Histologic and phenotypic factors and MC1R status associated with BRAF(V600E), BRAF(V600K), and NRAS mutations in a community-based sample of 414 cutaneous melanomas

Cutaneous melanomas arise through causal pathways involving interplay between exposure to UV radiation and host factors, resulting in characteristic patterns of driver mutations in BRAF, NRAS, and other genes. To gain clearer insights into the factors contributing to somatic mutation genotypes in melanoma, we collected clinical and epidemiologic data, performed skin examinations, and collected saliva and tumor samples from a community-based series of 414 patients aged 18 to 79, newly diagnosed with cutaneous melanoma. We assessed constitutional DNA for nine common polymorphisms in melanocortin-1 receptor gene (MC1R). Tumor DNA was assessed for somatic mutations in 25 different genes. We observed mutually exclusive mutations in BRAF (26%), BRAF (8%), BRAF (5%), and NRAS (9%). Compared to patients with BRAF wild-type melanomas, those with BRAF mutants were significantly younger, had more nevi but fewer actinic keratoses, were more likely to report a family history of melanoma, and had tumors that were more likely to harbor neval remnants. BRAF mutations were also associated with high nevus counts. Both BRAF and NRAS mutants were associated with older age but not with high sun exposure. We also found no association between MC1R status and any somatic mutations in this community sample of cutaneous melanomas, contrary to earlier reports

Effectiveness of a Community Program for Older Adults with Type 2 Diabetes and Multimorbidity: A Pragmatic Randomized Controlled Trial

Background Type II diabetes mellitus (T2DM) affects upwards of 25% of Canadian older adults and is associated with high comorbidity and burden. Studies show that lifestyle factors and self-management are associated with improved health outcomes, but many studies lack rigour or exclude older adults, particularly those with multimorbidity. More evidence is needed on the effectiveness of community-based self-management programs in older adults with T2DM and multimorbidity. The study purpose is to evaluate the effect of a community-based intervention versus usual care on physical functioning, mental health, depressive symptoms, anxiety, self-efficacy, self-management, and healthcare costs in older adults with T2DM and 2 or more comorbidities. Methods Community-living older adults with T2DM and two or more chronic conditions were recruited from three Primary Care Networks (PCNs) in Alberta, Canada. Participants were randomly allocated to the intervention or control group in this pragmatic randomized controlled trial comparing the intervention to usual care. The intervention involved up to three in-home visits, a monthly group wellness program, monthly case conferencing, and care coordination. The primary outcome was physical functioning. Secondary outcomes included mental functioning, anxiety, depressive symptoms, self-efficacy, self-management, and the cost of healthcare service use. Intention-to-treat analysis was performed using ANCOVA modeling. Results Of 132 enrolled participants (70-Intervention, 62-Control), 42% were 75 years or older, 55% were female, and over 75% had at least six chronic conditions (in addition to T2DM). No significant group differences were seen for the baseline to six-month change in physical functioning (mean difference: -0.74; 95% CI: − 3.22, 1.74; p-value: 0.56), mental functioning (mean difference: 1.24; 95% CI: − 1.12, 3.60; p-value: 0.30), or other secondary outcomes.. Conclusion No significant group differences were seen for the primary outcome, physical functioning (PCS). Program implementation, baseline differences between study arms and chronic disease management services that are part of usual care may have contributed to the modest study results. Fruitful areas for future research include capturing clinical outcome measures and exploring the impact of varying the type and intensity of key intervention components such as exercise and diet

PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition.

Phosphatidylinositol (PI)regulating enzymes are frequently altered in cancer and have become a focus for drug development. Here, we explore the phosphatidylinositol-5-phosphate 4-kinases (PI5P4K), a family of lipid kinases that regulate pools of intracellular PI, and demonstrate that the PI5P4Kα isoform influences androgen receptor (AR) signaling, which supports prostate cancer (PCa) cell survival. The regulation of PI becomes increasingly important in the setting of metabolic stress adaptation of PCa during androgen deprivation (AD), as we show that AD influences PI abundance and enhances intracellular pools of PI-4,5-P2. We suggest that this PI5P4Kα-AR relationship is mitigated through mTORC1 dysregulation and show that PI5P4Kα colocalizes to the lysosome, the intracellular site of mTORC1 complex activation. Notably, this relationship becomes prominent in mouse prostate tissue following surgical castration. Finally, multiple PCa cell models demonstrate marked survival vulnerability following stable PI5P4Kα inhibition. These results nominate PI5P4Kα as a target to disrupt PCa metabolic adaptation to castrate resistance

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053. Findings Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants’ systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups. Interpretation Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultraacute prehospital setting. Funding British Heart Foundation

Real Lives Half Lives: Fukushima

Real Lives Half Lives: Fukushima is an exhibition and season exploring cultural and societal responses to disaster, displacement and poisoned lands. What can art do in an ongoing catastrophe? How do citizens respond to a situation that forces tens of thousands of people out of their homes, land, and communities, many of whom probably cannot return for decades? Arts Catalyst presents artworks by artists that respond to the man-made disaster of the 2011 Fukushima Daiichi nuclear meltdown, alongside a series of events exploring the profound social, cultural and political impact of Fukushima in Japan and the lessons we may learn. A Walk in Fukushima - Don’t Follow the Wind The curatorial collective Don't Follow The Wind Chim↑Pom, Kenji Kubota, Eva and Franco Mattes, Jason Waite - who developed the long-term project and its ongoing off-site correspondences, was initiated by Chim↑Pom. On 11 March, 2015, an inaccessible exhibition entitled Don't Follow The Wind opened in Fukushima on the fourth anniversary of the earthquake and tsunami that triggered the ongoing crisis at the Fukushima Dai-ichi Nuclear Power Plant (owned by TEPCO). The exhibition is situated inside the radioactive, evacuated area surrounding the power plant at sites lent by former residents, which include a warehouse, farm, and a recreation centre. The curators collaborated with twelve artists including Ai Weiwei, Chim↑Pom, Grand Guignol Mirai, Nikolaus Hirsch and Jorge Otero-Pailos, Meiro Koizumi, Eva and Franco Mattes, Aiko Miyanaga, Ahmet Öğüt, Trevor Paglen, Taryn Simon, Nobuaki Takekawa, and Kota Takeuchi. Located inside the inaccessible Fukushima exclusion zone, the exhibition is open and yet remains unseen. It will continue to be invisible for years or even decades. At Arts Catalyst, the curatorial collective has formed a correspondence with the inaccessible exhibition. Whilst the artworks in the original exhibition remain unseen in the exclusion zone, other objects from the sites appear on display, bearing material witness to the ongoing catastrophe. These physical artefacts include the farmhouse keys and cafe furniture from a restaurant that had intended to open on the farm a few weeks after the disaster. The restaurant, its inauguration now perpetually deferred, has instead become a host for artworks that the former residents see as conceptual placeholders for their absence. A Walk in Fukushima is an immersive 360-degree video made by the curatorial collective. Filmed in and around the uninhabited radioactive area, the video presents an intimate experience of the inaccessible zone, the venues for the exhibition Don't Follow the Wind, and the power plant itself. The video follows the account of a former resident's visit to his abandoned home inside the exclusion zone; it is shown on headsets made by three generations of a Fukushima family living just outside the zone in a contaminated area deemed 'safe to live' by the government. The accompanying narratives of these headsets share personal accounts and experiences of this new reality: the restrictions, the rumours and the desires for a different future seen from their unstable present. Project Fukushima! - Hikaru Fujii Artist Hikaru Fujii’s film Project Fukushima! follows the preparations for a festival held in Fukushima city five months after the nuclear disaster. The festival, called simply “Fukushima!” was organised by a group of artists and musicians including Yoshihide Otomo. They aim to give visibility to Fukushima’s current state just as it was. The film features music and poetry by Yoshihide Otomo, Michiro Endo, Ryoichi Wago and people from Fukushima and other regions of Japan. It was not a typical festival since the organisers had to address questions such as: Would it be ethical to bring people to Fukushima? What about children? And what would it mean to the people of Fukushima if the festival had to be called off after all due to radiation concerns? Throughout the film we see how the lives of people in Fukushima have changed and what the future might look like for the next few generations. Born in 1976, Hikaru Fujii creates video installations that respond to contemporary social problems. He makes use of extensive research and fieldwork investigating existing systems and structures, based on the idea that art is produced out of the intimate relationship between society and history. His work explores modern education and social systems in Japan and Asia as well as the nature of museums and art museums. Events Programme The “triple disaster” of earthquake, tsunami and meltdown energised many people in Japan to become more proactive, vocal and dissenting. Mass anti-nuclear protests were held countrywide in the years following the disaster and smaller scale protests are still widespread. A citizen science movement sprang up in response to the slow release (some claimed withholding) of radiation data, with citizens using their own radiation-measuring devices to measure levels of radioactivity and post that data online. Legal challenges and petitions against nuclear power in Japan point to another tactic used by a citizenry that wishes to reclaim more governance over its environment and safety. Japanese artists have responded with an array of approaches, and have often been at the forefront of dissent and critique. A programme of talks, events and activities included contributors Sabu Kohso, Jason Waite, Anna Santomauro, Kaori Homma, and Kodwo Eshun

Graveyard of Lost Species - Critical Art Ensemble / YoHa

The Graveyard of Lost Species by Critical Art Ensemble and YoHa with Arts Catalyst, curated by Nicola Triscott and Claudia Lastra, is a temporary public monument, created from a local wreck, the Souvenir - a 40ft 12 ton Thames Bawley fishing boat, which was reclaimed from the estuary mud. With the names of varied "lost species" (flora, fauna, occupations, words) from the estuary laser carved onto the boat’s surface and interior, she was sailed back and installed on the Leigh marshes as a part of the local landscape. During 2015 and 2016, the artists led a set of enquiries with people in Leigh-on-Sea and Southend to gather local knowledge of and expertise about "lost species" - wildlife, marine creatures, livelihoods, fishing methods, landmarks and local dialects that once flourished in the Estuary and are now disappearing. Working with local craftsmen, the artists then laser cut the lost species into the vessel’s surface. The project is intended to act as a monument to Leigh’s past and future, as well as uncovering and highlighting local knowledge about the changing ecology, society and industry of the Thames estuary

The Potential of Probiotics as Ingestible Adjuvants and Immune Modulators for Antiviral Immunity and Management of SARS-CoV-2 Infection and COVID-19

Probiotic bacteria are able to modulate general antiviral responsiveness, including barrier functionality and innate and adaptive immune responses. The COVID-19 pandemic, resulting from SARS-CoV-2 infection, has created a need to control and treat this viral infection and its ensuing immunopathology with a variety of approaches; one such approach may involve the administration of probiotic bacteria. As with most viral infections, its pathological responses are not fully driven by the virus, but are significantly contributed to by the host’s immune response to viral infection. The potential adoption of probiotics in the treatment of COVID-19 will have to appreciate the fine line between inducing antiviral immunity without over-provoking immune inflammatory responses resulting in host-derived immunopathological tissue damage. Additionally, the effect exerted on the immune system by SARS-CoV-2 evasion strategies will also have to be considered when developing a robust response to this virus. This review will introduce the immunopathology of COVID-19 and the immunomodulatory effects of probiotic strains, and through their effects on a range of respiratory pathogens (IAV, SARS-CoV, RSV), as well as SARS-CoV-2, will culminate in a focus on how these bacteria can potentially manipulate both infectivity and immune responsiveness via barrier functionality and both innate and adaptive immunity. In conclusion, the harnessing of induction and augmentation of antiviral immunity via probiotics may not only act as an ingestible adjuvant, boosting immune responsiveness to SARS-CoV-2 infection at the level of barrier integrity and innate and adaptive immunity, but also act prophylactically to prevent infection and enhance protection afforded by current vaccine regimens.</jats:p