Development of a survey tool to assess the environmental determinants of health-enabling food retail practice in Aboriginal and Torres Strait Islander communities of remote Australia.

BACKGROUND: Environmental factors can impact the ability of food retail businesses to implement best practice health-enabling food retail. METHODS: We co-designed a short-item survey on factors influencing food retail health-enabling practice in a remote Australian setting. Publicly available submissions to an Australian Parliamentary Inquiry into food pricing and food security in remote Indigenous communities were coded using an existing remote community food systems assessment tool and thematically analysed. Themes informed survey questions that were then prioritised, refined and pre-tested with expert stakeholder input. RESULTS: One-hundred and eleven submissions were coded, and 100 themes identified. Supply chain related data produced the most themes (n = 25). The resulting 26-item survey comprised questions to assess the perceived impact of environmental factors on a store's health-enabling practice (n = 20) and frequency of occurrence (n = 6). CONCLUSIONS: The application of this evidence-informed, co-designed survey will provide a first-time cross-sectional analysis and the potential for ongoing longitudinal data and advocacy on how environmental factors affect the operations of remote stores.

Benchmarking for healthy food stores: protocol for a randomised controlled trial with remote Aboriginal and Torres Strait Islander communities in Australia to enhance adoption of health-enabling store policy and practice.

BACKGROUND: Aboriginal and Torres Strait Islander communities in remote Australia have initiated bold policies for health-enabling stores. Benchmarking, a data-driven and facilitated 'audit and feedback' with action planning process, provides a potential strategy to strengthen and scale health-enabling best-practice adoption by remote community store directors/owners. We aim to co-design a benchmarking model with five partner organisations and test its effectiveness with Aboriginal and Torres Strait Islander community stores in remote Australia. METHODS: Study design is a pragmatic randomised controlled trial with consenting eligible stores (located in very remote Northern Territory (NT) of Australia, primary grocery store for an Aboriginal community, and serviced by a Nutrition Practitioner with a study partner organisation). The Benchmarking model is informed by research evidence, purpose-built best-practice audit and feedback tools, and co-designed with partner organisation and community representatives. The intervention comprises two full benchmarking cycles (one per year, 2022/23 and 2023/24) of assessment, feedback, action planning and action implementation. Assessment of stores includes i adoption status of 21 evidence-and industry-informed health-enabling policies for remote stores, ii implementation of health-enabling best-practice using a purpose-built Store Scout App, iii price of a standardised healthy diet using the Aboriginal and Torres Strait Islander Healthy Diets ASAP protocol; and, iv healthiness of food purchasing using sales data indicators. Partner organisations feedback reports and co-design action plans with stores. Control stores receive assessments and continue with usual retail practice. All stores provide weekly electronic sales data to assess the primary outcome, change in free sugars (g) to energy (MJ) from all food and drinks purchased, baseline (July-December 2021) vs July-December 2023. DISCUSSION: We hypothesise that the benchmarking intervention can improve the adoption of health-enabling store policy and practice and reduce sales of unhealthy foods and drinks in remote community stores of Australia. This innovative research with remote Aboriginal and Torres Strait Islander communities can inform effective implementation strategies for healthy food retail more broadly. TRIAL REGISTRATION: ACTRN12622000596707, Protocol version 1.

Efficacious cellular therapy of descemetocele in a dog.

The cornea is comprised of 4 layers; the outermost layer is the epithelium, followed by the stroma, Descemet's membrane, and endothelium. Corneal descemetocele is a serious consequence of progressive corneal ulceration, characterized by a herniation of the Descemet membrane through an overlying stromal defect. It requires urgent intervention due to the risk of perforation. Although there are several treatments available for this type of corneal ulcer, conservative approaches may be inadequate due to the typical severity of this injury. Surgical interventions, including conjunctival autograft transplantation and corneoscleral transposition, are commonly used. Mesenchymal stem cells (MSCs) have been used to effectively treat corneal ulcers, but there are limited reports regarding its use for descemetocele. A 7-year-old female shih tzu was diagnosed with descemetocele. In this dog, 2 × 106 MSCs, provided by CellTech - Stem Cell Technologies, were injected bilaterally into the conjunctiva, with an additional 5 × 105 MSCs applied topically to each eye. The ulcer achieved complete remission with an absence of corneal opacity after 75 d, supporting the claim that MSCs are an effective and safe option for the treatment of descemetocele. Key clinical message: The dog's descemetocele healed completely after a single application of MSCs after 30 d, with scars and leukoma completely absent after 75 d. No surgical intervention was required.

Thérapie cellulaire efficace de la descemétocèle chez un chien. La cornée est composée de quatre couches; la couche la plus externe est l'épithélium, suivi du stroma, de la membrane de Descemet et de l'endothélium. La descémétocèle cornéenne est une conséquence grave de l'ulcération cornéenne progressive, caractérisée par une hernie de la membrane de Descemet à travers un défaut stromal sus-jacent. Elle nécessite une intervention urgente en raison du risque de perforation. Bien qu'il existe plusieurs traitements disponibles pour ce type d'ulcère cornéen, les approches conservatrices peuvent être inadéquates en raison de la gravité typique de cette blessure. Les interventions chirurgicales, y compris une autogreffe conjonctivale et la transposition cornéosclérale, sont couramment utilisées. Les cellules souches mésenchymateuses (MSCs) ont été utilisées pour traiter efficacement les ulcères cornéens, mais il existe peu de rapports concernant leur utilisation pour la descemétocèle. Une femelle shih tzu de 7 ans a été diagnostiquée avec descemetocele. Chez ce chien, 2 × 106 MSCs, fournies par CellTech ­ Stem Cell Technologies, ont été injectées bilatéralement dans la conjonctive, avec 5 × 105 MSCs supplémentaires appliquées localement sur chaque oeil. L'ulcère a obtenu une rémission complète avec une absence d'opacité cornéenne après 75 jours, soutenant l'affirmation selon laquelle les MSCs sont une option efficace et sûre pour le traitement de la descemétocèle.Message clinique clé:La descemétocèle de ce chien a complètement guéri après une seule application de MSCs après 30 jours, avec des cicatrices et un leucome complètement absents après 75 jours. Aucune intervention chirurgicale n'a été nécessaire.(Traduit par Dr Serge Messier).

The Pasifika Veilomani Project: a pilot online training programme for healthcare workers in managing gender-based violence and family violence and sharing experiences.

OBJECTIVE: Pacific Island Countries (PICs) record high rates of gender-based violence (GBV). COVID-19 has significantly increased the number of GBV cases globally. This research aims to understand educational pathways for PICs' healthcare workers (HCWs) to strengthen GBV clinical practices in the Pasifika Veilomani (sharing the love) project. METHOD: A literature review, content experts' discussion and review of stakeholder governance documents were used to inform the design of the telehealth training. HCWs were invited to share experiences, further exploring the capacity of online learning to meet clinical practice needs. RESULTS: Global health guidance was adapted by Pacific experts to deliver a 12-week multidisciplinary course. One hundred and thirty-six participants from nine PICs registered and participated in the telehealth sessions. Despite internet and technical difficulties, participants' responses were positive. Results indicated the online training improved their confidence, helped them to reflect on practice and that more training would be valued. CONCLUSIONS: The Pasifika Veilomani Project engaged HCW and clinical leaders to inform current practices, education, and public health approaches on GBV as a public health priority. This project demonstrates the potential for engaging and supporting HCW remotely across challenging geographic, service and cultural domains in the context of COVID-19 social and service demands.

How do Pacific Island countries add up on contraception, abortion and reproductive coercion? Guidance from the Guttmacher report on investing in sexual and reproductive health.

The Guttmacher-Lancet Commission report on Sexual and Reproductive Health and Rights called for the acceleration of progress to achieve SRHR that is essential for sustainable development. To integrate the essential services defined in this report into universal health coverage in the 11 sovereign nations in the Pacific, quality data is required to ensure needs are met efficiently and equitably. However, there are no comprehensive reports for Pacific Island countries that provide insight into all areas of SRHR. We collated the latest literature to identify the most up-to-date relevant data from United Nations and Guttmacher Institute reports to discern gaps in SRHR information and services relating to contraception, abortion and reproductive coercion. Investment is urgently required to strengthen health information systems for SRHR in the Pacific.

Factors associated with breast cancer awareness and breast self-examination in Fiji and Kashmir India - a cross-sectional study.

BACKGROUND: In low-income countries breast cancer awareness (BCA) is essential to reduce the proportion of advanced stage presentations of breast cancer. There is a lack of studies using multivariable techniques to explore factors related to BCA in low-income countries. The objective of this study was to identify to what extent women in Fiji and Kashmir, India have BCA and practice breast self-examination (BSE) as well as factors associated with BCA and BSE. METHODS: A survey of women aged ≥18 years was conducted in Fiji and Kashmir, India to assess BCA and rates of BSE. Comparison between Fiji and Kashmir was done using student's t-test for continuous data and chi-square for binary data. Factors associated with BCA and BSE were analysed using a multivariable logistic regression for Fiji and Kashmir separately. RESULTS: Data were collected from 399 and 1982 women in Kashmir and Fiji, respectively. Of 1968 women in Fiji 57% were deemed to have an acceptable BCA compared to only 7.3% of 395 women in Kashmir. Having some education was associated with having BCA with an odds ratio of 4.7 (1.7-13) in Fiji and 10 (1.7-59) in Kashmir. Of 1976 women in Fiji 40% had tertiary education while 40% of 392 women in Kashmir had no education at all. The marital status was similar in both samples (n = 1973 and 395) with 68-69% being married and 21-26% being single. The lack of female doctors or nurses with whom to discuss issues, was perceived as a problem in both countries. CONCLUSIONS: The key finding is an association between having any level of education and BCA. This correlation was much stronger than for a family history of breast cancer and BCA. Hence, general education to illiterate women may reduce the proportion of women in low-income countries presenting with advanced-stage breast cancer.

LEAN SIX SIGMA TECHNIQUES TO IMPROVE OPHTHALMOLOGY CLINIC EFFICIENCY.

PURPOSE: Ophthalmologists serve an increasing volume of a growing elderly population undergoing increasingly complex outpatient medical care, including extensive diagnostic testing and treatment. The resulting prolonged patient visit times ("patient flow times") limit quality, patient and employee satisfaction, and represent waste. Lean Six Sigma process improvement was used in a vitreoretinal practice to decrease patient flow time, demonstrating that this approach can yield significant improvement in health care. METHODS: Process flow maps were created to determine the most common care pathways within clinic. Three months' visits from the electronic medical record system, which tracks patient task times at each process step in the office were collected. Care tasks and care pathways consuming the greatest time and variation were identified and modified. Follow-up analysis from 6 weeks' visits was conducted to assess improvement. RESULTS: Nearly all patients took one of five paths through the office. Patient flow was redesigned to reduce waiting room time by having staff members immediately start patients into one of those five paths; staffing was adjusted to address high demand tasks, and scheduling was optimized around derived predictors of patient flow times. Follow-up analysis revealed a statistically significant decline in mean patient flow time by 18% and inpatient flow time SD by 4.6%. Patient and employee satisfaction scores improved. CONCLUSION: Manufacturing industry techniques, such as Lean and Six Sigma, can be used to improve patient care, minimize waste, and enhance patient and staff satisfaction in outpatient clinics.

The Effect of Vertical Versus Horizontal Vaginal Cuff Closure on Vaginal Length After Laparoscopic Hysterectomy.

STUDY OBJECTIVE: To determine whether vertical versus horizontal closure of the vaginal cuff during laparoscopic hysterectomy has an effect on postoperative vaginal length and pelvic organ prolapse. DESIGN: A prospective randomized controlled trial. Subjects were randomly assigned to vertical or horizontal vaginal cuff closure at the time of total laparoscopic hysterectomy. Pelvic organ prolapse quantization (POP-Q) tests were performed before surgery, 2 to 4 weeks after surgery, and 3 to 4 months after surgery (Canadian Task Force classification I). SETTING: An academic university-affiliated community hospital. PATIENTS: Patients undergoing laparoscopic or robotic-assisted laparoscopic total hysterectomy for benign or malignant disease, excluding those undergoing radical hysterectomy or concomitant pelvic floor procedure. INTERVENTIONS: Subjects were randomized into the vertical or horizontal vaginal cuff closure group. Total hysterectomy was completed with traditional laparoscopic techniques or with robotic assistance. A colpotomy ring was used in each subject. Vaginal cuff closure was performed with barbed suture in a running fashion according to the group assignment. MEASUREMENTS AND MAIN RESULTS: A total of 43 subjects were enrolled and randomized. One patient was excluded because the vaginal cuff was closed vaginally, 1 cancelled surgery, and 1 was completed without a uterine manipulator. The mean change in vaginal length was -0.89 cm (standard deviation [SD] = 1.03) in the horizontal group and -0.86 cm (SD = 1.19) in the vertical group (p = .57). POP-Q evaluation revealed no differences between groups and an overall trend toward improved POP-Q measurements. The average duration of vaginal cuff closure did not differ (p = .45), and there were no intraoperative complications related to vaginal cuff closure. CONCLUSION: Horizontal and vertical laparoscopic closure of the vaginal cuff after laparoscopic hysterectomy results in similar changes in vaginal length and other POP-Q scores.

Liberalization in the Danish waste sector: an institutional perspective.

The push for creating a more competitive and liberalized system for traditional public services, including waste management, has been on the European agenda since the late 1980s. In 2008, changes were made in EU waste legislation allowing source-separated industrial/commercial waste that is suitable for incineration to be traded within the European market. This change has had broad implications for the Danish waste sector, which is characterized by institutionalized municipal control with all streams of waste and municipal ownership of the major treatment facilities allowing the municipal sector to integrate combustible waste in local heat and power generation. This article, applying an institutional approach, maps the institutions and actors of the Danish waste sector and analyses how the regulatory as well as normative pressure to liberalize has been met and partly neutralized in the institutional and political context. The new Danish regulation of 2010 has thus accommodated the specific requirement for liberalization, but in fact only represents a very small step towards a market-based waste management system. On the one hand, by only liberalizing industrial/commercial waste, the Danish Government chose to retain the main features of the established waste system favouring municipal control and hence the institutionalized principles of decentralized enforcement of environmental legislation as well as welfare state considerations. On the other hand, this has led to a technological and financial deadlock, particularly when it comes to reaching the recycling targets of EU, which calls for further adjustments of the Danish waste sector.

Corrigendum: Genome-wide association study of motor coordination.

[This corrects the article DOI: 10.3389/fnhum.2021.669902.].

A gene edited pig model for studying LGR5+ stem cells: implications for future applications in tissue regeneration and biomedical research.

Recent advancements in genome editing techniques, notably CRISPR-Cas9 and TALENs, have marked a transformative era in biomedical research, significantly enhancing our understanding of disease mechanisms and helping develop novel therapies. These technologies have been instrumental in creating precise animal models for use in stem cell research and regenerative medicine. For instance, we have developed a transgenic pig model to enable the investigation of LGR5-expressing cells. The model was designed to induce the expression of H2B-GFP under the regulatory control of the LGR5 promoter via CRISPR/Cas9-mediated gene knock-in. Notably, advancements in stem cell research have identified distinct subpopulations of LGR5-expressing cells within adult human, mouse, and pig tissues. LGR5, a leucine-rich repeat-containing G protein-coupled receptor, enhances WNT signaling and these LGR5+ subpopulations demonstrate varied roles and anatomical distributions, underscoring the necessity for suitable translational models. This transgenic pig model facilitates the tracking of LGR5-expressing cells and has provided valuable insights into the roles of these cells across different tissues and species. For instance, in pulmonary tissue, Lgr5+ cells in mice are predominantly located in alveolar compartments, driving alveolar differentiation of epithelial progenitors via Wnt pathway activation. In contrast, in pigs and humans, these cells are situated in a unique sub-basal position adjacent to the airway epithelium. In fetal stages a pattern of LGR5 expression during lung bud tip formation is evident in humans and pigs but is lacking in mice. Species differences with respect to LGR5 expression have also been observed in the skin, intestines, and cochlea further reinforcing the need for careful selection of appropriate translational animal models. This paper discusses the potential utility of the LGR5+ pig model in exploring the role of LGR5+ cells in tissue development and regeneration with the goal of translating these findings into human and animal clinical applications.

JAK inhibition decreases the autoimmune burden in Down syndrome.

Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmune disorders and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined. Here, we report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS. We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. We then report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints. Analysis of the first 10 participants to complete the 16-week study shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS. ClinicalTrials.gov identifier: NCT04246372 .

Lentivirus-mediated chronic expression of dominant-negative CREB in the dorsal hippocampus impairs memory for place learning and contextual fear conditioning.

Extensive research has shown that the transcription factor CREB has an important role during memory formation. In the present study, we tested a new method for chronic, stable expression of a dominant-negative form of CREB (mCREB) in the dorsal hippocampus using lentiviral vectors. In specific, we tested whether lentivirus-mediated chronic expression of mutant CREB impairs memory for two hippocampus-dependent tasks - place training in the water maze and contextual fear conditioning. Two weeks following intra-hippocampal infusion, experimental (mCREB) and control (LacZ and saline) rats were trained for 30 trials in one session on a place task in a water plus-maze and tested for an additional 30 trials on day 2 and on day 7. On day 8, all rats were trained on a contextual fear conditioning task and tested 24h later. For place learning, there was no difference between treatment groups on day 1, indicating that treatment with the lentiviral vectors did not alter performance or acquisition of the task. In comparisons with controls, mCREB-treated rats were not significantly impaired on day 2, overall, but they showed significant impairment on day 7. Contextual fear memory was impaired in mCREB-infused rats in comparison with controls. At the end of the experiment, total CREB and phosphorylated CREB protein were measured by western blot. Levels of total CREB were increased by approximately 40% among mCREB-treated rats in comparisons with controls, whereas levels of pCREB did not differ between groups, suggesting that the treatment caused significant expression of mCREB. In addition, mCREB infused rats showed a significant reduction in the pCREB to CREB ratio in comparison with controls, suggesting that the memory deficit seen in mCREB rats is most likely due to disruption of gene regulation caused by expression of mutant CREB. Taken together, the present results show that lentivirus expressing mCREB can be used to effectively alter CREB function within the hippocampus and that the treatment impairs memory for hippocampus-dependent tasks.

Proteasome Inhibition Sensitizes Liposarcoma to MDM2 Inhibition with Nutlin-3 by Activating the ATF4/CHOP Stress Response Pathway.

Liposarcoma is the most commonly occurring soft-tissue sarcoma and is frequently characterized by amplification of chromosome region 12q13-15 harboring the oncogenes MDM2 and CDK4. This unique genetic profile makes liposarcoma an attractive candidate for targeted therapeutics. While CDK4/6 inhibitors are currently employed for treatment of several cancers, MDM2 inhibitors have yet to attain clinical approval. Here, we report the molecular characterization of the response of liposarcoma to the MDM2 inhibitor nutlin-3. Treatment with nutlin-3 led to upregulation of two nodes of the proteostasis network: the ribosome and the proteasome. CRISPR/Cas9 was used to perform a genome-wide loss of function screen that identified PSMD9, which encodes a proteasome subunit, as a regulator of response to nutlin-3. Accordingly, pharmacologic studies with a panel of proteasome inhibitors revealed strong combinatorial induction of apoptosis with nutlin-3. Mechanistic studies identified activation of the ATF4/CHOP stress response axis as a potential node of interaction between nutlin-3 and the proteasome inhibitor carfilzomib. CRISPR/Cas9 gene editing experiments confirmed that ATF4, CHOP, and the BH3-only protein, NOXA, are all required for nutlin-3 and carfilzomib-induced apoptosis. Furthermore, activation of the unfolded protein response using tunicamycin and thapsigargin was sufficient to activate the ATF4/CHOP stress response axis and sensitize to nutlin-3. Finally, cell line and patient-derived xenograft models demonstrated combinatorial effects of treatment with idasanutlin and carfilzomib on liposarcoma growth in vivo. Together, these data indicate that targeting of the proteasome could improve the efficacy of MDM2 inhibitors in liposarcoma. SIGNIFICANCE: Targeting the proteasome in combination with MDM2 inhibition activates the ATF4/CHOP stress response axis to induce apoptosis in liposarcoma, providing a potential therapeutic approach for the most common soft-tissue sarcoma.

Term alpaca placenta glycosylation profile and its correlation with pregnancy maintenance and fetal survival.

Alpaca is a South American camelid, particularly present in Peruvian highlands, where oxygen concentration and atmospheric pressure are very low. Due to this fact, gestational physiology has adapted to preserve the conceptus' and mother's health. In this context, several cellular and molecular features play an essential role during and at the end of gestation. Structural carbohydrates act on maternal-fetal communication, recognize exogenous molecules, and contribute to placental barrier selectivity. Therefore, this study aimed to characterize the structural carbohydrate profiles that are present in the term alpaca placenta, kept in their natural habitat of around 4,000 m height. For this propose, 12 term alpaca placentas were collected, and the material was obtained at the time of birth from camelids raised naturally in the Peruvian highlands, in the Cusco region. All placenta samples were processed for histological analysis. A lectin histochemical investigation was performed using 13 biotinylated lectins, allowing us to determine the location of carbohydrates and their intensity on a semi-quantitative scale. Our results demonstrated that during term gestation, the epitheliochorial alpaca placenta shows a high presence of carbohydrates, particularly glucose, α-linked mannose, N-acetylglucosamine ß (GlcNAc), galactose (αGal), and N-acetylgalactosamine α (GalNAc), present in the trophoblast, amnion epithelium, and mesenchyme, as well as the presence of sialic acid residues and low affinity for fucose. In fetal blood capillaries, the presence of bi- and tri-antennary complex structures and α-linked mannose was predominated. In conclusion, we characterized the glycosylation profile in the term alpaca placenta. Based on our data, compared to those reported in the bibliography, we suggest that these carbohydrates could participate in the labor of these animals that survive in Peruvian extreme environments.

Improving maternal and newborn health and reducing stillbirths in the Western Pacific Region - current situation and the way forward.

Despite positive trends in many indicators, there remains an unacceptable burden of preventable maternal, newborn deaths and stillbirths every year. This paper provides an overview of the maternal and perinatal outcomes across 22 Pacific Island Countries and Territories, including Papua New Guinea. We highlight some unique challenges and provide examples of initiatives in three of the larger countries to contribute to safer childbirth. There are high maternal and perinatal morbidity and mortality rates in many of the countries, although reliable data are limited. There are currently no data relating to the burden of intrapartum-related maternal and perinatal morbidity or stillbirth or the quality of intrapartum care. Varying definitions across countries for perinatal indicators mean that meaningful comparisons are difficult and unreliable. There is need for midwives and other maternal and newborn health providers to improve maternal and newborn indicators as countries advance towards the 2030 Sustainable Development Goals.

Mertk: An emerging target in cancer biology and immuno-oncology.

Mertk, a type I Receptor Tyrosine Kinase (RTK) and member of the TAM (Tyro3, Axl, and Mertk) family of homologous tyrosine kinases, has important roles in signal transduction both homeostatically on normal cells as well as patho-physiologically on both tumor-associated macrophages and malignant cells by its overexpression in a wide array of cancers. The main ligands of Mertk are Vitamin K-modified endogenous proteins Gas6 and Protein S (ProS1), heterobifunctional modular proteins that bind Mertk via two carboxyl-terminal laminin-like globular (LG) domains, and an N-terminal Gla domain that binds anionic phospholipids, whereby externalized phosphatidylserine (PS) on stressed viable and caspase-activated apoptotic cells is most emblematic. Recent studies indicate that Vitamin K-dependent γ-carboxylation on the N-terminal Gla domain of Gas6 and Protein S is necessary for PS binding and Mertk activation, implying that Mertk is preferentially active in tissues where there is high externalized PS, such as the tumor microenvironment (TME) and acute virally infected tissues. Once stimulated, activated Mertk can provide a survival advantage for cancer cells as well as drive compensatory proliferation. On monocytes and tumor-associated macrophages, Mertk promotes efferocytosis and acts as an inhibitory receptor that impairs host anti-tumor immunity, functioning akin to a myeloid checkpoint inhibitor. In recent years, inhibition of Mertk has been implicated in a dual role to enhance the sensitivity of cancer cells to cytotoxic agents along with improving host anti-tumor immunity with anti-PD-1/PD-L1 immunotherapy. Here, we examine the rationale of Mertk-targeted immunotherapies, the current and potential therapeutic strategies, the clinical status of Mertk-specific therapies, and potential challenges and obstacles for Mertk-focused therapies.

Genome-Wide Association Study of Motor Coordination.

The ability to finely control our movement is key to achieving many of the educational milestones and life-skills we develop throughout our lives. Despite the centrality of coordination to early development, there is a vast gap in our understanding of the underlying biology. Like most complex traits, both genetics and environment influence motor coordination, however, the specific genes, early environmental risk factors and molecular pathways are unknown. Previous studies have shown that about 5% of school-age children experience unexplained difficulties with motor coordination. These children are said to have Developmental Coordination Disorder (DCD). For children with DCD, these motor coordination difficulties significantly impact their everyday life and learning. DCD is associated with poorer academic achievement, reduced quality of life, it can constrain career opportunities and increase the risk of mental health issues in adulthood. Despite the high prevalence of coordination difficulties, many children remain undiagnosed by healthcare professionals. Compounding under-diagnosis in the clinic, research into the etiology of DCD is severely underrepresented in the literature. Here we present the first genome-wide association study to examine the genetic basis of early motor coordination in the context of motor difficulties. Using data from the Avon Longitudinal Study of Parents and Children we generate a derived measure of motor coordination from four components of the Movement Assessment Battery for Children, providing an overall measure of coordination across the full range of ability. We perform the first genome-wide association analysis focused on motor coordination (N = 4542). No single nucleotide polymorphisms (SNPs) met the threshold for genome-wide significance, however, 59 SNPs showed suggestive associations. Three regions contained multiple suggestively associated SNPs, within five preliminary candidate genes: IQSEC1, LRCC1, SYNJ2B2, ADAM20, and ADAM21. Association to the gene IQSEC1 suggests a potential link to axon guidance and dendritic projection processes as a potential underlying mechanism of motor coordination difficulties. This represents an interesting potential mechanism, and whilst further validation is essential, it generates a direct window into the biology of motor coordination difficulties. This research has identified potential biological drivers of DCD, a first step towards understanding this common, yet neglected neurodevelopmental disorder.

The Avon Longitudinal Study of Parents and Children - A resource for COVID-19 research: Home-based antibody testing results, October 2020. An emphasis on self-screening at a population level.

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort study which recruited pregnant women in 1990-1992 and has followed these women, their partners (Generation 0; G0) and offspring (Generation 1; G1) ever since. The study reacted rapidly to the COVID-19 pandemic, deploying online questionnaires in March and May 2020. Home-based antibody tests and a further questionnaire were sent to 5220 participants during a two-week period of October 2020.  4.2% (n=201) of participants reported a positive antibody test (3.2% G0s [n=81]; 5.6% G1s [n=120]). 43 reported an invalid test, 7 did not complete and 3 did not report their result. Participants uploaded a photo of their test to enable validation: all positive tests, those where the participant could not interpret the result and a 5% random sample were manually checked against photos. We report 92% agreement (kappa=0.853). Positive tests were compared to additional COVID-19 status information: 58 (1.2%) participants reported a previous positive test, 73 (1.5%) reported that COVID-19 was suspected by a doctor, but not tested and 980 (20.4%) believed they had COVID-19 due to their own suspicions.  Of those reporting a positive result on our antibody test, 55 reported that they did not think they had had COVID-19. Results from antibody testing and questionnaire data will be complemented by health record linkage and results of other biological testing- uniting Pillar testing data with home testing and self-report. Data have been released as an update to the original datasets released in July 2020. It comprises: 1) a standard dataset containing all participant responses to all three questionnaires with key sociodemographic factors and 2) as individual participant-specific release files enabling bespoke research across all areas supported by the study. This data note describes the antibody testing, associated questionnaire and the data obtained from it.

If it ain't broke don't fix it: Lack of review of antimicrobials in 'well' patients - time for a CRP change.

INTRODUCTION: The rising prevalence of multi-resistant organisms threatens the efficacy of current antimicrobial treatments. Antibiotic stewardship is a key factor in slowing the development of resistance and must become part of a clinician's regular practice. National guidance unanimously emphasises the importance of a 48-hour review of antimicrobial prescriptions. We assessed the compliance of antibiotic reviews across two sites in Wales. METHOD: Two cycles of data were retrospectively collected across two teaching hospitals in Wales prior and following introduction of an antimicrobial alert sticker. A univariate odds ratio for 48-hour referral stratified by C-reactive protein (CRP) was calculated in a logistic regression model for the cycle one data. RESULTS: One-hundred and thirty-nine patients were included in the cycle 1 data across both sites. We identified that patients with a CRP ≤100 mg/L (a marker of less severe infection) were less likely to have their antibiotic prescription reviewed by 48 hours. DISCUSSION: Patients with CRP ≤100 mg/L were less likely to receive a 48-hour review of their antimicrobial prescription. Compliance with review improved following introduction of a simple alert measure.