Planned Venovenous-Extracorporeal Membrane Oxygenation as a Bridge to Orthotopic Liver Transplant Performed for Very Severe Hepatopulmonary Syndrome: A Case Report.

Concerns related to poor oxygenation in patients with severe hepatopulmonary syndrome (HPS) may be prohibitive when considering their candidacy for liver transplantation. Extracorporeal membrane oxygenation (ECMO) has been utilized in only a few case reports as a bridge to liver transplant in patients with severe respiratory failure. We report a case of a 66-year-old man with cirrhosis and very severe (arterial oxygen pressure (PaO2) < 50 mmHg) hepatopulmonary syndrome who underwent an orthotopic liver transplant with the planned use of venovenous-ECMO. Pre-transplant echocardiography demonstrated a small-trivial patent foramen ovale (PFO) but following the resolution of hepatopulmonary shunting after liver transplantation, the PFO size enlarged and contributed to a thromboembolic stroke. We conclude that well-selected patients with HPS could benefit from the use of planned venovenous-ECMO and that a small-trivial PFO seen in a patient with HPS may warrant intervention prior to transplantation.

The splicing factor CCAR1 regulates the Fanconi anemia/BRCA pathway.

The twenty-three Fanconi anemia (FA) proteins cooperate in the FA/BRCA pathway to repair DNA interstrand cross-links (ICLs). The cell division cycle and apoptosis regulator 1 (CCAR1) protein is also a regulator of ICL repair, though its possible function in the FA/BRCA pathway remains unknown. Here, we demonstrate that CCAR1 plays a unique upstream role in the FA/BRCA pathway and is required for FANCA protein expression in human cells. Interestingly, CCAR1 co-immunoprecipitates with FANCA pre-mRNA and is required for FANCA mRNA processing. Loss of CCAR1 results in retention of a poison exon in the FANCA transcript, thereby leading to reduced FANCA protein expression. A unique domain of CCAR1, the EF hand domain, is required for interaction with the U2AF heterodimer of the spliceosome and for excision of the poison exon. Taken together, CCAR1 is a splicing modulator required for normal splicing of the FANCA mRNA and other mRNAs involved in various cellular pathways.

Multi-instance learning attention model for amyloid quantification of brain sub regions in longitudinal cognitive decline.

Amyloid PET scans help in identifying the beta-amyloid deposition in different brain regions. The purpose of this study is to develop a deep learning model that can automate the task of finding amyloid deposition in different regions of the brain only by using PET scan and without the corresponding MRI scan. 2647 18F-Florbetapir PET scans are collected from Alzheimer's Disease Neuroimaging Initiative (ADNI) from multiple centres taken over a period. A deep learning model based on multi-instance learning and attention is proposed which is trained and validated using 80% of the scans and the remaining 20% of the scans are used for testing the model. The performance of the model is validated using Mean Absolute Error (MAE) and Root Mean Squared Error (RMSE). The proposed model is further tested upon an external dataset consisting of 1413 18F-Florbetapir PET scans from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study. The proposed model achieves MAE of 0.0243 and RMSE of 0.0320 for summary Standardized Uptake Value Ratio (SUVR) based on composite reference region for ADNI test set. When tested on the A4-study dataset, the proposed model achieves MAE of 0.038 and RMSE of 0.0495 for summary SUVR based on the composite region. The results show that the proposed model provides less MAE and RMSE when compared with existing models. A graphical user interface is developed based on the proposed model where the predictions are made by selecting the files of 18F-Florbetapir PET scans.

Effectiveness of Simulation-Based, Peer Learning Intervention in Continuing Nursing Education: An Explorative Study.

BACKGROUND: Despite the vast research by nursing professionals on various methods of nursing education, little research has been conducted exploring the efficacy of peer learning as a teaching-learning tool amongst registered nurses. Hence, this study was conducted among in-service nursing officers to evaluate the usefulness of simulation-based peer learning sessions as an educational tool for capacity building. MATERIAL AND METHODS: Using a pre-test and post-test design, the study was conducted among 150 in-service nurses at a tertiary care hospital. Five structured simulation-based, peer learning modules were designed. The nurses were divided into five groups using random and purposive sampling. Each group attended one session of the peer learning module on advanced nursing care by simulated clinical and nursing care 'demonstrate, observe, assist, and perform' (DOAP) activity. Pre-test, post-test, and retention tests (after two months) were conducted, and the results were compared. RESULTS: There was a significant increase in mean knowledge (p-value < 0.05) in the post-test after all five sessions, which shows the effectiveness of such peer learning sessions in improving the baseline. There was a decline in mean scores in the retention test compared to that of the post-test, which was statistically significant in only the group of learners participating in the first session. CONCLUSION: The study provides substantial evidence that simulation-based peer learning is an effective tool for continuing nursing education, and it can be used as a valuable tool to reduce the documented theory-practice gap.

Single-stranded DNA Gap Accumulation is a Functional Biomarker for USP1 Inhibitor Sensitivity.

Recent studies suggest that PARP inhibitors and POLQ inhibitors confer synthetic lethality in BRCA1-deficient tumors by accumulation of single-stranded DNA (ssDNA) gaps at replication forks. Loss of USP1, a deubiquitinating enzyme, is also synthetic lethal with BRCA1 deficiency, and USP1 inhibitors are now undergoing clinical development for these cancers. Here, we show that USP1 inhibitors also promote the accumulation of ssDNA gaps during replication in BRCA1-deficient cells, and this phenotype correlates with the drug sensitivity. USP1 inhibition increased monoubiquitinated PCNA at replication forks, mediated by the ubiquitin ligase RAD18, and knockdown of RAD18 caused USP1 inhibitor resistance and suppression of ssDNA gaps. USP1 inhibition overcame PARP inhibitor resistance in a BRCA1-mutated xenograft model and induced ssDNA gaps. Furthermore, USP1 inhibition was synergistic with PARP and POLQ inhibition in BRCA1-mutant cells, with enhanced ssDNA gap accumulation. Finally, in patient-derived ovarian tumor organoids, sensitivity to USP1 inhibition alone or in combination correlated with the accumulation of ssDNA gaps. Assessment of ssDNA gaps in ovarian tumor organoids therefore represents a rapid approach for predicting response to USP1 inhibition in ongoing clinical trials.

Nucleosome reorganisation in breast cancer tissues.

BACKGROUND: Nucleosome repositioning in cancer is believed to cause many changes in genome organisation and gene expression. Understanding these changes is important to elucidate fundamental aspects of cancer. It is also important for medical diagnostics based on cell-free DNA (cfDNA), which originates from genomic DNA regions protected from digestion by nucleosomes. RESULTS: We have generated high-resolution nucleosome maps in paired tumour and normal tissues from the same breast cancer patients using MNase-assisted histone H3 ChIP-seq and compared them with the corresponding cfDNA from blood plasma. This analysis has detected single-nucleosome repositioning at key regulatory regions in a patient-specific manner and common cancer-specific patterns across patients. The nucleosomes gained in tumour versus normal tissue were particularly informative of cancer pathways, with ~ 20-fold enrichment at CpG islands, a large fraction of which marked promoters of genes encoding DNA-binding proteins. The tumour tissues were characterised by a 5-10 bp decrease in the average distance between nucleosomes (nucleosome repeat length, NRL), which is qualitatively similar to the differences between pluripotent and differentiated cells. This effect was correlated with gene activity, differential DNA methylation and changes in local occupancy of linker histone variants H1.4 and H1X. CONCLUSIONS: Our study offers a novel resource of high-resolution nucleosome maps in breast cancer patients and reports for the first time the effect of systematic decrease of NRL in paired tumour versus normal breast tissues from the same patient. Our findings provide a new mechanistic understanding of nucleosome repositioning in tumour tissues that can be valuable for patient diagnostics, stratification and monitoring.

A Young Female Newly Diagnosed With Takayasu's Arteritis Masquerading As Cerebrovascular Stroke.

The condition known as Takayasu's disease or Takayasu's arteritis is a type of vascular inflammation that affects the large and medium arteries. It can lead to a reduction in blood flow to various parts of the body, and it can cause severe complications. Patients with this disease may not have specific symptoms, which can lead to their diagnosis not being confirmed. Takayasu's disease is believed to be a probable cause of stroke in young patients. Although stroke is a common cause of morbidity, it is usually not an initial presentation in Takayasu's disease. In this study, a young female with left-sided hemiparesis was diagnosed with Takayasu's disease after a clinical and angiographic examination.

Fork restart: unloading FANCD2 to travel ahead.

In this issue of Molecular Cell, Brunner et al.1 reveal that eliminating FANCD2 from stalled forks via FBXL12-mediated degradation enables cells to tolerate oncogene-induced replication stress, making FBXL12 a promising target for cancer treatment.

Scleredema Adultorum of Buschke Associated With Diffuse Eosinophilia and Hepatitis B Virus Infection.

Scleredema adultorum of Buschke is a rare condition that presents as a scleroderma mimic and portends a diagnostic challenge to the clinician. It may be associated with monoclonal gammopathy, upper respiratory tract infection, or type II diabetes mellitus. In addition, it is associated with dermal collagen and aminoglycan deposits that cause the skin to thicken and stiffen. Typically, thickening and tightening begin in the neck and progress to the upper body, including the face, scalp, shoulders, and trunk, but sparing the palms and soles. Patients with minor skin involvement may not suffer any symptoms, whereas those with significant skin disease may develop stiffness and functional impairment. There are rare reports linking scleredema adultorum of Buschke with several infections such as human immunodeficiency virus infection, acquired immunodeficiency syndrome-related lipodystrophy syndrome, and streptococcal infection of the upper respiratory tract. Here, we present a case of scleredema adultorum of Buschke associated with hepatitis B infection.

Effectiveness of Physical Therapy in a Comminuted Patella Fracture Managed with Tension Band Wiring: A Case Report.

A patella fracture occurs when the patella bone, which covers the knee joint, breaks. A severe injury, such as a fall or a hit to the patella, is frequently the cause. There are two types of patella fractures: basic and complicated. The treatment of certain fractures necessitates surgery. Patella fracture symptoms include pain, swelling, bruising, inability to straighten the leg, and inability to walk. Rehabilitation aims to increase the range of motion, increase muscles' strength, and make the patient functionally independent. We report the case of a 69-year-old female with a comminuted patella fracture managed with open reduction and internal fixation (ORIF) with tension band wiring. A four-week inpatient rehabilitation increasing range of motion and improving strength has shown a tremendous improvement in the patient's symptoms.

Role of phosphate-buffered saline on push-out bond strength of MTA Flow™ and Biodentine™ after acid challenge: An in vitro study.

Context: The physical and chemical properties of root repair materials are adversely affected when placed in areas of inflammation with acidic pH. Aim: To evaluate the role of phosphate-buffered saline (PBS- pH 7.4) on push-out bond strength (POBS) of MTA flow and Biodentine (BD) after acid challenge with butyric acid buffered solution (BABS- pH 5.4). Subjects and Methods: Eighty mid-root dentin slices (2 mm thick; 1.3 mm lumen diameter) were prepared and were divided into two groups (n = 40) based on the type of material used for filling lumen: Group 1-MTA Flow and Group 2-BD. Each group was again divided into four subgroups (n = 10) based on the duration of exposure to storage media: (a) 3 days in PBS, (b) 3 days in BABS, (c) 3 days in BABS followed by 30 days in PBS, and (d) 33 days in PBS. POBS was then measured using the universal strength testing machine. Statistical Analysis Used: Statistical analysis was performed with one-way analysis of variance and post hoc test using SPSS software version 23.0. Results: Group 1b and 2b showed significantly lower bond strength values. No significant difference was observed between Group 1b and Group 1c (P > 0.05), whereas highly significant POBS values were observed between Group 2b and Group 2c (P = 0.000). Among all the tested groups, Group 2d showed the highest POBS values. Conclusion: On storage in PBS after acid challenge, BD attained the highest POBS values while no significant difference was observed in MTA Flow.

MYH7 variants cause complex congenital heart disease.

MYH7, encoding the myosin heavy chain sarcomeric ß-myosin heavy chain, is a common cause of both hypertrophic and dilated cardiomyopathy. Additionally, families with left ventricular noncompaction cardiomyopathy (LVNC) and congenital heart disease (CHD), typically septal defects or Ebstein anomaly, have been identified to have heterozygous pathogenic variants in MHY7. One previous case of single ventricle CHD with heart failure due to a MYH7 variant has been identified. Herein, we present a single center's experience of complex CHD due to MYH7 variants. Three probands with a history of CHD, LVNC, and/or arrhythmias were identified to have MYH7 variants through multigene panel testing or exome sequencing. These three patients collectively had 12 affected family members, four with a history of Ebstein anomaly and seven with a history of LVNC. These findings suggest a wider phenotypic spectrum in MYH7-related CHD than previously understood. Further investigation into the possible role of MYH7 in CHD and mechanism of disease is necessary to fully delineate the phenotypic spectrum of MYH7-related cardiac disease. MYH7 should be considered for families with multiple individuals with complex CHD in the setting of a family history of LVNC or arrhythmias.

CTV Based Sensor for the Rapid Detection of Nitro Toluene With Computational Studies and Molecular Modelling.

A new tri-naphthoylated Cyclotriveratrylene molecule has been synthesized for the rapid and sensitive detection of 4-nitrotoluene (4-NT) among various nitro aromatic compounds (NACs) by using a spectrofluorimetric method. The newly derrivatized cyclotriveratrylene compound is successfully confirmed by using the available techniques of 1H-NMR, 13CNMR, and ESI-MS. This synthesised molecule is 1NC-CTV (1-Naptholy Chloride-Cyclotriveratrylene). Strong quenching in the fluorescence intensity of 1NC-CTV was observed upon the addition of 4-NT. Further quantum yield studies were carried out and by using the stern volmer it was concluded that the fluorescence quenching mechanism is dynamic or static. The molecule 1NC-CTV was further studied with the help of computational methods such as molecular docking to study the binding interactions and properties of the molecule.

CTV Based Sensor for the Detection of Ni2+ Ions With Real Sample Analysis Based on Mechanism of Fluorescence Along with Computational Insights.

Identification and detection of harmful contaminants such as nickel and other materials from soil and water is critical necessity at the present moment. So with this motive to detect and identify harmful pollutants, a novel cyclotriveratrylene based derivative was prepared for the detection and binding of harmful pollutants which had the properties of fluorescence. The newly derivative of Cyclotriveratrylene was found to be highly sensitive and selective towards Ni2+ ions. The complexation behaviour of this newly synthesised molecule was studied in presence of transition elements. Also computational methods such as docking, molecular modelling and DFT were used to study the molecular orbitals and energies of CTG-NBEP. The detection of Ni2+ from water samples were also carried out successfully.

NucPosDB: a database of nucleosome positioning in vivo and nucleosomics of cell-free DNA.

Nucleosome positioning is involved in many gene regulatory processes happening in the cell, and it may change as cells differentiate or respond to the changing microenvironment in a healthy or diseased organism. One important implication of nucleosome positioning in clinical epigenetics is its use in the "nucleosomics" analysis of cell-free DNA (cfDNA) for the purpose of patient diagnostics in liquid biopsies. The rationale for this is that the apoptotic nucleases that digest chromatin of the dying cells mostly cut DNA between nucleosomes. Thus, the short pieces of DNA in body fluids reflect the positions of nucleosomes in the cells of origin. Here, we report a systematic nucleosomics database - NucPosDB - curating published nucleosome positioning datasets in vivo as well as datasets of sequenced cell-free DNA (cfDNA) that reflect nucleosome positioning in situ in the cells of origin. Users can select subsets of the database by a number of criteria and then obtain raw or processed data. NucPosDB also reports the originally determined regions with stable nucleosome occupancy across several individuals with a given condition. An additional section provides a catalogue of computational tools for the analysis of nucleosome positioning or cfDNA experiments and theoretical algorithms for the prediction of nucleosome positioning preferences from DNA sequence. We provide an overview of the field, describe the structure of the database in this context, and demonstrate data variability using examples of different medical conditions. NucPosDB is useful both for the analysis of fundamental gene regulation processes and the training of computational models for patient diagnostics based on cfDNA. The database currently curates ~ 400 publications on nucleosome positioning in cell lines and in situ as well as cfDNA from > 10,000 patients and healthy volunteers. For open-access cfDNA datasets as well as key MNase-seq datasets in human cells, NucPosDB allows downloading processed mapped data in addition to the regions with stable nucleosome occupancy. NucPosDB is available at https://generegulation.org/nucposdb/ .

Delayed lung function testing after COVID-19 to detect persistent lung function abnormalities - The DELTA - COVID-19 lung function study.

Background: Coronavirus disease 2019 (COVID-19) has made its presence felt as the worst pandemic witnessed till date in the 21st century. The mortality and morbidity associated with COVID-19 does not end with the acute pneumonia and respiratory failure and consequences extend well into the subsequent weeks to months in a minority. After recovery from severe disease, symptoms, lung function abnormalities and radiological changes are known to persist for varying length of time in a small proportion of patients. Various studies report different incidences of lung function abnormalities post-COVID-19. The present study describes the occurrence, severity, pattern and risk factors for persistent lung function abnormalities post-COVID-19 patients. Aim: The present study was aimed to find out the occurrence of persistent lung function abnormalities in patients hospitalised with COVID-19 at three months of discharge who had normal previous lung function prior to COVID-19. In those with persisting abnormal lung function, the severity, pattern and risk factors for persistent lung function abnormalities were also studied. Methods: The present study was a retrospective study in patients hospitalised with COVID-19 who had radiological evidence of pneumonia at admission. Patients with prior abnormal lung function were excluded from the study. Lung function was analysed with spirometry, 6-min walk test and diffusion capacity between day 85 and 95 of hospital discharge and the occurrence, severity and pattern of impairment was described. Lung function impairment was correlated with baseline characteristics and univariate regression analysis was done to identify risk factors for persisting functional impairment. Results: 39 patients were included in the study. Spirometry at follow up showed a restrictive ventilatory defect in 26 out of 39 patients (64%) and a normal study was noted in 12 patients. One patient had an obstructive ventilatory defect. Diffusion impairment was present in 27 patients and normal transfer factor was seen in 12 patients. The degree of diffusion impairment was mild in 16 patients and moderate in 11 patients. Univariate regression analysis revealed that age, history of systemic hypertension, severe hypoxia at presentation, and extent of lung involvement by CT chest were associated with lung function impairment. Conclusion: Almost two-thirds of patients hospitalised with COVID-19 pneumonia have persistent lung function abnormalities at three months post-discharge. Advanced age, severe disease and medical comorbidities increase the risk of persistent functional abnormalities.

Awareness and preparedness of first responders regarding chemical, biological, radiological, nuclear and explosive (CBRNE) disaster management of a tertiary medical institute in South India: A mixed methods study.

Background: In case of a CBRNE catastrophe, junior doctors (first responders) will be the first to respond to the CBRNE disaster, so they should be fully equipped with the knowledge and skills of managing CBRNE casualties and preventing the endangerment of lives. Objectives: To assess the awareness and preparedness of first responders in medical institutions regarding CBRNE casualties' management and to explore the perceptions of first responders towards CBRNE disaster management. Materials and Methods: The present study was a mixed methods study which was conducted during the months of January to March 2020 among 153 study participants. Focus group discussions (FGDs) were conducted along with free listing and pile sorting till data saturation. Data entry was done in an Excel sheet and data analysis was be done using SPSS software v. 21. Results: Out of the 153 participants only 37 participants (24.1%) had ever heard about the term "CBRNE" (chemical, biological, radiological and nuclear disasters) or "hazmat" (hazardous material). At the end of FGDs, participants could answer affirmatively that they had heard the term "decontamination" of CBRNE casualties. Very few participants could ambiguously explain the meaning of the term "decontamination" in the context of CBRNE casualty. Conclusion: There is an imperative need for enhancing not only knowledge and awareness, but also proper training for first responders to utilizing simulation sessions. This is particularly important as health care professionals are the first line of defence when it comes to identifying and treating patients that have come into contact with CBRNE hazards.

A Sensor for the Detection of Cr (III) and Fe (III) Ions Based on "Turn Off" Mechanism of Fluorescence with Computational Studies.

A new and innovative fluorescent structure was constructed on Cyclotriveratrylene affiliated to Dansyl chloride (DNSC) and was used to detect Cr (III) and Fe (III) among the various cations by using spectrofluorimetric method. The characterization of the new compound was carried out using the 1H-NMR, 13C-NMR, and ESI-MS techniques. The interaction and role of DNSC-CTV with cations was reviewed. A change in the spectra of absorption directed to the conclusion that there is substantial interaction of Cr (III) and Fe (III) with DNSC-CTV. Furthermore the interaction of the ligand DNSC-CTV with the metal ions Chromium (III) and Iron (III) showed quenching in the emission spectra. Quantum yield of the complexes were calculated and the stern volmer analysis was done to deduce the quenching mechanism of fluorescence to being either static or dynamic. The molecule DNSC-CTV was further studied with the help of computational methods such as molecular docking to study the binding interactions and properties of the molecule.