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At the end of 2019, a new form of Coronavirus, called COVID-19, has widely spread in the world. To quickly screen patients with the aim to detect this new form of pulmonary disease, in this paper we propose a method aimed to automatically detect the COVID-19 disease by analyzing medical images. We exploit supervised machine learning techniques building a model considering a data-set freely available for research purposes of 85 chest X-rays. The experiment shows the effectiveness of the proposed method in the discrimination between the COVID-19 disease and other pulmonary diseases. Pneumonia remains a threat to human health; the coronavirus disease 2019 (COVID-19) that began at the end of 2019 had a major impact on the world. It is still raging in many countries and has caused great losses to people’s lives and property. In this paper, we present a method based on DeepConv-DilatedNet of identifying and localizing pneumonia in chest X-ray (CXR) images. Two-stage detector Faster R-CNN is adopted as the structure of a network. Feature Pyramid Network (FPN) is integrated into the residual neural network of a dilated bottleneck so that the deep features are expanded to preserve the deep feature and position information of the object. In the case of DeepConv-DilatedNet, the deconvolution network is used to restore high-level feature maps into its original size, and the target information is further retained.

Introduction Soft-tissue thumb defects are common reconstructive challenges, the main goals being restoration of tactile sensibility, range of movement, pulp padding, length, and cosmesis. The reverse-flow dorsoulnar and dorsoradial collateral artery flaps are homodigital flaps used to cover both distal dorsal and volar thumb defects. These flaps can be used as compound flaps including skin, fat, and/or nerves. As there is no critical analysis of these studies, this study aims to create a synthesized comprehensive systematic review. Methods Systematic review was performed using the databases PubMed, Embase, and Medline. Eligible studies followed the inclusion criteria: English language and all studies published to date. The primary outcome was flap survival. Other data collected included anatomical area of the defect, flap constituents and dimensions, donor-site closure and complications, transfer method, reoperation, revision, and functional outcomes. Results A total of 19 articles incorporating 189 flaps met the inclusion criteria. These flaps were categorized and analyzed as dorsoradial (50%), dorsoulnar (39%), and turnover flaps (11%). Dorsoradial flaps were used in fasciocutaneous fashion alone. Partial flap failures occurred in five cases. Dorsoulnar flaps were used as fasciocutaneous or as osteocutaneous flaps. Complete flap failure was reported in one patient alone, whereas partial necrosis was reported in four patients. Adipofascial turnover flaps had two partial flap failures reported but no complete failures. The overall complete and partial flap failure rates were 0.5 and 6.5%, respectively. Conclusion Reverse-flow homodigital random or axial-based flaps provide a reliable means of reconstruction for soft-tissue defects with reasonable success rate and good functional outcomes. They have a consistent anatomy with a good potential for personalization and therefore increased versatility.

The COVID-19 Pandemic has had a significant disruption to the provision of Surgical Training. Core and Improving Surgical Trainees (CSTs and ISTs) are noted to be a group profoundly affected due to the impact of the pandemic in reducing operative time, cancelled elective procedures and redeployment to other specialities We aimed to evaluate the benefit of Small Group Surgical Simulation teaching for CSTs and ISTs recently deployed in the Norfolk and Norwich University Hospital.Physical simulation models were designed with the use of animal tissue and/or surgical simulators (such as laparoscopic box trainers) to simulate surgical procedures appropriate for the grade of trainees.We designed a monthly Surgical Simulation Programme, which took place in the Surgical Skills Laboratory. Topics were selected from those suitable for Simulation from the Intercollegiate Surgical Curriculum Programme (ISCP) Core Surgical Curriculum Participants felt that the COVID pandemic affected opportunities to perform/assist or observe the surgical skills. Participant comments on COVID affecting opportunities included ‘Reduced opportunities due to cancelled lists’, ‘Fewer elective cases so less opportunity ‘ and ‘Affected in the Peak of COVID but it is improving. Following the session, 100% of participants found the sessions to be effective in improving confidence in performing the surgical skill and 87% found the sessions to be extremely effective. Participants found the teaching sessions to be useful due to the opportunities of ‘Close supervision and direct feedback’, ‘Set of tasks’, ‘Practise with animal models’, ‘Having the tutor there to assist and help us’ and ‘[Discussing] theory prior to learning the procedure’.Surgical simulation provides opportunities for early-year trainees to learn and perform surgical skills during the COVID-19 pandemic. Small-group surgical simulation allows CSTs and ISTs to develop and practise skills under supervision of tutors, with trainees finding real-time feedback useful. In a post-COVID era, a surgical simulation teaching programme could provide an effective training opportunity to shorten the steep learning curve of core surgical training.

Kidney donation results in reductions in kidney function and lasting perturbations in phosphate homeostasis, which may lead to adverse cardiovascular sequelae. However, the acute effects of kidney donation on bone mineral parameters including regulators of calcium and phosphate metabolism are unknown. We conducted a prospective observational controlled study to determine the acute effects of kidney donation on mineral metabolism and skeletal health. Biochemical endpoints were determined before and after donation on days 1, 2 and 3, 6 weeks and 12 months in donors and at baseline, 6 weeks and 12 months in controls. Baseline characteristic of donors (n = 34) and controls (n = 34) were similar: age (53±10 vs 50±14 years, p = 0.33), BMI (26.3±2.89 vs 25.9±3.65, p = 0.59), systolic BP (128±13 vs 130±6 mmHg, p = 0.59), diastolic BP (80±9 vs 81±9 mmHg, p = 0.68) and baseline GFR (84.4±20.2 vs 83.6±25.2 ml/min/1.73m2, p = 0.89). eGFR reduced from 84.4±20.2 to 52.3±17.5 ml/min/1.73m2 (p

The innumerable application domains of Internet of Things (IoT) make security a big concern for the protection of devices and shared data from unauthorized access. The existing Internet Security protocols cannot be conformed for IoT entities due to their heterogeneity and resource constrained nature. Thus, there is a requirement of trust management systems as trust grants an IoT entity the ability to differentiate and govern the information disclosure in the network which ensures privacy and security. This paper proposes an Enhanced Dirichlet Trust Management Algorithm for healthcare domain which ensures reliable trust evaluation by considering direct observations and recommendations. The functional properties of the nodes form a key part of the algorithm. The existing Dirichlet algorithm has been enhanced by introducing Neighbour Node detection mechanism which helps to grant initial estimates of trust values to the nodes in the network. The proposed algorithm has been tested against various IoT attacks and the system performance has been summarized in the paper.

Study Objective Video gaming experience and practice is known to help attain and improve laparoscopic skills. We compared the impact of Wii (Nintendo, Kyoto, Japan) and XBox (Microsoft Inc., Redmond, WA) gaming experience on laparoscopic skills. Design Observational study. Setting Tertiary hospital. Participants Twenty-seven selected medical student volunteers with no previous laparoscopy experience. Interventions A selected cohort of medical students completed a questionnaire on their video gaming experience and were asked to play a game each on the Wii console and on the Xbox for 10 minutes each. They were then assessed on predefined laparoscopic skills with standardized objective scoring by 2 independent assessors. The skills tested were stacking ice cubes in set time, putting discs through strings in set time, and circle cutting. Measurements and Main Results Score was allocated for each video gaming session and for the laparoscopic session. The video gaming skills score was based on points achieved during a stipulated time period on 2 different consoles. Laparoscopy skills were assessed based on an agreed scoring matrix that involved appropriate weighting of the score based on importance of the task. The laparoscopy skills scores correlated significantly with both Xbox and Wii scores. Correlations between laparoscopic task scores were further analyzed by game console, Wii and Xbox. There was a stronger correlation between the Wii highest score and the total of the laparoscopic skills score (Spearman correlation coefficient = .734; p = .0001) compared with the correlation between the Xbox and the total laparoscopic skills score (Spearman correlation coefficient = .412; p = .033). Conclusion We confirm the correlation between video gaming and laparoscopic skills. Further, we conclude that the correlation is stronger with the Wii console compared with the Xbox for psychomotor skills, perhaps due to the similarity of action between the Nintendo Wii remote and laparoscopic instruments. Thus, practicing video gaming on the Nintendo Wii console over Xbox may improve manual dexterity laparoscopic skills. However, research of larger cohort studies with different games would provide further insight into the best methods for future simulated learning.

Disturbance of rapid eye movement (REM) sleep appears early in both patients with Huntington's disease (HD) and mouse models of HD. Selective serotonin reuptake inhibitors are widely prescribed for patients with HD, and are also known to suppress REM sleep in healthy subjects. To test whether selective serotonin reuptake inhibitors can correct abnormal REM sleep and sleep-dependent brain oscillations in HD mice, we treated wild-type and symptomatic R6/2 mice acutely with vehicle and paroxetine (5, 10, and 20 mg/kg). In addition, we treated a group of R6/2 mice chronically with vehicle or paroxetine (20 mg/kg/day) for 8 weeks, with treatment starting before the onset of overt motor symptoms. During and after treatment, we recorded electroencephalogram/electromyographm from the mice. We found that both acute and chronic paroxetine treatment normalized REM sleep in R6/2 mice. However, only chronic paroxetine treatment prevented the emergence of abnormal low-gamma (25-45 Hz) electroencephalogram oscillations in R6/2 mice, an effect that persisted for at least 2 weeks after treatment stopped. Chronic paroxetine treatment also normalized REM sleep theta rhythm in R6/2 mice, but, interestingly, this effect was restricted to the treatment period. By contrast, acute paroxetine treatment slowed REM sleep theta rhythm in WT mice but had no effect on abnormal theta or low-gamma oscillations in R6/2 mice. Our data show that paroxetine treatment, when initiated before the onset of symptoms, corrects both REM sleep disturbances and abnormal brain oscillations, suggesting a possible mechanistic link between early disruption of REM sleep and the subsequent abnormal brain activity in HD mice.

Disturbance of rapid eye movement (REM) sleep appears early in both patients with Huntington’s disease (HD) and mouse models of HD. Selective serotonin reuptake inhibitors are widely prescribed for patients with HD, and are also known to suppress REM sleep in healthy subjects. To test whether selective serotonin reuptake inhibitors can correct abnormal REM sleep and sleep-dependent brain oscillations in HD mice, we treated wild-type and symptomatic R6/2 mice acutely with vehicle and paroxetine (5, 10, and 20 mg/kg). In addition, we treated a group of R6/2 mice chronically with vehicle or paroxetine (20 mg/kg/day) for 8 weeks, with treatment starting before the onset of overt motor symptoms. During and after treatment, we recorded electroencephalogram/electromyogram from the mice. We found that both acute and chronic paroxetine treatment normalized REM sleep in R6/2 mice. However, only chronic paroxetine treatment prevented the emergence of abnormal low-gamma (25–45 Hz) electroencephalogram oscillations in R6/2 mice, an effect that persisted for at least 2 weeks after treatment stopped. Chronic paroxetine treatment also normalized REM sleep theta rhythm in R6/2 mice, but, interestingly, this effect was restricted to the treatment period. By contrast, acute paroxetine treatment slowed REM sleep theta rhythm in WT mice but had no effect on abnormal theta or low-gamma oscillations in R6/2 mice. Our data show that paroxetine treatment, when initiated before the onset of symptoms, corrects both REM sleep disturbances and abnormal brain oscillations, suggesting a possible mechanistic link between early disruption of REM sleep and the subsequent abnormal brain activity in HD mice. Electronic supplementary material The online version of this article (doi:10.1007/s13311-017-0546-7) contains supplementary material, which is available to authorized users.

Glioblastoma multiforme (GBM) is the most common type of primary malignant brain cancer and has a very poor prognosis. A subpopulation of cells known as GBM stem-like cells (GBM-SC) have the capacity to initiate and sustain tumor growth and possess molecular characteristics similar to the parental tumor. GBM-SCs are known to be enriched in hypoxic niches and may contribute to therapeutic resistance. Therefore, to identify genetic determinants important for the proliferation and survival of GBM stem cells, an unbiased pooled shRNA screen of 10,000 genes was conducted under normoxic as well as hypoxic conditions. A number of essential genes were identified that are required for GBM-SC growth, under either or both oxygen conditions, in two different GBM-SC lines. Interestingly, only about a third of the essential genes were common to both cell lines. The oxygen environment significantly impacts the cellular genetic dependencies as 30% of the genes required under hypoxia were not required under normoxic conditions. In addition to identifying essential genes already implicated in GBM such as CDK4, KIF11, and RAN, the screen also identified new genes that have not been previously implicated in GBM stem cell biology. The importance of the serum and glucocorticoid-regulated kinase 1 (SGK1) for cellular survival was validated in multiple patient-derived GBM stem cell lines using shRNA, CRISPR, and pharmacologic inhibitors. However, SGK1 depletion and inhibition has little effect on traditional serum grown glioma lines and on differentiated GBM-SCs indicating its specific importance in GBM stem cell survival. Implications: This study identifies genes required for the growth and survival of GBM stem cells under both normoxic and hypoxic conditions and finds SGK1 as a novel potential drug target for GBM. Mol Cancer Res; 16(1); 103–14. ©2017 AACR.

BPM31510 is a metabolic modulating agent composed of a parenteral nanodispersion of ubidecarenone which is currently in clinical studies for glioblastoma. Glioblastoma is a highly metabolic and aggressive malignancy with limited treatment options and dismal median survival. Temozolomide (TMZ) as a first line treatment option, however, 90% of recurrent gliomas acquire TMZ chemoresistance. Recently, acquisition to TMZ resistance has been correlated to alterations in mitochondrial metabolism. Thus, in the present study we sought to investigate whether BPM31510 could elicit anti-cancer activity in TMZ naïve and TMZ-chemoresistant glioma models. In vitro, in a 2D model BPM31510 treatment demonstrated anti-cancer activity in a panel of glioma cell lines (rat C6 and human U251-MG and U87-MG), and this effect was translatable in spheroidal 3D cultures. Importantly, in an aggressive rat C6 orthotopic glioma model, treatment with BPM31510 (50mg/kg/day, b.i.d) starting between 4 and 8 days post-implantation resulted in a 32% cure rate compared to 0% in controls (P < 0.001, Fisher's exact test), demonstrating an improved survival (P < 0.01, log rank survival), despite producing a minimal change in median survival (13 vs. 12 days). A marked increase in caspase3 staining was observed in tumors from BPM31510 treated animals compared to controls assessed at a similar time point post-tumor implantation, suggesting a strong apoptotic effect of this agent in vivo. Next, BPM31510 was examined in a cellular model of acquired TMZ resistance (TMZ-R) generated by exposing parental (chemosensitive naïve) U251-MG and U87-MG cells to increasing concentrations of TMZ for 9-12 months. Similar to parental cells, BPM31510 displayed anti-cancer activity in both TMZ-R cell models, as decreased cell viability and an increase in the percentage of apoptotic cells was observed upon BPM31510 treatment. Consistent with prior studies, compared to parental cells, TMZ-R cells demonstrated metabolic rewiring characterized by increases in mitochondrial function parameters and decreased extracellular acidification rate, indicative of glycolytic flux. Regardless of chemosensitivity, BPM31510 decreased mitochondrial substrate oxidation (e.g., succinate, glycerol-3-phosphate) at doses which induce cell death. Concomitantly, increases in the reactive oxygen species production were observed with BPM 31510 treatment in both parental and TMZ-R cell lines. Together, these data define a link between regulation of mitochondrial function and the anti-cancer activity of BPM31510 in both TMZ chemo-sensitive and resistant glioblastoma models, demonstrating a distinct approach in targeting mitochondrial metabolism for the treatment of this clinically intractable disease. Citation Format: Tulin Dadali, Shreya Kulkarni, Ryan Ng, Pallavi Awate, Saie Mogre, Anne R. Diers, Taichang Jang, Milton Merchant, Jiaxin Sun, Stephane Gesta, Khampaseuth Thapa, Seema Nagpal, Lawrence Recht, Niven R. Narain, Rangaprasad Sarangarajan. BPM 31510, a clinical stage metabolic modulator, demonstrates therapeutic efficacy in glioblastoma models of temozolomide chemo-sensitive and resistance by targeting mitochondrial function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 873.

Objective: The objective of this study is to design an automated ocular drug delivery system controlled by an open-source syringe pump, which in turn is to be controlled using Arduino UNO.Methods: The Arduino UNO is the microcontroller used to control the entire setup. The drug delivery is executed using the open-source syringe pump. A 12V NEMA 17 stepper motor is used to execute the pump movements. To facilitate the ease of use, an Android application developed using Android Studio has been developed, where inputs are given in the form of the required drug dose. The application plays the role of converting the requested drug dose into the number of steps required to run the stepper motor. The stepper motor works based on simple lead-screw mechanism.Results: The designed syringe pump has been tested using water. It was determined that for 42 steps a drug volume of 30 μl is dispensed by the designed device. Typically, a drop volume ranges from 33.8 μl to 63.4 μl and the device that has been discussed in this article can deliver a minimum volume of 30 μl.Conclusion: Using this device, excessive use of drugs can be minimalized, thus reducing the capital investment put behind ocular drugs.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into three phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are 15 genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all three subgroups of ASD are 20 novel genes mostly in putative noncoding regions, which appear to associate with androgen sensitivity and which may underlie the strong 4:1 bias toward affected males.

Protein phosphatase 2A (PP2A) regulates almost all cell signaling pathways. It consists of a scaffolding A subunit to which a catalytic C subunit and one of many regulatory B subunits bind. Of the more than 80 PP2A isoforms, 10% use Aβ as a scaffold. This study demonstrates the isoform-specific function of the A scaffold subunits. Polyomaviruses have shown the importance of phosphotyrosine, PI3K, and p53 in transformation. Comparisons of polyoma and SV40 small T antigens implicate Aβ in the control of differentiation. Knockdown of Aβ enhanced differentiation. Akt signaling regulated differentiation; its activation or inhibition promoted or blocked it, respectively. Aβ bound Akt. Enhancement of PP2A Aβ/Akt interaction by polyoma small T antigen increased turnover of Akt Ser-473 phosphorylation. Conversely, knockdown of Aβ promoted Akt activity and reduced turnover of phosphate at Ser-473 of Akt. These data provide new insight into the regulation of Akt, a protein of extreme importance in cancer. Furthermore, our results suggest that the role for Aβ in differentiation and perhaps tumor suppression may lie partly in its ability to negatively regulate Akt.

Glioblastoma Multiforme (GBM) is the most common type of malignant brain cancer. Due to its aggressive and invasive phenotype, GBMs are classified as a grade IV tumor, and have a very poor prognosis. The GBM tumor cell population is heterogeneous and a small percentage of the tumor population, known as GBM stem cells, has the capacity to initiate and sustain tumor growth. These GBM stem cells (GBM-SCs) possess properties of self-renewal, high proliferation, radio- and chemo-resistant and have the ability to survive in hypoxic niches. In order to more effectively treat the tumor and prevent relapse, it is important to target the GBM-SC population within the tumor in addition to the bulk tumor population, which is not achieved by the conventional therapy. We are using an in vitro pooled RNAi screening approach to identify novel genetic targets for the development of drugs targeting the GBM stem cell population. In this approach, we will knockdown 10,000 genes in the GBM stem cells and perform a loss-of-function screen in order to identify the shRNAs that are inhibitory to the cellular growth in hypoxic as well as under normoxic conditions by quantifying the shRNA depletion between the conditions and a reference sample. Using this approach, we have not only identified genes which have been previously characterized to be important in GBM-SC biology such as CDK4, KIF11 and Ran, we have also identified genes, which have not been well studied in the context of GBM stem cell biology. Serum and Glucorticoid regulated Kinase -1 (SGK1) is a AGC Kinase family member which was scored as a hit in two different GBM-SC lines in the pooled screening, as well as in a separate kinase specific arrayed shRNA screen performed in the lab under both normoxic and hypoxic conditions. SGK1 is a known modulator in the PI-3 Kinase pathway and is thought to have a complementary role to Akt signaling. We have validated SGK1 as a gene important in GBM-SC survival using shRNA mediated knockdown as well as using pharmacological inhibition of the kinase in 4 different patient derived GBM stem cell lines. Furthermore, depletion of SGK1 protein results in an increase in cleaved PARP protein, which is a known marker of apoptosis induction, indicating SGK1s role as a pro-survival kinase. Further experiments are being performed to elucidate the important of this kinase in vivo using mouse xenograft experiments, as well as the pathway mediators through which SGK1 signaling occurs in GBM. Using this non-biased screening approach, we identified several genes important in GBM stem cell survival in hypoxic and normoxic conditions. Further, pathway analysis of the putative hits in will also provide us with an insight into the biochemical pathways that regulate these cells leading to development to better therapeutics for GBM. Citation Format: Shreya Kulkarni, Surbhi Goel-Bhattacharya, Sejuti Sengupta, Brent Cochran. Identification of genes required for glioblastoma stem cell growth and survival using pooled RNAi screening with next generation sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1104. doi:10.1158/1538-7445.AM2015-1104

Glioblastoma stem like cells are known to have phenotypes and gene expression patterns distinct from traditional glioma cell lines grown in serum. They also may have increased resistance to drugs and radiation and are likely to be responsible for tumor recurrence following therapy. As a result, it is important to identify therapeutic targets for these cells. To do this, we have conducted RNAi screens in glioblastoma stem cells against the human kinome since kinases are druggable targets and many kinase inhibitors are known. In addition, glioblastomas often have significant regions of hypoxia and glioblastoma stem cells tend to be resistant to hypoxia. We have therefore conducted shRNA screens in both normoxic and hypoxic conditions. We have screened 2 independent cell lines to date and are working on others. Defining a hit as a gene that has at least 2 independent shRNAs that give at least 50% growth inhibition as compared to controls, we found that 79 and 84 of (501 kinase genes) are hits under either normoxia or hypoxia for the GS6-22 and GS7-2 stem-like cell lines, respectively. We found that 56 and 63 kinases were hits under both conditions. 15 and 16 genes gave preferential inhibition under normoxia and 8 and 4 genes preferentially inhibited under hypoxia. 31 kinases were inhibitory in both cell lines. Thus, there is considerable variation between cell lines. Several of the identified hits are well known to have a role in glioblastoma such as EGFR and CDK4, and were inhibitory in both cell lines. About a third of the hits have previously been implicated in glioblastoma. One of the hits we have independently validated is the SMG1 kinase is preferentially inhibitory in hypoxia in only one of the cell lines. Together, these data give support to the idea of developing personalized therapies for glioblastoma.