Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease.

Alagille syndrome (ALGS) is a multisystem condition characterized by cholestasis and bile duct paucity on liver biopsy and variable involvement of the heart, skeleton, eyes, kidneys, and face and caused by pathogenic variants in the JAG1 or NOTCH2 gene. The variable expressivity of the clinical phenotype and the lack of genotype-phenotype correlations lead to significant diagnostic difficulties. Here we present an analysis of 18 patients with cholestasis who were diagnosed with ALGS. We used an NGS panel targeting coding exons of 52 genes, including the JAG1 and NOTCH2 genes. Sanger sequencing was used to verify the mutation in the affected individuals and family members. The specific facial phenotype was seen in 16/18 (88.9%). Heart defects were seen in 8/18 (44.4%) patients (pulmonary stenosis in 7/8). Butterfly vertebrae were seen in 5/14 (35.7%) patients. Renal involvement was detected in 2/18 (11.1%) cases-one patient had renal cysts, and one had obstructive hydronephrosis. An ophthalmology examination was performed on 12 children, and only one had posterior embryotoxon (8.3%). A percutaneous liver biopsy was performed in nine cases. Bile duct paucity was detected in six/nine cases (66.7%). Two patients required liver transplantation because of cirrhosis. We identified nine novel variants in the JAG1 gene-eight frameshift variants (c.1619_1622dupGCTA (p.Tyr541X), c.1160delG (p.Gly387fs), c.964dupT (p.C322fs), c.120delG (p.L40fs), c.1984dupG (p.Ala662Glyfs), c.3168_3169delAG (p.R1056Sfs*51), c.2688delG (p.896CysfsTer49), c.164dupG (p.Cys55fs)) and one missense variant, c.2806T > G (p.Cys936Gly). None of the patients presented with NOTCH2 variants. In accordance with the classical criteria, only six patients could meet the diagnostic criteria in our cohort without genetic analysis. Genetic testing is important in the diagnosis of ALGS and can help differentiate it from other types of cholestasis.

Impedance-based sensors discriminate among different types of blood thrombi with very high specificity and sensitivity.

BACKGROUND: Intracranial occlusion recanalization fails in 20% of endovascular thrombectomy procedures, and thrombus composition is likely to be an important factor. In this study, we demonstrate that the combination of electrical impedance spectroscopy (EIS) and machine learning constitutes a novel and highly accurate method for the identification of different human thrombus types. METHODS: 134 samples, subdivided into four categories, were analyzed by EIS: 29 'White', 26 'Mixed', 12 'Red' thrombi, and 67 liquid 'Blood' samples. Thrombi were generated in vitro using citrated human blood from five healthy volunteers. Histological analysis was performed to validate the thrombus categorization based on red blood cell content. A machine learning prediction model was trained on impedance data to differentiate blood samples from any type of thrombus and in between the four sample categories. RESULTS: Histological analysis confirmed the similarity between the composition of in vitro generated thrombi and retrieved human thrombi. The prediction model yielded a sensitivity/specificity of 90%/99% for distinguishing blood samples from thrombi and a global accuracy of 88% for differentiating among the four sample categories. CONCLUSIONS: Combining EIS measurements with machine learning provides a highly effective approach for discriminating among different thrombus types and liquid blood. These findings raise the possibility of developing a probe-like device (eg, a neurovascular guidewire) integrating an impedance-based sensor. This sensor, placed in the distal part of the smart device, would allow the characterization of the probed thrombus on contact. The information could help physicians identify optimal thrombectomy strategies to improve outcomes for stroke patients.

Special Characteristics of the Resilience of Russian Families in the Face of Modern Challenges (A Preliminary Study).

Background: A challenge is considered a "wake-up call" for family resilience, requiring a proper response (willingness to evaluate, understand an event and its signals, and also give an adequate response). Family resilience is defined as an adequate response to challenges, that is, the ability to cope with them based on the cultural-historical context and family resources, such as clear and open family communication and connectedness, the use of social resources, a broad system of values and senses, the ability to derive meaning from adversity, acceptance, and flexibility. Objective: This article reports on a study which aimed to analyze components of the resilience of Russian families in response to life circumstances that have become challenges for them. Design: The study was conducted from March 20 to May 7, 2022. Participants took an online survey on Yandex-forms; the link to the survey was distributed through social networks on public pages and in private messages. Two hundred seventy-four (274) representatives of Russian families responded, including 234 women and 40 men (14.6%) ranging from age 17 to 65 (cf. 34.1+12.5). After removing the data of 15 participants who did not report a negative event in their families, the final sample consisted of 259 people. Results: Challenges for modern Russian families can be categorized as loss challenges, relationship challenges, global challenges, challenges of illness, and challenges of financial well-being. The challenges of loss stimulate flexibility of response, acceptance, and overcoming suffering through mutual understanding. Global challenges and the challenges of illness awaken family spirituality. The ability to discuss problems together and share decision making becomes a resource to meet the challenge of families' financial well-being. Confidence in solving problems and a positive outlook become resources to face relationship challenges. The intensity of events is a signal for a family to evoke communication and connectedness, acceptance, and flexibility, as well as family resilience as a whole. Conclusion: There is a connection between the difficulties that respondents regard as challenges and the characteristics of their family resilience; the most adequate response to challenges is to increase family resilience.

Hepatic glycogen synthase (GYS2) deficiency: seven novel patients and seven novel variants.

Glycogen storage disease type 0 (GSD 0) is an autosomal recessive disorder of glycogen metabolism caused by mutations in the GYS2 gene manifesting in infancy or early childhood and characterized by ketotic hypoglycemia after prolonged fasting, and postprandial hyperglycemia and hyperlactatemia. GSD 0 is a rare form of hepatic glycogen storage disease with less than 30 reported patients in the literature so far.DNA samples of 93 Russian patients with clinical diagnoses of hepatic GSDs were collected and analyzed by next-generation sequencing custom target panel and by direct sequencing. Seven new GSD 0 patients with variable phenotypes were found showing 10 variants. Seven variants are novel.We present seven new GSD 0 patients with variable phenotypes. Overall, 10 different mutant alleles of the GYS2 gene were found. Seven of them are novel: c.214delC, c.845delT, c.1644C>A, c.205T>A, c.929G>T, c.1169G>C and c.1703C>A. Three of the novel variants were annotated as pathogenic and likely pathogenic; four other variants have an uncertain significance.The current results expand the spectrum of known mutations in GYS2 and suggest that phenotypes of GSD 0 are more variable and less specific than the reported ones. SYNOPSIS: Seven new patients with glycogen storage disease type 0 were found using next-generation sequencing and seven novel variants of GYS2 gene were annotated.

Molecular dynamics simulation of thermomechanical properties of montmorillonite crystal. 3. montmorillonite crystals with PEO oligomer intercalates.

We present the results of molecular dynamics (MD) simulation of the structure and thermomechanical behavior of Wyoming-type Na+-montmorillonite (MMT) with poly(ethylene oxide) (PEO) oligomer intercalates. Periodic boundary conditions in all three directions and simulation cells containing two MMT lamellae [Si248Al8][Al112Mg16]O640[OH]128 oriented parallel to the XY-plane were used. The interlamellar space, or gallery, between neighboring MMT lamellae was populated by 24 Na+ counterions and PEO macromolecules of different lengths, ranging from 2 up to 240 repeat units. We considered three different loadings of PEO within the gallery: 80, 160, and 240 repeat units, corresponding to 13, 23, and 31 wt % PEO based on total mass of the nanocomposite, respectively. In the cases of 13 and 23 wt %, the polymer chains formed one or two well-defined amorphous layers with interlayer distances of 1.35 and 1.8 nm, respectively. We have observed also formation of a wider monolayer gallery with interlayer distances of 1.6 nm. Three-layer PEO films formed in the case of 31 wt % loading. The thermal properties were analyzed over the range 300-400 K, and the isothermal linear compressibility, transversal moduli, and shear moduli were calculated at 300 K. These properties are compared with the results of our simulation of thermal and mechanical properties of MMT crystal with galleries filled by one or two water layers as well as with those of an isolated clay nanoplate.

Molecular dynamics simulation of thermomechanical properties of montmorillonite crystal. 1. Isolated clay nanoplate.

The structure and mechanical properties of clay nanoparticles is a subject of growing interest because of their numerous applications in engineering. We present the results of molecular dynamics simulation for a single nanoplate of pyrophyllite - a 2:1 clay mineral consisting of two tetrahedral sheets of SiO4 and an intervening octahedral AlO6 sheet. Simulations were performed in the temperature interval from 5 to 750 K using the ionic-type potentials of Cygan et al. On this basis the temperature dependences of structural parameters, characterizing both tetrahedral and octahedral sheets as well as single lamella, have been studied. Two slightly different structures were observed in this wide temperature interval. The mechanical properties of the nanoplate were calculated from stress-strain diagrams, which have been obtained at relatively slow rates of deformation (for molecular simulations). Using different types of loading, we calculated the full elasticity tensor and estimated the influence of temperature on its components. We estimated also the bending and torsion stiffnesses of the nanoplate as specific characteristics of this type of particle. Because the nanoplate is atomically thin, a reasonable determination of the thickness is a nontrivial problem, both in the modeling of mechanical properties and in physical interpretation of the obtained data. We propose a procedure for its calculation.