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.

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/ .

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 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.

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.

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.

Evaluation of Different Preosteotomy Determinants as Affecting the Success of Implant Therapy: A "CBCT"-based Clinical Study.

AIM: The success of implant therapy is of greatest concern for clinicians because a minor negligence can lead to ultimate failure of treatment. However, comprehensive and precise treatment planning can ensure high success rate of implant therapy. Cone-beam computed tomography (CBCT) is an innovation that allows clinicians to explore all related factors in details. This study was conducted to evaluate different preosteotomy determinants as affecting the success of implant therapy in the maxillary anterior region using CBCT. MATERIALS AND METHODS: This study was conducted on 98 partially or complete denture patients willing for artificial replacement of their missing teeth by implant or implant over-denture. Demographic details of participating patients were collected. Furthermore, comprehensive local examination was also done to finalize the site of placement of implant. Cone-beam computed tomography was attempted in all patients for determining accurate implant location, status of bone, and other interrelated determinants of implant success. Cone-beam computed tomography was also prescribed for patients so as to have presurgical idea of implant dimensions as shown in virtual placement of implant. To rule out any interobserver bias, the interpretations of CBCT images were completed by two independent experienced observers. RESULTS: In the 98 studied patients, 61 were males and 37 were females. The study was restricted to the maxillary anterior region only. The studied preosteotomy determinants were available bone height and width in the edentulous region from ridge crest up to the maxillary sinus floor or the nasal fossa floor. A total of 107 implants were placed virtually (on CBCT) in the maxillary anterior region and compared quantitatively in postosteotomy phases. Implant placement sites were the maxillary central incisor region (39), the lateral incisor region (31), and canine (37). Authors also noticed that the relative length and width of virtual implant remained unaffected in 97% of the cases. CONCLUSION: Cone-beam computed tomography showed accurate status of various presurgical determinants like trabeculae, peri-ridiculer pathology, and amount of horizontal and vertical bone losses. Hence, it was further concluded that all these presurgical determinants greatly affect the final success rate of implant therapy. It is therefore deemed necessary to judiciously consider and clinically manage such factors before attempting implant in the maxillary anterior region. CLINICAL SIGNIFICANCE: Presurgical evaluation of factors associated with implant dimensions significantly assists clinicians in deciding the finest treatment option. All additional information provided by CBCT genuinely led to a change in the treatment plan that provides enhanced clinical outcome with lesser postoperative complications. How to cite this article: Jain S, Kapoor K, Sethi K, et al. Evaluation of Different Preosteotomy Determinants as Affecting the Success of Implant Therapy: A "CBCT"-based Clinical Study. J Contemp Dent Pract 2019;20(10):1212-1216.

Outbreak of mumps virus genotype G infection in tribal individuals during 2016-17 in India.

Tribal individuals presented with fever and uni- or bi-lateral parotitis in Galonda and Silli villages (Dadra and Nagar Haveli, India) between 2 October 2016 and 19 March 2017. Consequently, the magnitude and epidemiological characteristics of the outbreak were investigated. Overall, 139 cases of suspected mumps were identified in both the above villages. Most of the suspected cases were 5-15 years old, the exceptions being three adults who had no noticeable complications. Specimens were collected from 42 of the suspected cases and their close contacts (n = 39) for laboratory investigation. Mumps infection was laboratory-confirmed in 73.8% and 20.5% of the suspected cases and contacts, respectively. Mumps was confirmed in seven adults aged 17-42 years, including three suspected cases and four contacts. To the best of our knowledge, this is the first report of a complete virus genome circulating among tribal individuals. Sequencing and phylogenetic studies revealed circulation of mumps virus genotype G in these tribal villages with 99% identity to a mumps virus detected in the UK (1996) and Canada (2009). Comparison with Indian mumps viruses revealed 99% and 98% identity to previously reported isolates from Pune during 2012 and 1986, respectively. Although the outbreak was large, no major complications were reported in the tribal villages. Detection of asymptomatic mumps in numerous close contacts indicates the importance of laboratory investigations in an outbreak setting.

Migraine Aura Without Headache [corrected].

PURPOSE OF REVIEW: This review evaluates and explains our current understanding of a rare subtype of migraine, typical aura without headache, also known as migraine aura without headache or acephalgic migraine. RECENT FINDINGS: Typical aura without headache is a known entity within the spectrum of migraine. Its pathophysiology is suggested to be similar to classic migraines, with cortical spreading depression leading to aura formation but without an associated headache. No clinical trials have been performed to evaluate treatment options, but case reports suggest that most patients will respond to the traditional treatments for migraine with aura. Bilateral greater occipital nerve blocks may be helpful in aborting migraine with prolonged aura. Transcranial magnetic stimulation has shown efficacy in aborting attacks of migraine with aura but has not been specifically tested in isolated aura. Typical aura without headache occurs exclusively in 4% patients with migraine, and may take place at some point in 38% of patients with migraine with aura. Typical aura without headache commonly presents with visual aura without headache, brainstem aura without headache, and can also develop later in life, known as late-onset migraine accompaniment.

Correction to: Migraine Aura Without Headache.

The original version of this article contains an error in the title. The title should be: Migraine Aura Without Headache. The title is corrected in this correction article.

Shortened preprocedural fasting in the pediatric emergency department.

BACKGROUND: There is no evidence of an association between fasting time and the incidence of adverse events during procedural sedation and analgesia. Pediatric and adult emergency medicine guidelines support avoiding delaying procedures based on fasting time. General pediatric guidelines outside emergent care settings continue to be vague and do not support a set fasting period for urgent and emergent procedures. OBJECTIVE: To describe shortened preprocedural fasting and vomiting event rates during the implementation of a shortened fasting protocol. METHODS: This was a prospective study of patients undergoing procedural sedation and analgesia (PSA) in an urban, tertiary care children's hospital emergency center from March 2010-February 2012. All consecutive patients had documentation of preprocedural fasting time and adverse events recorded on a standardized data collection form. RESULTS: PSA occurred in 2426 patients with fasting data available for 2188 (90.2%); 1472 were fasted ≥6 h for solids and 716 patients were in the shortened fasting group (<6 h). There is no evidence of an association between emesis at any time and shortened fasting time unadjusted (OR = 1.18 (95% CI 0.75-1.84) or adjusted for known risk factors including age >12 years, initial ketamine dose >2.5 mg/kg or total dose >5.0 mg/kg (OR = 1.14 (95% CI 0.74-1.75). CONCLUSION: Analysis of a large prospective cohort study failed to find evidence of an association between emesis and shortened fasting time upon implementation of a shortened fasting protocol for procedural sedation and analgesia.

Validation of the 10-Item Orientation Questionnaire: A New Tool for Monitoring Post-Electroconvulsive Therapy Disorientation.

OBJECTIVES: Assessment of post-electroconvulsive therapy (ECT) disorientation at a single time point after ECT treatment may prove an effective and clinically useful method for monitoring the severity of disorientation and predicting ECT-induced retrograde amnesia. In this study, we aimed to validate a novel instrument (10-Item Orientation Questionnaire) developed to assess the level of disorientation after ECT. METHODS: Twenty-four depressed inpatients who were prescribed an acute course of ECT were administered the 10-Item Orientation Questionnaire at 30 minutes after ECT and had time to reorientation assessed at 3 time points after ECT (10, 30, and 60 minutes) at ECT treatments 1 to 3. The association between average performance of the 10-Item Orientation Questionnaire across the acute ECT course and retrograde amnesia at post-ECT was examined using the Autobiographical Memory Interview-Short Form. RESULTS: Mean performance on the 10-Item Orientation Questionnaire across treatments 1 to 3 was moderately correlated with average time to reorientation (r = -0.52, P = 0.02, n = 20). Across the acute ECT course, poorer performance on the 10-Item Orientation Questionnaire was associated with greater retrograde amnesia at post-ECT (r = 0.53, P = 0.03, n = 16). CONCLUSIONS: The 10-Item Orientation Questionnaire when administered at 30 minutes after ECT is sensitive for detecting patients with slow recovery of orientation after ECT. Use of this instrument therefore has potential for improving routine patient monitoring in clinical practice and identifying patients at increased risk of retrograde memory adverse effects following treatment.

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.

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.

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.

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.

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.

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.

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.