Laser-free pelvic alignment in an online adaptive radiotherapy environment.

The MR-Linac (MRL) provides a novel treatment modality that enables online adaptive treatments, but also creates new challenges for patient positioning in a laser-free environment. The accuracy and duration of prostate patient set-up on the MRL using two different methods for patient alignment was determined to establish standard of practice on the MRL. Differences in set-up accuracy were significant in the longitudinal direction and are accounted for in online plan adaption. Both methods recorded similar set-up times. The vendor recommended alignment method involves less manipulation of the patient and will be adopted as the standard positioning method for prostate and other pelvic patients on the MRL in future

MRI-guided adaptive radiotherapy for prostate cancer: When do we need to account for intra-fraction motion?

A shift of the daily plan can mitigate target position changes that occur between daily MR acquisition and treatment for MR-linac radiotherapy, but increases the session time. We demonstrated that our workflow strategy and decision-making process, to determine whether a subsequent shift is necessary, is appropriate

A role for core planar polarity proteins in cell contact-mediated orientation of planar cell division across the mammalian embryonic skin

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2017. Supplementary information accompanies this paper at doi:10.1038/s41598-017-01971-2.The question of how cell division orientation is determined is fundamentally important for understanding tissue and organ shape in both healthy or disease conditions. Here we provide evidence for cell contact-dependent orientation of planar cell division in the mammalian embryonic skin. We propose a model where the core planar polarity proteins Celsr1 and Frizzled-6 (Fz6) communicate the long axis orientation of interphase basal cells to neighbouring basal mitoses so that they align their horizontal division plane along the same axis. The underlying mechanism requires a direct, cell surface, planar polarised cue, which we posit depends upon variant post-translational forms of Celsr1 protein coupled to Fz6. Our hypothesis has parallels with contact-mediated division orientation in early C. elegans embryos suggesting functional conservation between the adhesion-GPCRs Celsr1 and Latrophilin-1. We propose that linking planar cell division plane with interphase neighbour long axis geometry reinforces axial bias in skin spreading around the mouse embryo body.Peer reviewe

Protectors of Wellbeing During the COVID-19 Pandemic: Key Roles for Gratitude and Tragic Optimism in a UK-Based Cohort

The COVID-19 pandemic has presented a global threat to physical and mental health worldwide. Research has highlighted adverse impacts of COVID-19 on wellbeing but has yet to offer insights as to how wellbeing may be protected. Inspired by developments in wellbeing science and guided by our own theoretical framework (the GENIAL model), we examined the role of various potentially protective factors in a sample of 138 participants from the United Kingdom. Protective factors included physical activity (i.e., a health behaviour that helps to build psychological wellbeing), tragic optimism (optimism in the face of tragedy), gratitude (a prosocial emotion), social support (the perception or experience of being loved, cared for, and valued by others), and nature connectedness (physical and psychological connection to nature). Initial analysis involved the application of one-sample t-tests, which confirmed that wellbeing (measured by the Warwick-Edinburgh Mental Well-being scale) in the current sample (N = 138; M = 46.08, SD = 9.22) was significantly lower compared to previous samples (d = −0.36 and d = −0.41). Protective factors were observed to account for up to 50% of variance in wellbeing in a hierarchical linear regression that controlled for a range of sociostructural factors including age, gender, and subjective social status, which impact on wellbeing but lie beyond individual control. Gratitude and tragic optimism emerged as significant contributors to the model. Our results identify key psychological attributes that may be harnessed through various positive psychology strategies to mitigate the adverse impacts of hardship and suffering, consistent with an existential positive psychology of suffering

Interim Toxicity Analysis From the Randomized HERMES Trial of 2- and 5-Fraction Magnetic Resonance Imaging-Guided Adaptive Prostate Radiation Therapy.

PURPOSE: Ultrahypofractionated radiation therapy (UHRT) is an effective treatment for localized prostate cancer with an acceptable toxicity profile; boosting the visible intraprostatic tumor has been shown to improve biochemical disease-free survival with no significant effect on genitourinary (GU) and gastrointestinal (GI) toxicity. METHODS AND MATERIALS: HERMES is a single-center noncomparative randomized phase 2 trial in men with intermediate or lower high risk prostate cancer. Patients were allocated (1:1) to 36.25 Gy in 5 fractions over 2 weeks or 24 Gy in 2 fractions over 8 days with an integrated boost to the magnetic resonance imaging (MRI) visible tumor of 27 Gy in 2 fractions. A minimization algorithm with a random element with risk group as a balancing factor was used for participant randomization. Treatment was delivered on the Unity MR-Linac (Elekta AB) with daily online adaption. The primary endpoint was acute GU Common Terminology Criteria for Adverse Events version 5.0 toxicity with the aim of excluding a doubling of the rate of acute grade 2+ GU toxicity seen in PACE. Analysis was by treatment received and included all participants who received at least 1 fraction of study treatment. This interim analysis was prespecified (stage 1 of a 2-stage Simon design) for when 10 participants in each treatment group had completed the acute toxicity monitoring period (12 weeks after radiation therapy). RESULTS: Acute grade 2 GU toxicity was reported in 1 (10%) patient in the 5-fraction group and 2 (20%) patients in the 2-fraction group. No grade 3+ GU toxicities were reported. CONCLUSIONS: At this interim analysis, the rate of GU toxicity in the 2-fraction and 5-fraction treatment groups was found to be below the prespecified threshold (5/10 grade 2+) and continuation of the study to complete recruitment of 23 participants per group was recommended

Plasmacytoid Dendritic Cells Are Proportionally Expanded at Diagnosis of Type 1 Diabetes and Enhance Islet Autoantigen Presentation to T-Cells Through Immune Complex Capture

OBJECTIVE—Immune-mediated destruction of β-cells resulting in type 1 diabetes involves activation of proinflammatory, islet autoreactive T-cells, a process under the control of dendritic cells of the innate immune system. We tested the hypothesis that type 1 diabetes development is associated with disturbance of blood dendritic cell subsets that could enhance islet-specific autoimmunity

The need for multidisciplinarity in specialist training to optimize future patient care

Harmonious interactions between radiation, medical, interventional and surgical oncologists, as well as other members of multidisciplinary teams, are essential for the optimization of patient care in oncology. This multidisciplinary approach is particularly important in the current landscape, in which standard-of-care approaches to cancer treatment are evolving towards highly targeted treatments, precise image guidance and personalized cancer therapy. Herein, we highlight the importance of multidisciplinarity and interdisciplinarity at all levels of clinical oncology training. Potential deficits in the current career development pathways and suggested strategies to broaden clinical training and research are presented, with specific emphasis on the merits of trainee involvement in functional multidisciplinary teams. Finally, the importance of training in multidisciplinary research is discussed, with the expectation that this awareness will yield the most fertile ground for future discoveries. Our key message is for cancer professionals to fulfil their duty in ensuring that trainees appreciate the importance of multidisciplinary research and practice

Objective Patterns of Face Recognition Deficits in 165 Adults with Self-Reported Developmental Prosopagnosia

In the last 15 years, increasing numbers of individuals have self-referred to research laboratories in the belief that they experience severe everyday difficulties with face recognition. The condition “developmental prosopagnosia” (DP) is typically diagnosed when impairment is identified on at least two objective face-processing tests, usually involving assessments of face perception, unfamiliar face memory, and famous face recognition. While existing evidence suggests that some individuals may have a mnemonic form of prosopagnosia, it is also possible that other subtypes exist. The current study assessed 165 adults who believe they experience DP, and 38% of the sample were impaired on at least two of the tests outlined above. While statistical dissociations between face perception and face memory were only observed in four cases, a further 25% of the sample displayed dissociations between impaired famous face recognition and intact short-term unfamiliar face memory and face perception. We discuss whether this pattern of findings reflects (a) limitations within dominant diagnostic tests and protocols, (b) a less severe form of DP, or (c) a currently unrecognized but prevalent form of the condition that affects long-term face memory, familiar face recognition or semantic processing.British Academy Mid-Career Fellowship; Economic and Social Research Counci

Daily adaptive radiotherapy for patients with prostate cancer using a high field MR-linac: Initial clinical experiences and assessment of delivered doses compared to a C-arm linac.

Introduction:MR-guided adapted radiotherapy (MRgART) using a high field MR-linac has recently become available. We report the estimated delivered fractional dose of the first five prostate cancer patients treated at our centre using MRgART and compare this to C-Arm linac daily Image Guided Radiotherapy (IGRT). Methods:Patients were treated using adapted treatment plans shaped to their daily anatomy. The treatments were recalculated on an MR image acquired immediately prior to treatment delivery in order to estimate the delivered fractional dose. C-arm linac non-adapted VMAT treatment plans were recalculated on the same MR images to estimate the fractional dose that would have been delivered using conventional radiotherapy techniques using a daily IGRT protocol. Results:95% and 93% of mandatory target coverage objectives and organ at risk dose constraints were achieved by MRgART and C-arm linac delivered dose estimates, respectively. Both delivery techniques were estimated to have achieved 98% of mandatory Organ At Risk (OAR) dose constraints whereas for the target clinical goals, 86% and 80% were achieved by MRgART and C-arm linac delivered dose estimates. Conclusions:Prostate MRgART can be delivered using the a high field MR-linac. Radiotherapy performed on a C-arm linac offers a good solution for prostate cancer patients who present with favourable anatomy at the time of reference imaging and demonstrate stable anatomy throughout the course of their treatment. For patients with critical OARs abutting target volumes on their reference image we have demonstrated the potential for a target dose coverage improvement for MRgART compared to C-arm linac treatment

A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes

Aim We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia. Methods We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: i) 45mg loading-weeks 0/4/16, ii) 45mg maintenance-weeks 0/4/16/28/40, iii) 90mg loading-weeks 0/4/16 and iv) 90mg maintenance-weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses. Results Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90mg maintenance dosing cohort had the smallest mean decline in C-peptide AUC (0.1pmol/mL). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1 and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A. Conclusion Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response