4D-PET reconstruction using a spline-residue model with spatial and temporal roughness penalties

4D reconstruction of dynamic positron emission tomography (dPET) data can improve the signal-to-noise ratio in reconstructed image sequences by fitting smooth temporal functions to the voxel time-activity-curves (TACs) during the reconstruction, though the optimal choice of function remains an open question. We propose a spline-residue model, which describes TACs as weighted sums of convolutions of the arterial input function with cubic B-spline basis functions. Convolution with the input function constrains the spline-residue model at early time-points, potentially enhancing noise suppression in early time-frames, while still allowing a wide range of TAC descriptions over the entire imaged time-course, thus limiting bias. 
 Spline-residue based 4D-reconstruction is compared to that of a conventional (non-4D) maximum a posteriori (MAP) algorithm, and to 4D-reconstructions based on adaptive-knot cubic B-splines, the spectral model and an irreversible two-tissue compartment ('2C3K') model. 4D reconstructions were carried out using a nested-MAP algorithm including spatial and temporal roughness penalties. The algorithms were tested using Monte-Carlo simulated scanner data, generated for a digital thoracic phantom with uptake kinetics based on a dynamic [18F]-Fluromisonidazole scan of a non-small cell lung cancer patient. For every algorithm, parametric maps were calculated by fitting each voxel TAC within a sub-region of the reconstructed images with the 2C3K model. 
 Compared to conventional MAP reconstruction, spline-residue-based 4D reconstruction achieved >50% improvements for 5 of the 8 combinations of the 4 kinetics parameters for which parametric maps were created with the bias and noise measures used to analyse them, and produced better results for 5/8 combinations than any of the other reconstruction algorithms studied, while spectral model-based 4D reconstruction produced the best results for 2/8. 2C3K model-based 4D reconstruction generated the most biased parametric maps. Inclusion of a temporal roughness penalty function improved the performance of 4D reconstruction based on the cubic B-spline, spectral and spline-residue models.&#13

Development of HIV-1 rectal-specific microbicides and colonic tissue evaluation

The gastrointestinal tract is structurally and functionally different from the vagina. Thus, the paradigm of topical microbicide development and evaluation has evolved to include rectal microbicides (RMs). Our interest was to create unique RM formulations to safely and effectively deliver antiretroviral drugs to mucosal tissue. RMs were designed to include those that spread and coat all surfaces of the rectum and distal colon rapidly (liquid) and those that create a deformable, erodible barrier and remain localized at the administration site (gel). Tenofovir (TFV) (1%) was formulated as an aqueous thermoreversible fluid and a carbopol-based aqueous hydrogel. Lipid-based liquid and gel formulations were prepared for UC781 (0.1%) using isopropyl myristate and GTCC (Caprylic/Capric Triglycerides), respectively. Formulations were characterized for pH, viscosity, osmolality, and drug content. Pre-clinical testing incorporated ex vivo colonic tissue obtained through surgical resections and flexible sigmoidoscopy (flex sig). As this was the first time using tissue from both sources side-by-side, the ability to replicate HIV-1 was compared. Efficacy of the RM formulations was tested by applying the products with HIV-1 directly to polarized colonic tissue and following viral replication. Safety of the formulations was determined by MTT assay and histology. All products had a neutral pH and were isoosmolar. While HIV-1BaL and HIV-1 JR-CSF alone and in the presence of semen had similar replication trends between surgically resected and flex sig tissues, the magnitude of viral replication was significantly better in flex sig tissues. Both TFV and UC781 formulations protected the colonic tissue, regardless of tissue source, from HIV-1 and retained tissue viability and architecture. Our in vitro and ex vivo results show successful formulation of unique RMs. Moreover, the results of flex sig and surgically resected tissues were comparable suggesting the incorporation of both in pre-clinical testing algorithms. © 2014 Dezzutti et al

Investigation of atovaquone-induced spatial changes in tumour hypoxia assessed by hypoxia PET/CT in non-small cell lung cancer patients

Background Tumour hypoxia promotes an aggressive tumour phenotype and enhances resistance to anticancer treatments. Following the recent observation that the mitochondrial inhibitor atovaquone increases tumour oxygenation in NSCLC, we sought to assess whether atovaquone affects tumour subregions differently depending on their level of hypoxia. Methods Patients with resectable NSCLC participated in the ATOM trial (NCT02628080). Cohort 1 (n = 15) received atovaquone treatment, whilst cohort 2 (n = 15) did not. Hypoxia-related metrics, including change in mean tumour-to-blood ratio, tumour hypoxic volume, and fraction of hypoxic voxels, were assessed using hypoxia PET imaging. Tumours were divided into four subregions or distance categories: edge, outer, inner, and centre, using MATLAB. Results Atovaquone-induced reduction in tumour hypoxia mostly occurred in the inner and outer tumour subregions, and to a lesser extent in the centre subregion. Atovaquone did not seem to act in the edge subregion, which was the only tumour subregion that was non-hypoxic at baseline. Notably, the most intensely hypoxic tumour voxels, and therefore the most radiobiologically resistant areas, were subject to the most pronounced decrease in hypoxia in the different subregions. Conclusions This study provides insights into the action of atovaquone in tumour subregions that help to better understand its role as a novel tumour radiosensitiser. Trial registration: ClinicalTrials.gov, NCT0262808. Registered 11th December 2015, https://clinicaltrials.gov/ct2/show/NCT0262808

4D-PET reconstruction of dynamic non-small cell lung cancer [18-F]-FMISO-PET data using adaptive-knot cubic B-splines

4D-PET reconstruction has the potential to significantly increase the signal-to-noise ratio in dynamic PET by fitting smooth temporal functions during the reconstruction. However, the optimal choice of temporal function remains an open question. A 4D-PET reconstruction algorithm using adaptive-knot cubic B-splines is proposed. Using realistic Monte-Carlo simulated data from a digital patient phantom representing an [18-F]-FMISO-PET scan of a non-small cell lung cancer patient, this method was compared to a spectral model based 4D-PET reconstruction and the conventional MLEM and MAP algorithms. Within the entire patient region the proposed algorithm produced the best bias-noise trade-off, while within the tumor region the spline- and spectral model-based reconstructions gave comparable results

Radiogenomic analysis of primary breast cancer reveals [18F]-fluorodeoxglucose dynamic flux-constants are positively associated with immune pathways and outperform static uptake measures in associating with glucose metabolism

Background: PET imaging of 18F-fluorodeoxygucose (FDG) is used widely for tumour staging and assessment of treatment response, but the biology associated with FDG uptake is still not fully elucidated. We therefore carried out gene set enrichment analyses (GSEA) of RNA sequencing data to find KEGG pathways associated with FDG uptake in primary breast cancers. Methods: Pre-treatment data were analysed from a window-of-opportunity study in which 30 patients underwent static and dynamic FDG-PET and tumour biopsy. Kinetic models were fitted to dynamic images, and GSEA was performed for enrichment scores reflecting Pearson and Spearman coefficients of correlations between gene expression and imaging. Results: A total of 38 pathways were associated with kinetic model flux-constants or static measures of FDG uptake, all positively. The associated pathways included glycolysis/gluconeogenesis (‘GLYC-GLUC’) which mediates FDG uptake and was associated with model flux-constants but not with static uptake measures, and 28 pathways related to immune-response or inflammation. More pathways, 32, were associated with the flux-constant K of the simple Patlak model than with any other imaging index. Numbers of pathways categorised as being associated with individual micro-parameters of the kinetic models were substantially fewer than numbers associated with flux-constants, and lay around levels expected by chance. Conclusions: In pre-treatment images GLYC-GLUC was associated with FDG kinetic flux-constants including Patlak K, but not with static uptake measures. Immune-related pathways were associated with flux-constants and static uptake. Patlak K was associated with more pathways than were the flux-constants of more complex kinetic models. On the basis of these results Patlak analysis of dynamic FDG-PET scans is advantageous, compared to other kinetic analyses or static imaging, in studies seeking to infer tumour-to-tumour differences in biology from differences in imaging. Trial registration NCT01266486, December 24th 2010

Campus Mental Health: Implications for Instructors Supporting Students

The recent escalation in student suicides due to mental health problems has encouraged higher education institutions to not only modify their overall support structures, but to also (re)define the role of faculty and staff. Despite the increased attention given to student mental health in Canadian higher education institutions, little is known and understood about how instructors view their role as supporters or promoters of student mental health. The purpose of this study was to explore the role of college instructors in supporting students with mental health problems or illnesses. Participants were 42 instructors between the ages of 25 to 64 from Molize College in Toronto, Ontario. Qualitative ethnography was employed to gather data from participants, specifically through a survey questionnaire and interviews. A constructivist framework was adopted to analyze and understand the values, perceptions, meanings, and practices post-secondary instructors carry around notions of student mental health and intervention. Findings revealed that instructors were generally aware of student mental health concerns in post-secondary institutions, but that greater awareness was still warranted, namely in the areas of instructor mental health and location of support services. Findings also demonstrated that most instructors evaluated their knowledge and confidence in relation to student mental health as poor, which was often credited to limited relevant professional development and training. Additionally, data indicated that instructors carried skepticism towards the role of some student support services departments, as well as towards their own role when supporting the mental health and well-being of students. On a final note, findings revealed that instructors commonly employed four practices to support the mental health and well-being of students: conversation, referral, accommodations, and curricular inclusion and instruction. Future studies are encouraged to acknowledge the narratives of instructors through ethnographic inquiry, to allow for greater insights into their awareness, knowledge/confidence, responsibilities, and practices when it comes to supporting the mental health and well-being of students in higher education settings. Incorporating the instructor may not be a panacea for the shortcomings of current mental health policies and practices in higher education settings, but it can certainly represent a colossal step in that direction. KEYWORDS: student mental health, higher education, instructor

A Phase 1 Randomized, Double Blind, Placebo Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel (MTN-007)

Objective: Rectal microbicides are needed to reduce the risk of HIV acquisition associated with unprotected receptive anal intercourse. The MTN-007 study was designed to assess the safety (general and mucosal), adherence, and acceptability of a new reduced glycerin formulation of tenofovir 1% gel. Methods: Participants were randomized 1:1:1:1 to receive the reduced glycerin formulation of tenofovir 1% gel, a hydroxyethyl cellulose placebo gel, a 2% nonoxynol-9 gel, or no treatment. Each gel was administered as a single dose followed by 7 daily doses. Mucosal safety evaluation included histology, fecal calprotectin, epithelial sloughing, cytokine expression (mRNA and protein), microarrays, flow cytometry of mucosal T cell phenotype, and rectal microflora. Acceptability and adherence were determined by computer-administered questionnaires and interactive telephone response, respectively. Results: Sixty-five participants (45 men and 20 women) were recruited into the study. There were no significant differences between the numbers of ≥ Grade 2 adverse events across the arms of the study. Likelihood of future product use (acceptability) was 87% (reduced glycerin formulation of tenofovir 1% gel), 93% (hydroxyethyl cellulose placebo gel), and 63% (nonoxynol-9 gel). Fecal calprotectin, rectal microflora, and epithelial sloughing did not differ by treatment arms during the study. Suggestive evidence of differences was seen in histology, mucosal gene expression, protein expression, and T cell phenotype. These changes were mostly confined to comparisons between the nonoxynol-9 gel and other study arms. Conclusions: The reduced glycerin formulation of tenofovir 1% gel was safe and well tolerated rectally and should be advanced to Phase 2 development. Trial Registration: ClinicalTrials.gov NCT01232803

Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.

Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive rhomboid protease RHBDF2 (iRHOM2) regulates thickening of the footpad epidermis through its interaction with K16. K16 expression is absent in the thinned footpads of irhom2-/- mice compared with irhom2+/+mice, due to reduced keratinocyte proliferation. Gain-of-function mutations in iRHOM2 underlie Tylosis with oesophageal cancer (TOC), characterized by palmoplantar thickening, upregulate K16 with robust downregulation of its type II keratin binding partner, K6. By orchestrating the remodelling and turnover of K16, and uncoupling it from K6, iRHOM2 regulates the epithelial response to physical stress. These findings contribute to our understanding of the molecular mechanisms underlying hyperproliferation of the palmoplantar epidermis in both physiological and disease states, and how this 'stress' keratin is regulated

Examining intervention mechanisms of action using mediation analysis within a randomised trial of a whole-school health intervention

BACKGROUND: Interventions to modify school environments are effective in promoting young people's health across outcomes, but mechanisms are poorly understood. We assessed mediation in a trial of the Learning Together intervention, building on the recent publication of results of effectiveness for reducing bullying and benefits across secondary outcomes and generally good implementation fidelity. METHODS: Within a cluster-randomised trial involving 40 English schools, we examined student-reported and staff-reported school climate and student-reported involvement with delinquent peers at 24-month and 36-month follow-up, assessing the reliability of measures and whether these mediated health outcomes at a final follow-up. RESULTS: Response rates and reliability were good for student-reported but not staff-reported measures. The intervention increased student-reported but not staff-reported-positive school climate but, like effects on student health outcomes, these manifested only at a final follow-up. The intervention reduced student-reported contact with delinquent peers at an interim follow-up. Student-reported potential mediators measured at the interim follow-up were associated with most health outcomes at the final follow-up. Adjustment for student-reported school climate and contact with delinquent peers at the interim follow-up did not reduce the associations between trial arm and our health outcomes. CONCLUSION: Despite being constrained by imperfect measures and by the late manifestation of impacts on student-reported school climate undermining ability to assess mediation, our study for the first time provides tentative evidence that mediation of intervention effects via improved climate and disengagement from delinquent peers is plausible. Our study provides the first evidence from a trial that whole-school interventions may work by modifying school environments and student relationships. TRIAL REGISTRATION NUMBER: ISRCTN10751359