Rac1 plays a role in CXCL12 but not CCL3-induced chemotaxis and Rac1 GEF inhibitor NSC23766 has off target effects on CXCR4

Cell mi­gra­tion to­wards a chemo­tac­tic stim­u­lus re­lies on the re-arrange­ment of the cy­toskele­ton, which is trig­gered by ac­ti­va­tion of small G pro­teins RhoA, Rac1 and Cd­c42, and leads to for­ma­tion of lamel­lopo­dia and actin poly­meri­sa­tion amongst other ef­fects. Here we show that Rac1 is im­por­tant for CX­CR4 in­duced chemo­taxis but not for CCR1/​CCR5 in­duced chemo­taxis. For CX­CL12-in­duced mi­gra­tion via CX­CR4, breast can­cer MCF-7 cells are re­liant on Rac1, sim­i­larly to THP-1 mono­cytes and Ju­rkat T-cells. For CCL3-in­duced mi­gra­tion via CCR1 and/​or CCR5, Rac1 sig­nalling does not reg­u­late cell mi­gra­tion in ei­ther sus­pen­sion or ad­her­ent cells. We have con­firmed the in­volve­ment of Rac1 with the use of a spe­cific Rac1 block­ing pep­tide. We also used a Rac1 in­hibitor EHT 1864 and a Rac1-GEF in­hibitor NSC23766 to probe the im­por­tance of Rac1 in chemo­taxis. Both in­hibitors did not block CCL3-in­duced chemo­taxis, but they were able to block CX­CL12-in­duced chemo­taxis. This con­firms that Rac1 ac­ti­va­tion is not es­sen­tial for CCL3-in­duced mi­gra­tion, how­ever NSC23766 might have sec­ondary ef­fects on CX­CR4. This small mol­e­cule ex­hibits ag­o­nis­tic fea­tures in in­ter­nal­i­sa­tion and cAMP as­says, whereas it acts as an an­tag­o­nist for CX­CR4 in mi­gra­tion and cal­cium re­lease as­says. Our find­ings strongly sug­gest that Rac1 ac­ti­va­tion is not nec­es­sary for CCL3 sig­nalling, and re­veal that NSC23766 could be a novel CX­CR4 re­cep­tor lig­and

Recent high school graduates support mandatory cardiopulmonary resuscitation education in Australian high schools

Objective: To evaluate recent high school graduates\u27 opinions on mandatory cardiopulmonary resuscitation (CPR) training in the high school curriculum as a solution to improving bystander CPR rates. Methods: Participants completed questionnaires assessing their CPR training history during their high school education, their willingness to learn CPR during their high school years and their opinion on making CPR training mandatory for high school curricula. Results: Of the 178 participants in this study, 60% had undertaken CPR training during their high school education. Of those who had not undertaken CPR training, 75% reported that they would have been willing to learn CPR had they been provided with the opportunity. A total of 97% of participants were in support of mandatory CPR training in high school education. Conclusion: Implementing mandatory CPR training in high school education would be embraced by students. Implications for public health: Findings of this study support our recommendation to implement mandatory CPR training in the high school curriculum. This will likely increase the number of bystanders in the community who would spontaneously administer CPR, thereby improving outcomes for patients experiencing out‐of‐hospital cardiac arrest

Building an initial understanding of UK Recovery College dementia courses: A national survey of Recovery College and memory services staff. Journal: Working with Older People Working with Older People

PurposeRecovery Colleges were developed to support the recovery of people with mental health difficulties through courses co-produced by professionals and people with lived experience. This study aims to examine the use of Recovery Colleges to support people with dementia.Design/methodology/approachA survey was circulated to UK Recovery College and memory service staff, exploring provision, delivery and attendance of dementia courses. Open responses provided insight into participant views about recovery in post-diagnostic support and the practicalities of running dementia courses.FindingsA total of 51 Recovery College staff and 210 memory service staff completed the survey. Twelve Recovery College dementia courses were identified across the UK. Three categories emerged from the qualitative data: post-diagnostic support, recovery in the context of dementia, challenges and areas of innovation

Design, Delivery, Maintenance, and Outcomes of Peer-to-Peer Online Support Groups for People With Chronic Musculoskeletal Disorders: Systematic Review

Background: Online support groups (OSGs) are one way for people with chronic diseases, their family or friends, and health professionals to communicate, gain information, and provide social support. As the number of peer-to-peer OSGs for chronic musculoskeletal conditions grows, it is important to gain insight into the different designs of groups available, who is accessing them, if and how they may be effective, and what strategies are being used to implement or increase consumer engagement. Objective: The objectives of this systematic review of people with musculoskeletal conditions were to (1) describe the design features (functions, usage options, moderation, and expert input) of peer-to-peer OSGs, (2) describe the characteristics of the individuals using peer-to-peer OSGs, (3) synthesize the evidence on outcomes of participation, and (4) identify strategies used in the delivery and maintenance of OSGs. Methods: A search comprising terms related to the population (people with musculoskeletal disorders) and the intervention (peer-to-peer OSGs) was conducted in 6 databases. Results were filtered from 1990 (internet inception) to February 2019. Studies identified in the search were screened according to predefined eligibility criteria using a 2-step process. Quantitative studies were appraised by 2 reviewers using the Risk Of Bias In Non-Randomized Studies of Interventions tool. Qualitative studies were appraised by 2 different reviewers using the Critical Appraisal Skills Programme checklist. Extracted data were synthesized narratively. Results: We examined 21 studies with low to moderate risk of bias. Of these studies, 13 studies included OSGs hosted on public platforms, 11 studies examined OSGs that were conducted in English, and 6 studies used moderators or peer leaders to facilitate engagement. Studies either reported the number of OSG members (n=1985 across all studies) or the number of posts (range: 223-200,000). The majority of OSG members were females who were not full-time employees and with varied levels of education. There were no randomized controlled trials measuring the efficacy of OSGs. Qualitative and quantitative studies identified empowerment, social support, self-management behavior, and health literacy as primary constructs to measure OSG efficacy. Neutral or marginal improvement was reported in these constructs. Sharing experiences and a greater level of engagement appeared to have an important influence on OSGs efficacy. The extent to which members posted on the website influenced engagement. Conclusions: Across a diverse range of designs, languages, included features, and delivery platforms, peer-to-peer OSGs for chronic musculoskeletal conditions attract predominantly female participants of all ages and education levels. The level of participation of a member appears to be related to their perceived benefit, health literacy, and empowerment. Future studies are needed to identify which design and maintenance strategies have superior efficacy and whether there are concomitant improvements in health outcomes for people with chronic musculoskeletal conditions resulting from participation in OSGs

Dynamics of direct inter-pack encounters in endangered African wild dogs

Aggressive encounters may have important life history consequences due to the potential for injury and death, disease transmission, dispersal opportunities or exclusion from key areas of the home range. Despite this, little is known of their detailed dynamics, mainly due to the difficulties of directly observing encounters in detail. Here, we describe detailed spatial dynamics of inter-pack encounters in African wild dogs (Lycaon pictus), using data from custom-built high-resolution GPS collars in 11 free-ranging packs. On average, each pack encountered another pack approximately every 7 weeks and met each neighbour twice each year. Surprisingly, intruders were more likely to win encounters (winning 78.6% of encounters by remaining closer to the site in the short term). However, intruders did tend to move farther than residents toward their own range core in the short-term (1 h) post-encounter, and if this were used to indicate losing an encounter, then the majority (73.3%) of encounters were won by residents. Surprisingly, relative pack size had little effect on encounter outcome, and injuries were rare (<15% of encounters). These results highlight the difficulty of remotely scoring encounters involving mobile participants away from static defendable food resources. Although inter-pack range overlap was reduced following an encounter, encounter outcome did not seem to drive this, as both packs shifted their ranges post-encounter. Our results indicate that inter-pack encounters may be lower risk than previously suggested and do not appear to influence long-term movement and ranging

The combination of autofluorescence endoscopy and molecular biomarkers is a novel diagnostic tool for dysplasia in Barrett's oesophagus.

OBJECTIVE: Endoscopic surveillance for Barrett's oesophagus (BO) is limited by sampling error and the subjectivity of diagnosing dysplasia. We aimed to compare a biomarker panel on minimal biopsies directed by autofluorescence imaging (AFI) with the standard surveillance protocol to derive an objective tool for dysplasia assessment. DESIGN: We performed a cross-sectional prospective study in three tertiary referral centres. Patients with BO underwent high-resolution endoscopy followed by AFI-targeted biopsies. 157 patients completed the biopsy protocol. Aneuploidy/tetraploidy; 9p and 17p loss of heterozygosity; RUNX3, HPP1 and p16 methylation; p53 and cyclin A immunohistochemistry were assessed. Bootstrap resampling was used to select the best diagnostic biomarker panel for high-grade dysplasia (HGD) and early cancer (EC). This panel was validated in an independent cohort of 46 patients. RESULTS: Aneuploidy, p53 immunohistochemistry and cyclin A had the strongest association with dysplasia in the per-biopsy analysis and, as a panel, had an area under the receiver operating characteristic curve of 0.97 (95% CI 0.95 to 0.99) for diagnosing HGD/EC. The diagnostic accuracy for HGD/EC of the three-biomarker panel from AFI+ areas was superior to AFI- areas (p<0.001). Compared with the standard protocol, this panel had equal sensitivity for HGD/EC, with a 4.5-fold reduction in the number of biopsies. In an independent cohort of patients, the panel had a sensitivity and specificity for HGD/EC of 100% and 85%, respectively. CONCLUSIONS: A three-biomarker panel on a small number of AFI-targeted biopsies provides an accurate and objective diagnosis of dysplasia in BO. The clinical implications have to be studied further

Presenting Symptoms in Men and Women Diagnosed With Myocardial Infarction Using Sex‐Specific Criteria

Background: Sex‐specific criteria are recommended for the diagnosis of myocardial infarction, but the impact of these on presenting characteristics is unknown. Methods and Results: We evaluated patient‐reported symptoms in 1941 patients (39% women) with suspected acute coronary syndrome attending the emergency department in a substudy of a prospective trial. Standardized criteria defined typical and atypical presentations based on pain nature, location, radiation, and additional symptoms. Diagnosis of myocardial infarction was adjudicated using a high‐sensitivity cardiac troponin I assay with sex‐specific thresholds (&gt;16 ng/L women, &gt;34 ng/L men). Patients identified who were missed by the contemporary assay with a uniform threshold (≥50 ng/L) were reclassified by this approach. Type 1 myocardial infarction was diagnosed in 16% (184/1185) of men and 12% (90/756) of women, with 9 (5%) men and 27 (30%) women reclassified using high‐sensitivity cardiac troponin I and sex‐specific thresholds. Chest pain was the presenting symptom in 91% (1081/1185) of men and 92% (698/756) of women. Typical symptoms were more common in women than in men with myocardial infarction (77% [69/90] versus 59% [109/184]; P=0.007), and differences were similar in those reclassified (74% [20/27] versus 44% [4/9]; P=0.22). The presence of ≥3 typical features was associated with a positive likelihood ratio for the diagnosis of myocardial infarction in women (positive likelihood ratio, 1.18; 95% CI, 1.03–1.31) but not in men (positive likelihood ratio 1.09; 95% CI, 0.96–1.24). Conclusions: Typical symptoms are more common and have greater predictive value in women than in men with myocardial infarction whether or not they are diagnosed using sex‐specific criteria

A conceptual thematic framework of psychological adjustment in caregivers of children with craniofacial microsomia

Objective: Children with craniofacial microsomia (CFM) have complex healthcare needs, resulting in evaluations and interventions from infancy onward. Yet, little is understood about families’ treatment experiences or the impact of CFM on caregivers’ well-being. To address this gap, the NIH-funded ‘Craniofacial microsomia: Accelerating Research and Education (CARE)’ program sought to develop a conceptual thematic framework of caregiver adjustment to CFM. Design: Caregivers reported on their child's medical and surgical history. Narrative interviews were conducted with US caregivers (n = 62) of children aged 3-17 years with CFM. Transcripts were inductively coded and final themes and subthemes were identified. Results: Components of the framework included: 1) Diagnostic Experiences, including pregnancy and birth, initial emotional responses, communication about the diagnosis by healthcare providers, and information-seeking behaviors; 2) Child Health and Healthcare Experiences, including feeding, the child's physical health, burden of care, medical decision-making, surgical experiences, and the perceived quality of care; 3) Child Development, including cognition and behavior, educational provision, social experiences, and emotional well-being; and 4) Family Functioning, including parental well-being, relationships, coping strategies, and personal growth. Participants also identified a series of “high” and “low” points throughout their journey and shared their priorities for future research. Conclusions: Narrative interviews provided rich insight into caregivers’ experiences of having a child with CFM and enabled the development of a conceptual thematic framework to guide clinical care and future research. Information gathered from this study demonstrates the need to incorporate evidence-based psychological support for families into the CFM pathway from birth onward

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Collaboration for conservation: assessing countrywide carnivore occupancy dynamics from sparse data

Aim: Assessing the distribution and persistence of species across their range is a crucial component of wildlife conservation. It demands data at adequate spatial scales and over extended periods of time, which may only be obtained through collaborative efforts, and the development of methods that integrate heterogeneous datasets. We aimed to combine existing data on large carnivores to evaluate population dynamics and improve knowledge on their distribution nationwide. Location: Botswana. Methods: Between 2010 and 2016, we collated data on African wild dog, cheetah, leopard, brown and spotted hyaena and lion gathered with different survey methods by independent researchers across Botswana. We used a multi-species, multi-method dynamic occupancy model to analyse factors influencing occupancy, persistence and colonization, while accounting for imperfect detection. Lastly, we used the gained knowledge to predict the probability of occurrence of each species countrywide. Results: Wildlife areas and communal rangelands had similar occupancy probabilities for most species. Large carnivore occupancy was low in commercial farming areas and where livestock density was high, except for brown hyaena. Lion occupancy was negatively associated with human density; lion and spotted hyaena occupancy was high where rainfall was high, while the opposite applied to brown hyaena. Lion and leopard occupancy remained constant countrywide over the study period. African wild dog and cheetah occupancy declined over time in the south and north, respectively, whereas both hyaena species expanded their ranges. Countrywide predictions identified the highest occupancy for leopards and lowest for the two hyaena species. Main Conclusions: We highlight the necessity of data sharing and propose a generalizable analytical method that addresses the challenges of heterogeneous data common in ecology. Our approach, which enables a comprehensive multi-species assessment at large spatial and temporal scales, supports the development of data-driven conservation guidelines and the implementation of evidence-based management strategies nationally and internationally