSSION: Regional post-ablation pericarditis is a relatively rare type of post-cardiac injury syndrome (PCIS). The varying severity of the PCIS clinical course makes the diagnosis of post-ablation pericarditis initially difficult, especially in patients undergoing an uneventful CA procedure. Non-invasive imaging modalities as CMR and CCT should be considered initially in elusive cases of PCIS.

Overlapping Phenotype of Adult-Onset ALPK3-Cardiomyopathy in the Setting of Two Novel Variants.

Inherited cardiomyopathies (CMPs) are fairly common causes of morbidity and mortality, particularly, in young individuals. In substantial number of cases, only morphological diagnostic criteria cannot distinguish one CMP from another because of incomplete penetrance, advanced stage of the disease, or overlapping phenotypes. Genetic testing has become a mandatory tool for definite diagnosis that is required for family screening, individual prognosis, and personalized treatment strategy in routine practice. In parallel, accumulation of genotype-phenotype correlations, especially for rare genes, promotes the deciphering of underling molecular mechanisms and the development of targeting treatment of CMPs. Here we present an adult-onset case comprised morphological features of several CMPs: asymmetric left ventricle (LV) hypertrophy, severe systolic dysfunction, LV hypertrabeculation and restrictive physiology. Using next-generation sequencing, two novel variants (NM_020778.5:c.1958C>G:p.Ser653* and c.3491G>A:p.Arg1164Gln) in alpha-protein kinase 3 (ALPK3) gene were identified and confirmed with Sanger sequencing. The trans-position (location on different alleles) of identified ALPK3 variants was established by plasmid cloning method. The ALPK3 gene, encoding nuclear alpha-protein kinase 3, has only recently been associated with CMPs and there are still few clinical data on ALPK3 variant carriers. To date, only five affected individuals with adult-onset CMPs in the setting of biallelic variants of ALPK3 gene have been reported.

Scintigraphy false-positive results for cardiac amyloidosis in a patient with Danon disease.

Common diagnostic approach in patients with suspected cardiac amyloidosis includes cardiac magnetic resonance imaging and scintigraphy. We report the first clinical case of false-positive results of scintigraphy in a patient with Danon disease.

The Double Mutation DSG2-p.S363X and TBX20-p.D278X Is Associated with Left Ventricular Non-Compaction Cardiomyopathy: Case Report.

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare heart disease, with or without left ventricular dysfunction, which is characterized by a two-layer structure of the myocardium and an increased number of trabeculae. The study of familial forms of LVNC is helpful for risk prediction and genetic counseling of relatives. Here, we present a family consisting of three members with LVNC. Using a next-generation sequencing approach a combination of two (likely) pathogenic nonsense mutations DSG2-p.S363X and TBX20-p.D278X was identified in all three patients. TBX20 encodes the cardiac T-box transcription factor 20. DSG2 encodes desmoglein-2, which is part of the cardiac desmosomes and belongs to the cadherin family. Since the identified nonsense variant (DSG2-p.S363X) is localized in the extracellular domain of DSG2, we performed in vitro cell transfection experiments. These experiments revealed the absence of truncated DSG2 at the plasma membrane, supporting the pathogenic relevance of DSG2-p.S363X. In conclusion, we suggest that in the future, these findings might be helpful for genetic screening and counseling of patients with LVNC.

Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset.

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2-c.378+1G>T) in the first patient and a nonsense mutation (DSG2-p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

The Desmin (DES) Mutation p.A337P Is Associated with Left-Ventricular Non-Compaction Cardiomyopathy.

Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing gene panel approach for the identification of the underlying mutation. Interestingly, DES-p.A337P was identified in the genomes of both patients, whereas only the index patient carried DSP-p.L1348X. DES encodes the muscle-specific intermediate filament protein desmin and DSP encodes desmoplakin, which is a cytolinker protein connecting desmosomes with the intermediate filaments. Because the majority of DES mutations cause severe filament assembly defects and because this mutation was found in both affected patients, we analyzed this DES mutation in vitro by cell transfection experiments in combination with confocal microscopy. Of note, desmin-p.A337P forms cytoplasmic aggregates in transfected SW-13 cells and in cardiomyocytes derived from induced pluripotent stem cells underlining its pathogenicity. In conclusion, we suggest including the DES gene in the genetic analysis for LVNC patients in the future, especially if clinical involvement of the skeletal muscle is present.

Neural Correlates of Group Versus Individual Problem Solving Revealed by fMRI.

Group problem solving is a prototypical complex collective intellectual activity. Psychological research provides compelling evidence that problem solving in groups is both qualitatively and quantitatively different from doing so alone. However, the question of whether individual and collective problem solving involve the same neural substrate has not yet been addressed, mainly due to methodological limitations. In the current study, functional magnetic resonance imaging was performed to compare brain activation when participants solved Raven-like matrix problems in a small group and individually. In the group condition, the participant in the scanner was able to discuss the problem with other team members using a special communication device. In the individual condition, the participant was required to think aloud while solving the problem in the silent presence of the other team members. Greater activation was found in several brain regions during group problem solving, including the medial prefrontal cortex; lateral parietal, cingulate, precuneus and retrosplenial cortices; frontal and temporal poles. These areas have been identified as potential components of the so-called "social brain" on the basis of research using offline judgments of material related to socializing. Therefore, this study demonstrated the actual involvement of these regions in real-time social interactions, such as group problem solving. However, further connectivity analysis revealed that the social brain components are co-activated, but do not increase their coupling during cooperation as would be suggested for a holistic network. We suggest that the social mode of the brain may be described instead as a re-configuration of connectivity between basic networks, and we found decreased connectivity between the language and salience networks in the group compared to the individual condition. A control experiment showed that the findings from the main experiment cannot be entirely accounted for by discourse comprehension. Thus, the study demonstrates affordances provided by the presented new technique for neuroimaging the "group mind," implementing the single-brain version of the second-person neuroscience approach.

Modulation of Intrinsic Brain Connectivity by Implicit Electroencephalographic Neurofeedback.

Despite the increasing popularity of neurofeedback, its mechanisms of action are still poorly understood. This study aims to describe the processes underlying implicit electroencephalographic neurofeedback. Fifty-two healthy volunteers were randomly assigned to a single session of infra-low frequency neurofeedback or sham neurofeedback, with electrodes over the right middle temporal gyrus and the right inferior parietal lobule. They observed a moving rocket, the speed of which was modulated by the waveform derived from a band-limited infra-low frequency filter. Immediately before and after the session, the participants underwent a resting-state fMRI. Network-based statistical analysis was applied, comparing post- vs. pre-session and real vs. sham neurofeedback conditions. As a result, two phenomena were observed. First, we described a brain circuit related to the implicit neurofeedback process itself, consisting of the lateral occipital cortex, right dorsolateral prefrontal cortex, left orbitofrontal cortex, right ventral striatum, and bilateral dorsal striatum. Second, we found increased connectivity between key regions of the salience, language, and visual networks, which is indicative of integration in sensory processing. Thus, it appears that a single session of implicit infra-low frequency electroencephalographic neurofeedback leads to significant changes in intrinsic brain connectivity.

Alterations of Functional Brain Connectivity After Long-Duration Spaceflight as Revealed by fMRI.

The present study reports alterations of task-based functional brain connectivity in a group of 11 cosmonauts after a long-duration spaceflight, compared to a healthy control group not involved in the space program. To elicit the postural and locomotor sensorimotor mechanisms that are usually most significantly impaired when space travelers return to Earth, a plantar stimulation paradigm was used in a block design fMRI study. The motor control system activated by the plantar stimulation involved the pre-central and post-central gyri, SMA, SII/operculum, and, to a lesser degree, the insular cortex and cerebellum. While no post-flight alterations were observed in terms of activation, the network-based statistics approach revealed task-specific functional connectivity modifications within a broader set of regions involving the activation sites along with other parts of the sensorimotor neural network and the visual, proprioceptive, and vestibular systems. The most notable findings included a post-flight increase in the stimulation-specific connectivity of the right posterior supramarginal gyrus with the rest of the brain; a strengthening of connections between the left and right insulae; decreased connectivity of the vestibular nuclei, right inferior parietal cortex (BA40) and cerebellum with areas associated with motor, visual, vestibular, and proprioception functions; and decreased coupling of the cerebellum with the visual cortex and the right inferior parietal cortex. The severity of space motion sickness symptoms was found to correlate with a post- to pre-flight difference in connectivity between the right supramarginal gyrus and the left anterior insula. Due to the complex nature and rapid dynamics of adaptation to gravity alterations, the post-flight findings might be attributed to both the long-term microgravity exposure and to the readaptation to Earth's gravity that took place between the landing and post-flight MRI session. Nevertheless, the results have implications for the multisensory reweighting and gravitational motor system theories, generating hypotheses to be tested in future research.

Noncompaction cardiomyopathy is caused by a novel in-frame desmin (DES) deletion mutation within the 1A coiled-coil rod segment leading to a severe filament assembly defect.

Mutations in DES, encoding desmin protein, are associated with different kinds of skeletal and/or cardiac myopathies. However, it is unknown, whether DES mutations are associated with left ventricular hypertrabeculation (LVHT). Here, we performed a clinical examination and subsequent genetic analysis in a family, with two individuals presenting LVHT with conduction disease and skeletal myopathy. The genetic analysis revealed a novel small in-frame deletion within the DES gene, p.Q113_L115del, affecting the α-helical rod domain. Immunohistochemistry analysis of explanted myocardial tissue from the index patient revealed an abnormal cytoplasmic accumulation of desmin and a degraded sarcomeric structure. Cell transfection experiments with wild-type and mutant desmin verified the cytoplasmic aggregation and accumulation of mutant desmin. Cotransfection experiments were performed to model the heterozygous state of the patients and revealed a dominant negative effect of the mutant desmin on filament assembly. DES:p.Q113_L115del is classified as a pathogenic mutation associated with dilated cardiomyopathy with prominent LVHT.