Predicting FDG-PET Images From Multi-Contrast MRI Using Deep Learning in Patients With Brain Neoplasms.

BACKGROUND: 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is valuable for determining presence of viable tumor, but is limited by geographical restrictions, radiation exposure, and high cost. PURPOSE: To generate diagnostic-quality PET equivalent imaging for patients with brain neoplasms by deep learning with multi-contrast MRI. STUDY TYPE: Retrospective. SUBJECTS: Patients (59 studies from 51 subjects; age 56 ± 13 years; 29 males) who underwent 18 F-FDG PET and MRI for determining recurrent brain tumor. FIELD STRENGTH/SEQUENCE: 3T; 3D GRE T1, 3D GRE T1c, 3D FSE T2-FLAIR, and 3D FSE ASL, 18 F-FDG PET imaging. ASSESSMENT: Convolutional neural networks were trained using four MRIs as inputs and acquired FDG PET images as output. The agreement between the acquired and synthesized PET was evaluated by quality metrics and Bland-Altman plots for standardized uptake value ratio. Three physicians scored image quality on a 5-point scale, with score ≥3 as high-quality. They assessed the lesions on a 5-point scale, which was binarized to analyze diagnostic consistency of the synthesized PET compared to the acquired PET. STATISTICAL TESTS: The agreement in ratings between the acquired and synthesized PET were tested with Gwet's AC and exact Bowker test of symmetry. Agreement of the readers was assessed by Gwet's AC. P = 0.05 was used as the cutoff for statistical significance. RESULTS: The synthesized PET visually resembled the acquired PET and showed significant improvement in quality metrics (+21.7% on PSNR, +22.2% on SSIM, -31.8% on RSME) compared with ASL. A total of 49.7% of the synthesized PET were considered as high-quality compared to 73.4% of the acquired PET which was statistically significant, but with distinct variability between readers. For the positive/negative lesion assessment, the synthesized PET had an accuracy of 87% but had a tendency to overcall. CONCLUSION: The proposed deep learning model has the potential of synthesizing diagnostic quality FDG PET images without the use of radiotracers. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Glioma synapses recruit mechanisms of adaptive plasticity.

The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1-3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9-15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17-22 that contributes to memory and learning in the healthy brain23-26. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.

Making Meaning of Surviving the Oklahoma City Bombing Seven Years Later.

Objective: No previous studies examined how survivors made meaning (i.e. interpreted the personal significance) of a disaster experience after seven years. This qualitative study follows up on a previously published analysis of 182 directly-exposed survivors of the Oklahoma City bombing, assessed after six months had elapsed for bombing-related psychopathology and meaning-making processes. The current study examines how 113 survivors (62% follow-up rate) made meaning of their bombing experience after seven years. Method: Survivors answered questions about the effects of the bombing on their beliefs and perspectives. Their responses were hand recorded by interviewers and transcribed. Content was coded into themes, allowing codes of multiple themes. Excellent interrater reliability was obtained (Cohen's kappa≥.8). Results: The survivors were 50% (57/113) male, 93% (105/113) Caucasian, 34% (38/113) college educated, and 71% (80/113) married with a mean (SD) age of 42.5 (10.6) (range = 19-69) years at the time of the bombing. Eight themes emerged and indicated that survivors matured in personal goals and character, interpersonal relationships, and philosophical thought (e.g., reconsideration of human nature and religion). More than one third of the comments included negative remarks about personal harm, especially psychological effects. Conclusions: Nearly two thirds of the material was positive in tone and consistent between six months and seven years. Negative content was entirely new relative to six-month baseline interview responses, suggesting many survivors incorporate greater reflection on negative outcomes in meaning-making processes over time. After several years, clinicians could encourage survivors to integrate positive and negative consequences as meaning. Longer-term studies are needed.

Effectiveness of Bupropion and Varenicline for Smokers With Baseline Depressive Symptoms.

INTRODUCTION: Smokers with concurrent depression are less likely to achieve abstinence, even with pharmacotherapy. The purpose of this secondary data analysis was to evaluate if the presence of any depressive symptoms at baseline alters the effectiveness of bupropion and varenicline for smoking cessation. AIMS AND METHODS: Eligible participants were enrolled via the internet and randomized 1:1 to receive a 12-week supply of either bupropion (n = 465) or varenicline (n = 499). Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-2). Follow-up surveys were conducted at weeks 4, 8, 12, 26, and 52 to assess self-reported quit. The primary outcome was 7-day point prevalence abstinence at 12 weeks follow-up (end-of-treatment). RESULTS: Participants who endorsed any depressive symptoms (PHQ-2 > 0; n = 280) were less likely to be quit at end-of-treatment compared to participants who did not endorse any symptoms (PHQ-2 = 0; n = 684) (OR = 0.56, 95% CI: 0.38 to 0.8, p = .003). Within the varenicline group, quit outcomes did not differ between those with and without depressive symptoms (21.3% vs. 26.9%, respectively). Within the bupropion group, however, those with symptoms had a significantly reduced quit rate compared to those without symptoms (7.0% vs. 17.3%, respectively). CONCLUSIONS: The presence of even one symptom of depression at the start of a quit attempt may adversely affect quit outcomes. Patients should be assessed for depressive symptoms when planning to quit smoking as it may inform the approach to treatment. However, future studies are needed to confirm these findings. IMPLICATIONS: Findings from the current study illustrate the importance of evaluating baseline sub-clinical depressive symptoms before a quit attempt using first-line pharmacotherapies. This secondary analysis of a large-scale randomized trial suggests that bupropion may be less effective for those with baseline depressive symptoms while varenicline may be equally effective for those with and without depressive symptoms.

Active versus sham transcranial direct current stimulation (tDCS) as an adjunct to varenicline treatment for smoking cessation: Study protocol for a double-blind single dummy randomized controlled trial.

BACKGROUND: Smoking is a chronic and relapsing disease, with up to 60% of quitters relapsing within the first year. Transcranial Direct Current Stimulation (tDCS), targets cortical circuits and acutely reduces craving and withdrawal symptoms among cigarette smokers. However, the efficacy of tDCS as an adjunct to standard smoking cessation treatments has not been studied. This study aims to investigate the effectiveness of tDCS in combination with varenicline for smoking cessation. We hypothesize that active tDCS combined with varenicline will improve cessation outcomes compared to sham tDCS combined with varenicline. METHODS: This is a double-blind, sham-controlled randomized clinical trial where fifty healthy smokers will be recruited in Toronto, Canada. Participants will be randomized 1:1 to either active tDCS (20 minutes at 2 mA) or sham tDCS (30 seconds at 2 mA, 19 minutes at 0 mA) for 10 daily sessions (2 weeks) plus 5 follow up sessions, occurring every two weeks for 10 weeks. All participants will be given standard varenicline treatment concurrently for the 12-week treatment period. The primary outcome is 30 day continuous abstinence at end of treatment, confirmed with urinary cotinine. Measurements made at each study visit include expired carbon monoxide, self-reported craving and withdrawal. Three magnetic resonance imaging (MRI) scans will be conducted: two at baseline and one at end of treatment, to assess any functional or structural changes following treatment. DISCUSSION: For every two smokers who quit, one life is saved from a tobacco-related mortality. Therefore, it is important to develop new and more effective treatment approaches that can improve and maintain long-term abstinence, in order to decrease the prevalence of tobacco-related deaths and disease. Furthermore, the addition of longitudinal neuroimaging can shed light on neural circuitry changes that might occur as a result of brain stimulation, furthering our understanding of tDCS in addiction treatment. TRIAL REGISTRATION: This trial has been registered with Clinicaltrials.gov: NCT03841292 since February 15th 2019 (https://clinicaltrials.gov/ct2/show/NCT03841292)-retrospectively registered.

Differences in attentional bias to smoking-related, affective, and sensation-seeking cues between smokers and non-smokers: an eye-tracking study.

RATIONALE: One of the behavioural features of tobacco use disorder is the presence of attentional bias (AB) to smoking-related stimuli. However, much of the research investigating these associations have been limited to the use of reaction-based indices. OBJECTIVES: We aimed to investigate differences in AB to smoking, affective, and sensation-seeking cues in smokers and non-smokers using novel, free-viewing, eye-tracking technology. Secondary aims included investigating impulsivity-by-group interaction effects on AB to sensation-seeking cues. METHODS: Participants were either otherwise-healthy smokers of at least 8 cigarettes per day or otherwise-healthy non-smokers (< 100 cigarettes in their lifetime and no smoking in the past year). AB was measured using a free-viewing, eye-tracking system. Participants were presented a series of slides divided into 3 themes: smoking, affective, and sensation-seeking. Each slide contained 4 images (1 theme-related, 1 neutral, 2 competitive). Primary outcome measure was the difference in the proportion of time spent viewing the theme-related cue to neutral cue. Impulsivity was measured using a monetary delayed discounting task. RESULTS: The sample consisted of 50 smokers (41 ± 12 years old) and 50 age- and sex-matched non-smokers (40 ± 14 years old). Smokers spent over 2 times longer looking at smoking-related images than non-smokers (F = 25.50, p < 0.001). As well, greater impulsivity was significantly associated with increased AB to sensation-seeking cues (R2 = 0.059, F = 2.98, p = 0.04) in smokers but not non-smokers. No differences were found on AB to affective cues. CONCLUSION: The eye-tracking procedure is a sensitive tool for assessing AB in smokers compared to non-smokers to both smoking and sensation-seeking cues.

Improving the care of patients with COVID-19 with a medical student-run telemedicine clinic.

INTRODUCTION: In March 2020, the Dallas Fort Worth Metroplex experienced a surge in acute COVID-19 infections. At that time, no consistent protocols existed for follow-up of discharged patients with COVID-19 from the William P Clements Jr University Hospital at the University of Texas Southwestern Medical Center. Simultaneously, medical students were suspended from in-person clinical activities to limit viral spread. In response to these events, a telemedicine elective was created to provide timely and high-quality telehealth follow-up for recently discharged patients with COVID-19. METHODS: The pilot team, consisting of several second-year through fourth-year medical students, developed a call script that included warning signs and symptoms, Centers for Disease Control and Prevention (CDC) guidelines for isolation and primary care physician referral information. Patients with COVID-19 discharged from the emergency department (ED) and inpatient services were identified and assigned to student callers. All patients were discussed with an attending physician, who was available if an acute issue arose. The elective also included education on the SBAR (situation, background, assessment, and recommendation) handover technique, telehealth education, updated COVID-19 literature and CDC guidelines. RESULTS: Improvement was noted in students' ability to identify patients who required escalation of care, as seen by over 60% of patients who were advised to return to ED required hospital admission. Statistically significant improvement was observed in the students' degree of feeling informed about the current state of COVID-19 and their degree of comfort with interviewing patients over the phone. DISCUSSION: This elective provided quality virtual healthcare to patients with COVID-19 while allowing medical students to progress in their medical education and participate in patient care.

Evaluating the effectiveness of bupropion and varenicline for smoking cessation using an internet-based delivery system: A pragmatic randomized controlled trial (MATCH study).

BACKGROUND: Traditional randomized controlled trials have demonstrated the efficacy of pharmacotherapy for smoking cessation. However, accessibility to treatments remains a barrier, necessitating the remote delivery of evidence-based cessation interventions. The aim of this study was to evaluate the effectiveness of an online treatment that included first-line prescription medications using a pragmatic randomized controlled trial design. METHODS: This study was a two-group, parallel block randomized, open label, controlled trial, and conducted exclusively online. Participants were randomised (1:1) to either bupropion (150 mg) or varenicline (1 mg) for twelve weeks. Medication was couriered to participants. The primary outcome was 7-day point prevalence abstinence (PPA; defined as 0 cigarette puffs in the last 7 days) at 12 weeks. Secondary outcomes were 7-day PPA at 4-, 8-, 26-, and 52-weeks follow-up. Adverse events were evaluated at each follow-up session during treatment. RESULTS: The varenicline group (n = 499) had significantly higher 7-day PPA (30.3%) compared to the bupropion group (n = 465; 19.6%) at end of treatment (OR=2.08, 95% CI: 1.49-2.90, p < 0.001). Seven-day PPA was also higher for the varenicline group at 4-weeks (OR=1.71, 95% CI: 1.23-2.40 p = 0.0001), and 8-weeks follow-up (OR=1.95, 95% CI: 1.43-2.67 p < 0.0001), but not at post-treatment follow-up. More adverse events were reported in the varenicline group, compared to bupropion. CONCLUSIONS: This internet-based pharmacotherapy intervention was a feasible and effective method of treatment delivery for smoking cessation. This method can be used to increase the accessibility and availability of cessation interventions, decreasing the burden of smoking-related diseases. TRIAL REGISTRATION: This trial was registered with clinical trials.gov under NCT02146911. Registered 26 May 2014, https://clinicaltrials.gov/ct2/show/NCT02146911.

Varenicline and Bupropion for Long-Term Smoking Cessation (the MATCH Study): Protocol for a Real-World, Pragmatic, Randomized Controlled Trial.

BACKGROUND: Varenicline and bupropion are efficacious, prescription-only pharmacotherapies for smoking cessation; however, their real-world impact is limited by prescriber knowledge, affordability, and accessibility. OBJECTIVE: The primary objective of the MATCH (Medication Aids for Tobacco Cessation Health) study was to evaluate the real-world, long-term effectiveness of mailed bupropion and varenicline in a sample of interested smokers with the utilization of Web-based recruitment and follow-up. In addition, the study aims to investigate the genotypic and phenotypic predictors of cessation. METHODS: This is a two-group, parallel block, randomized (1:1) open-label clinical trial. This study will be conducted online with the baseline enrollment through the study's website and follow-up by emails. In addition, medication prescriptions will be filled by the study contract pharmacy and couriered to participants. Individuals who smoke ≥10 cigarettes per day and intend to quit within the next 30 days will be recruited through Public Health Units and Tobacco Control Area Networks throughout Ontario by word-of-mouth and the internet. Eligible participants will receive an email with a prescription for 12-week assigned medication and a letter to take to their physician. The recruitment and randomization will continue until 500 participants per arm have received medication. All participants will receive weekly motivational emails during the treatment phase. The primary outcome measure is the smoking status after 6 months, biochemically confirmed by mailed-in salivary cotinine. Follow-ups will be conducted through emails after 4, 8, 12, 26, and 52 weeks of starting the treatment to assess the smoking prevalence and continuous smoking abstinence. In addition, mailed-in saliva samples will be used for genetic and nicotine metabolism analyses. Furthermore, personality characteristics will be assessed using the Big Five Aspect Scales. RESULTS: The project was funded in 2014 and enrollment was completed in January 2017. Data analysis is currently underway. CONCLUSIONS: To the best of our knowledge, this is the first randomized controlled trial to mass distribute prescription medications for smoking cessation. We expect this method to be logistically feasible and cost effective with quit outcomes that are comparable to published clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02146911; https://clinicaltrials.gov/ct2/show/NCT02146911 (Archived by WebCite at http://www.webcitation.org/72CZ6AvXZ). REGISTERED REPORT IDENTIFIER: RR1-10.2196/10826.

Intravenous miR-144 reduces left ventricular remodeling after myocardial infarction.

MicroRNA-144 is a cytoprotective miRNA. Our previous study showed that miR-144 provides potent acute cardioprotection in an ischemia/reperfusion injury model. This study was performed to further assess whether miR-144 improves post-MI remodeling in a non-reperfused myocardial infarction (MI) model. C57BL/6 mice were subjected to MI by permanent left anterior descending artery (LAD) ligation. miR-144 was delivered by intravenous injections of 8 mg/kg, 16 mg/kg, or 32 mg/kg at day 0, day 1, day 3, and then a similar dose given once every 3 days, until day 28 after MI. Cardiac function was evaluated using echocardiography. At the end of the study, heart function was also evaluated using a pressure volume catheter. The percentage of the length of the infarct scar on the left ventricle (LV) circumferential length was calculated for heart each section. The miR-144 KO mice showed a worse heart failure phenotype with ventricular dilation and impaired contractility after LAD ligation. Ischemia decreased miR-144 levels, and the miR-144 level was restored to baseline by administration of intravenous miR-144. Cy3-labeled miR-144 was localized to the infarct and border zone, and was taken up by cardiomyocytes and macrophages. In miR-144-treated groups, at 28 days MI size was significantly reduced, and cardiac function was improved [LV fractional shortening, end-systolic volume (µL), end-diastolic volume (µL), ejection fraction (%), dP/dt max (mmHg/s), dP/dt min (mmHg/s), Tau (ms)], compared with controls (p < 0.01). This beneficial effect was associated with reduced border zone fibrosis, inflammation and apoptosis, these effects were associated with significant changes in autophagy signaling. Intravenous miR-144 has potent effects on post-MI remodeling. These findings suggest that miR-144 has potential as a therapeutic agent after MI.

Biochemical and biophysical characterization of PlyGRCS, a bacteriophage endolysin active against methicillin-resistant Staphylococcus aureus.

The increasing rate of resistance of pathogenic bacteria, such as Staphylococcus aureus, to classical antibiotics has driven research toward identification of other means to fight infectious disease. One particularly viable option is the use of bacteriophage-encoded peptidoglycan hydrolases, called endolysins or enzybiotics. These enzymes lyse the bacterial cell wall upon direct contact, are not inhibited by traditional antibiotic resistance mechanisms, and have already shown great promise in the areas of food safety, human health, and veterinary science. We have identified and characterized an endolysin, PlyGRCS, which displays dose-dependent antimicrobial activity against both planktonic and biofilm S. aureus, including methicillin-resistant S. aureus (MRSA). The spectrum of lytic activity for this enzyme includes all S. aureus and Staphylococcus epidermidis strains tested, but not other Gram-positive pathogens. The contributions of the PlyGRCS putative catalytic and cell wall binding domains were investigated through deletion analysis. The cysteine, histidine-dependent amidohydrolase/peptidase (CHAP) catalytic domain displayed activity by itself, though reduced, indicating the necessity of the binding domain for full activity. In contrast, the SH3_5 binding domain lacked activity but was shown to interact directly with the staphylococcal cell wall via fluorescent microscopy. Site-directed mutagenesis studies determined that the active site residues in the CHAP catalytic domain were C29 and H92, and its catalytic functionality required calcium as a co-factor. Finally, biochemical assays coupled with mass spectrometry analysis determined that PlyGRCS displays both N-acetylmuramoyl-L-alanine amidase and D-alanyl-glycyl endopeptidase hydrolytic activities despite possessing only a single catalytic domain. These results indicate that PlyGRCS has the potential to become a revolutionary therapeutic option to combat bacterial infections.

Cancer drug development in China: recent advances and future challenges.

Over the past 10 years, the Chinese Government, academic organizations, and biopharmaceutical companies have tried to transition the nation from a consumer of generic drugs into a developer of innovative therapies. Here, we present a timeline of recent innovative cancer drug development, with a particular focus on four case studies that have reshaped perceptions of what can be done in China. We present metrics comparing China with other countries alongside analysis of what national authorities are doing to close the gap in areas where China still lags behind the West.