Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression.

Dysregulation of the alternative pathway (AP) of the complement system is a significant contributor to age-related macular degeneration (AMD), a primary cause of irreversible vision loss worldwide. Here, we assess the contribution of the liver-produced complement factor H-related 4 protein (FHR-4) to AMD initiation and course of progression. We show that FHR-4 variation in plasma and at the primary location of AMD-associated pathology, the retinal pigment epithelium/Bruch's membrane/choroid interface, is entirely explained by three independent quantitative trait loci (QTL). Using two distinct cohorts composed of a combined 14,965 controls and 20,741 cases, we ascertain that independent QTLs for FHR-4 are distinct from variants causally associated with AMD, and that FHR-4 variation is not independently associated with disease. Additionally, FHR-4 does not appear to influence AMD progression course among patients with disease driven predominantly by AP dysregulation. Modulation of FHR-4 is therefore unlikely to be an effective therapeutic strategy for AMD.

Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

Differential bleaching susceptibility among coral taxa and colony sizes, relative to bleaching severity across Australia's Great Barrier Reef and Coral Sea Marine Parks.

Climate-induced coral bleaching represents the foremost threat to coral assemblages globally, however bleaching susceptibility varies among and within coral taxa. We compared bleaching susceptibility among 10 coral morpho-taxa and two colony size classes relative to reef-scale bleaching severity at 33 reefs across the Great Barrier Reef and Coral Sea Marine Parks in February-March 2020. Colony size and bleaching severity caused the hierarchy of bleaching susceptibility among taxa to change considerably. Notably, massive Porites shifted from being among the least likely taxa to exhibit bleaching, to among the most susceptible as overall bleaching severity increased. Juvenile corals (≤5 cm diameter) were generally more resistant to bleaching, except for Montipora and Pocillopora colonies, which were more likely to bleach than adults (>5 cm). These findings suggest that colony size and reef-scale bleaching severity are important determinants of bleaching susceptibility among taxa and provide insights into possible shifts in the structure of coral assemblages caused by bleaching events.

What women want: A mixed-methods study of women's health priorities, preferences, and experiences in care in three Rwandan rural districts.

OBJECTIVE: To explore Rwandan women's experiences, priorities, and preferences in accessing health care for non-pregnancy-related conditions and inform development of healthcare services related to these conditions among women of reproductive age at district hospitals and health centers in Rwanda. METHODS: We used a mixed-methods, exploratory sequential design. Semi-structured qualitative interviews were conducted with Rwandan women and coded thematically. A cross-sectional quantitative survey based on the qualitative data was administered to women attending health centers. RESULTS: Seventeen interviews and 150 surveys were conducted. Women identified conditions including back pain, gynecologic cancers, and abnormal vaginal bleeding as concerns. They generally reported positive experiences while accessing health care and knowledge of accessing health care. Barriers to care were identified, including transportation costs and inability to miss work. Women expressed a desire for more control over their care and the importance of maintaining their dignity while accessing health care. CONCLUSION: These findings provide useful insights to inform development of non-pregnancy-related healthcare services for women in Rwanda according to their priorities and preferences. The reported end-user health concerns, barriers to care, and diminished control over their care point to a need to evolve health systems around user-tailored needs and design interventions optimizing access whilst promoting dignified care.

Infection and disruption of placental multidrug resistance (MDR) transporters: Implications for fetal drug exposure.

P-glycoprotein (P-gp, encoded by the ABCB1 gene) and breast cancer resistance protein (BCRP/ABCG2) are efflux multidrug resistance (MDR) transporters localized at the syncytiotrophoblast barrier of the placenta and protect the conceptus from drug and toxin exposure throughout pregnancy. Infection is an important modulator of MDR expression and function. This review comprehensively examines the effect of infection on the MDR transporters, P-gp and BCRP in the placenta. Infection PAMPs such as bacterial lipopolysaccharide (LPS) and viral polyinosinic-polycytidylic acid (poly I:C) and single-stranded (ss)RNA, as well as infection with Zika virus (ZIKV), Plasmodium berghei ANKA (modeling malaria in pregnancy - MiP) and polymicrobial infection of intrauterine tissues (chorioamnionitis) all modulate placental P-gp and BCRP at the levels of mRNA, protein and or function; with specific responses varying according to gestational age, trophoblast type and species (human vs. mice). Furthermore, we describe the expression and localization profile of Toll-like receptor (TLR) proteins of the innate immune system at the maternal-fetal interface, aiming to better understand how infective agents modulate placental MDR. We also highlight important gaps in the field and propose future research directions. We conclude that alterations in placental MDR expression and function induced by infective agents may not only alter the intrauterine biodistribution of important MDR substrates such as drugs, toxins, hormones, cytokines, chemokines and waste metabolites, but also impact normal placentation and adversely affect pregnancy outcome and maternal/neonatal health.

Development, implementation and evaluation of a seven-day clinical pharmacy service in a tertiary referral teaching hospital during surge-2 of the COVID-19 pandemic.

BACKGROUND: Seven-day clinical pharmacy services in the acute sector of the National Health Service are limited. There is a paucity of evidential patient benefit. This limits investment and infrastructure, despite United Kingdom wide calls. AIM: To optimise medicines seven-days a week during surge-2 of the COVID-19 pandemic through implementation of a seven-day clinical pharmacy service. This paper describes service development, evaluation and sustainability. SETTING: A tertiary-referral teaching hospital, London, United Kingdom. DEVELOPMENT: The seven-day clinical pharmacy service was developed to critical care, acute and general medical patients. Clinical leads developed the service specification and defined priorities, targeting complex patients and transfer of care. Contributing staff were briefed and training materials developed. IMPLEMENTATION: The service was implemented in January 2021 for 11 weeks. Multidisciplinary team communication brought challenges; strategies were employed to overcome these. EVALUATION: A prospective observational study was conducted in intervention wards over two weekends in February 2021. 1584 beds were occupied and 602 patients included. 346 interventions were reported and rated; 85.6% had high or moderate impact; 56.7% were time-critical. The proportion of medicines reconciliation within 24-h of admission was analysed across the hospital between November 2020 and May 2021. During implementation, patients admitted Friday-Sunday were more likely to receive medicines reconciliation within 24-h (RR 1.41 (95% CI 1.34-1.47), p < 0.001). Rostered services were delivered sustainably in terms of shift-fill rate and medicines reconciliation outcome. CONCLUSION: Seven-day clinical pharmacy services benefit patient outcome through early medicines reconciliation and intervention. Investment to permanently embed the service was sustained.

Mid-pregnancy poly(I:C) viral mimic disrupts placental ABC transporter expression and leads to long-term offspring motor and cognitive dysfunction.

Limited information is available about the effect of mid-pregnancy viral infections on the placental expression of efflux transporters and offspring behavior. We hypothesized that maternal exposure to polyinosinic-polycytidylic acid [poly(I:C)], a synthetic double-stranded RNA viral mimic, would impair placental cell turnover, the expression of selected ABC transporters and adult offspring behavior. C57BL/6 mice were administered poly(I:C) (10 mg/Kg;ip) or vehicle at gestational day (GD) 13.5 (mid-pregnancy). Dams were euthanized for blood collection 4 h after injection, fetal and placental collection at GD18.5 or allowed to deliver spontaneously at term. At GD 13.5, poly(I:C) induced an acute pro-inflammatory response characterized by an increase in maternal plasma levels of IL-6, CXCL-1 and CCL-2/MCP-1. At GD 18.5, poly(I:C) decreased cell proliferation/death in the labyrinthine and increased cell death in the junctional zones, characterizing a disruption of placental cell turnover. Abca1 and Abcg1 immunolabelling was decreased in the labyrinthine zone, whereas Abca1, Abcg1 and breast cancer resistance transporter (Bcrp) expression increased in the junctional zone. Moreover, adult offspring showed motor and cognitive impairments in the Rotarod and T-water maze tests. These results indicate that viral infection during mid-pregnancy may disrupt relevant placental efflux transporters, as well as placental cell turnover and offspring behavior in adult life.

A small molecule UPR modulator for diabetes identified by high throughput screening

Unfolded protein response (UPR) is a stress response that is specific to the endoplasmic reticulum (ER). UPR is activated upon accumulation of unfolded (or misfolded) proteins in the ER's lumen to restore protein folding capacity by increasing the synthesis of chaperones. In addition, UPR also enhances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accumulation of unfolded proteins in the ER. Herein, we describe a cell-based ultra-high throughput screening (uHTS) campaign that identifies a small molecule that can modulate UPR and ER stress in cellular and

Larval connectivity and water quality explain spatial distribution of crown-of-thorns starfish outbreaks across the Great Barrier Reef.

Outbreaks of the coral eating crown-of-thorns starfish (COTS; Acanthasts cf. solaris) occur in cyclical waves along the Great Barrier Reef (GBR), contributing significantly to the decline in hard coral cover over the past 30 years. One main difficulty faced by scientists and managers alike, is understanding the relative importance of contributing factors to COTS outbreaks such as increased nutrients and water quality, larval connectivity, fishing pressure, and abiotic conditions. We analysed COTS abundances from the most recent outbreak (2010-2018) using both boosted regression trees and generalised additive models to identify key predictors of COTS outbreaks. We used this approach to predict the suitability of each reef on the GBR for COTS outbreaks at three different levels: (1) reefs with COTS present intermittently (Presence); (2) reefs with COTS widespread and present in most samples and (Prevalence) (3) reefs experiencing outbreak levels of COTS (Outbreak). We also compared the utility of two auto-covariates accounting for spatial autocorrelation among observations, built using weighted inverse distance and weighted larval connectivity to reefs supporting COTS populations, respectively. Boosted regression trees (BRT) and generalised additive mixed models (GAMM) were combined in an ensemble model to reduce the effect of model uncertainty on predictions of COTS presence, prevalence and outbreaks. Our results from best performing models indicate that temperature (Degree Heating Week exposure: relative importance=13.1%) and flood plume exposure (13.0%) are the best predictors of COTS presence, variability in chlorophyll concentration (12.6%) and flood plume exposure (8.2%) best predicted COTS prevalence and larval connectivity potential (22.7%) and minimum sea surface temperature (8.0%) are the best predictors of COTS outbreaks. Whether the reef was open or closed to fishing, however, had no significant effect on either COTS presence, prevalence or outbreaks in BRT results (<0.5%). We identified major hotspots of COTS activity primarily on the mid shelf central GBR and on the southern Swains reefs. This study provides the first empirical comparison of the major hypotheses of COTS outbreaks and the first validated predictions of COTS outbreak potential at the GBR scale incorporating connectivity, nutrients, biophysical and spatial variables, providing a useful aid to management of this pest species on the GBR.

COTSMod: A spatially explicit metacommunity model of outbreaks of crown-of-thorns starfish and coral recovery.

Outbreaks of the Pacific crown-of-thorns starfish (COTS; Acanthaster cf. solaris) have been responsible for 40% of the decline in coral cover on the GBR over the last 35 years. With the intensity and frequency of bleaching and cyclonic disturbances increasing, effectively managing these outbreaks may allow reefs an opportunity to recover from these cumulative impacts. Significant research effort has been directed toward developing regional scale models for COTS outbreaks, but these have yet to be fit explicitly to long term time series at the scale of the entire GBR, nor do previous research efforts incorporate explicit estimates of cumulative disturbance history. We developed a stage-based metapopulation model for COTS at a 1×1km resolution using long-term time series and modelled estimates of COTS larval connectivity, nutrient concentrations and important vital rates estimated from the literature. We coupled this metapopulation model to an existing spatially explicit model of coral cover growth, disturbance and recovery across the GBR from 1996 to 2017 to create a metacommunity model. Our results were validated against a spatially and temporally extensive dataset of COTS and coral cover across the GBR, predicting an average coral decline of 1.3% p.a. across the GBR, and accurately recreating coral cover trajectories (mean prediction error=7.1%) and COTS outbreak classification (accuracy=80%). Sensitivity analyses revealed that overall model accuracy was most sensitive to larval predation (boosted regression tree; relative importance=46.7%) and two parameters defining juvenile density dependent mortality (21.5% and 17.5%). The COTS model underestimated peak COTS densities particularly in the Swains and Townsville sectors of the reef, while overestimating COTS density during non-outbreak years. A better understanding of inter-annual variability in larval connectivity, and regionally variable density dependence for adult COTS life stages may improve model fit during these extreme outbreak events. Our model provides a platform to develop upon, and with improvements to estimates of larval connectivity and larval predation could be used to simulate the effects of implementing varying combinations of COTS interventions. This research highlights the importance of the early life history stages of COTS as drivers of outbreak dynamics, emphasizing the need for further empirical research to estimate these parameters.

Dysphagia presentation and management following COVID-19: an acute care tertiary centre experience.

OBJECTIVES: As the pathophysiology of COVID-19 emerges, this paper describes dysphagia as a sequela of the disease, including its diagnosis and management, hypothesised causes, symptomatology in relation to viral progression, and concurrent variables such as intubation, tracheostomy and delirium, at a tertiary UK hospital. RESULTS: During the first wave of the COVID-19 pandemic, 208 out of 736 patients (28.9 per cent) admitted to our institution with SARS-CoV-2 were referred for swallow assessment. Of the 208 patients, 102 were admitted to the intensive treatment unit for mechanical ventilation support, of which 82 were tracheostomised. The majority of patients regained near normal swallow function prior to discharge, regardless of intubation duration or tracheostomy status. CONCLUSION: Dysphagia is prevalent in patients admitted either to the intensive treatment unit or the ward with COVID-19 related respiratory issues. This paper describes the crucial role of intensive swallow rehabilitation to manage dysphagia associated with this disease, including therapeutic respiratory weaning for those with a tracheostomy.

Breast cancer resistance protein (Bcrp/Abcg2) is selectively modulated by lipopolysaccharide (LPS) in the mouse yolk sac.

Bacterial infection alters placental ABC transporters expression. These transporters provide fetal protection against circulating xenobiotics and environmental toxins present in maternal blood. We hypothesized that lipopolysaccharide (LPS-bacterial mimic) alters the yolk sac morphology and expression of key ABC transporters in a gestational-age dependent manner. Yolk sac samples from C57BL/6 mice were obtained at gestational ages (GD) 15.5 and GD18.5, 4 or 24 h after LPS exposure (150ug/kg; n = 8/group). Samples underwent morphometrical, qPCR and immunohistochemistry analysis. The volumetric proportions of the histological components of the yolk sac did not change in response to LPS. LPS increased Abcg2 expression at GD15.5, after 4 h of treatment (p < 0.05). No changes in Abca1, Abcb1a/b, Abcg1, Glut1, Snat1, Il-1ß, Ccl2 and Mif were observed. Il-6 and Cxcl1 were undetectable in the yolk sac throughout pregnancy. Abca1, breast cancer resistance protein (Bcrp, encoded by Abcg2) and P-glycoprotein (P-gp/ Abcb1a/b) were localized in the endodermal (uterine-facing) epithelium and to a lesser extent in the mesothelium (amnion-facing), whereas Abca1 was also localized to the endothelium of the yolk sac blood vessels. LPS increased the labeling area and intensity of Bcrp in the yolk sac's mesothelial cells at GD15.5 (4 h), whereas at GD18.5, the area of Bcrp labeling in the mesothelium (4 and 24 h) was decreased (p < 0.05). Bacterial infection has the potential to change yolk sac barrier function by affecting Bcrp and Abcg2 expression in a gestational-age dependent-manner. These changes may alter fetal exposure to xenobiotics and toxic substances present in the maternal circulation and in the uterine cavity.

Evidence for enemy release in invasive common dace Leuciscus leuciscus in Ireland: a helminth community survey and systematic review.

Invasive species lose parasites in the process of invasion and tend to be less parasitized than conspecifics in the native range and sympatric native species in the invasive range (enemy release). We evaluated enemy release in an invasive freshwater fish in Ireland, common dace Leuciscus leuciscus, using helminth parasite community surveys at the core and front of the invasive range of common dace. Furthermore, we undertook a systematic literature review of helminth infection in common dace across its native range in Great Britain and Europe and invasive range in Ireland. The helminth parasite community survey revealed that invasive common dace were infected with fewer helminth species at the invasion front than at the core. Four helminth taxa - Acanthocephala, Monogenea, Digenea and Nematoda - were present in dace at the invasion core compared to only a single helminth species (Pomphorhynchus tereticollis) at the front. The systematic review revealed that invasive common dace in Ireland hosted fewer species of helminths than common dace in the native range. We report a total of three helminth species in common dace in Ireland compared to 24 in Great Britain and 84 in Continental Europe. Our results support the hypotheses that invasive populations are less parasitized than native populations and that more recently established populations host fewer parasites. However, we demonstrate that invasive species may continue to experience release from parasites long after initial invasion.

The role of imaging in malignant pleural mesothelioma: an update after the 2018 BTS guidelines.

Malignant pleural mesothelioma (MPM) is a primary malignancy of the pleura and is associated with a poor outcome. The symptoms and signs of malignant mesothelioma present late in the natural history of the disease and are non-specific, making the diagnosis challenging and imaging key. In 2018, the British Thoracic Society (BTS) updated the guideline on diagnosis, staging, and follow-up of patients with MPM. These recommendations are discussed in this review of the current literature on imaging of MPM. It is estimated MPM will continue to cause serious morbidity and mortality in the UK late into the 21st century, and internationally, people continue to be exposed to asbestos. We aim to update the reader on current and future imaging strategies, which could aid early diagnosis of pleural malignancy and provide an update on staging and assessment of tumour response.

Prenatal stress and epigenetics.

In utero exposure to environmental stress in both animals and humans could result in long-term epigenome alterations which further lead to consequences for adaptation and development in the offspring. Epigenetics, especially DNA methylation, is considered one of the most widely studied and well-characterized mechanisms involved in the long-lasting effects of in utero stress exposure. In this review, we outlined evidence from animal and human prenatal research supporting the view that prenatal stress could lead to lasting, broad and functionally organized signatures in DNA methylation which, in turn, could mediate exposure-phenotype associations. We also emphasized the advantage of using stressor from quasi-randomly assigned experiments. Furthermore, we discuss challenges that still need to be addressed in this field in the future.

Dysregulation of placental ABC transporters in a murine model of malaria-induced preterm labor.

Malaria in Pregnancy (MiP) is characterized by placental accumulation of Plasmodium-infected erythrocytes, intrauterine growth restriction (IUGR) and preterm delivery (PTD). Placental ATP-binding cassette (ABC) transporters mediate the efflux of nutrients, cytokines and xenobiotics. The expression and activity of these transporters are highly responsive to infection. We hypothesized that MiP would perturb the expression of placental ABC transporters, promoting PTD. Peripheral blood, spleens, livers and placentas of pregnant mice, infected with Plasmodium berghei ANKA on gestational day (GD) 13.5, were collected and analyzed on GD18.5. The primary consequences of human MiP, including IUGR, PTD (20%) and placental inflammation, were recapitulated in our mouse model. Electron microscopy revealed attenuated presence of labyrinthine microvilli and dilated spongiotrophoblasts -granular endoplasmic reticulum cisternae. Additionally, a decrease in placental Abca1 (ABCA1), Abcb1b (P-glycoprotein), Abcb9 and Abcg2 (BCRP) expression was observed in MiP mice. In conclusion, MiP associated with PTD impairs placental ABC transporters' expression, potentially modulating placental nutrient, environmental toxin and xenobiotic biodistribution within the fetal compartment, and may, at some degree, be involved with pregnancy outcome in MiP.

Germination characteristics of Rhinanthus minor influence field emergence, competitiveness and potential use in restoration projects.

The facultative root hemi-parasite Rhinanthus minor is often used in grassland habitat restoration projects to regulate ecosystem structure and function. Its impact on community productivity and diversity as a function of resource supply, sward composition and management has been widely investigated. However, there is a lack of information about the possible influence of seed quality on the efficacy of the hemi-parasite. Ten seed lots from commercial sources were sown in the field and their germination characteristics investigated in the laboratory. Seeds from four lots were also germinated and sown in pots alongside plants of two host species, Lotus corniculatus and Holcus lanatus. Plant establishment, height and flowering density were evaluated for the hemi-parasite, while plant biomass was measured for both R. minor and its host. Two aspects of seed quality influenced the field emergence of seed lots of R. minor, the radicle emergence (%) and the length of the lag period from the beginning of imbibition to germination (mean germination time), which indicates seed vigour. A longer lag period (lower vigour) was associated with higher levels of seedling mortality and lower plant vigour, in terms of plant height and biomass accumulation and was also reflected in the parasitic impact of the seed lots. Seed quality, specifically germination and vigour, can influence the establishment, survival, subsequent plant productivity and parasitic impact of R. minor in vegetation restoration projects. Seed quality is discussed as a key factor to consider when predicting the impact of the hemi-parasite on community productivity and diversity.

Does screening neonates in the neonatal intensive care unit for Pseudomonas aeruginosa colonization help prevent infection?

BACKGROUND: Pseudomonas aeruginosa (PA) is a Gram-negative environmental organism that can cause severe infection in immunosuppressed patients, including preterm neonates. In recent years, it has become common practice to screen neonates for PA colonization. AIM: To assess the value of screening neonates for PA in (1) predicting the risk of developing severe PA infection and (2) directing infection control practice. METHODS: Between August 2012 and September 2015, babies admitted to the neonatal intensive care unit (NICU) at North Bristol NHS Trust were screened routinely for PA colonization on admission and weekly thereafter. Data were also collected on babies who developed PA infection. Environmental samples from the NICU were tested for the presence of PA. Variable number tandem repeat (VNTR) typing was performed on all strains of PA from babies and the environment. FINDINGS: No babies with positive screens subsequently developed PA infection. There was no VNTR strain evidence supporting cross-infection from the environment or other babies. CONCLUSION: Screening neonates for PA did not identify babies who subsequently developed PA infection. Following cessation of screening in September 2015, there was no increase in the number of babies identified with PA infection.

Current, future and potential use of mobile and wearable technologies and social media data in the ABCD study to increase understanding of contributors to child health.

Mobile and wearable technologies and novel methods of data collection are innovating health-related research. These technologies and methods allow for multi-system level capture of data across environmental, physiological, behavioral, and psychological domains. In the Adolescent Brain Cognitive Development (ABCD) Study, there is great potential for harnessing the acceptability, accessibility, and functionality of mobile and social technologies for in-vivo data capture to precisely measure factors, and interactions between factors, that contribute to childhood and adolescent neurodevelopment and psychosocial and health outcomes. Here we discuss advances in mobile and wearable technologies and methods of analysis of geospatial, ecologic, social network and behavioral data. Incorporating these technologies into the ABCD study will allow for interdisciplinary research on the effects of place, social interactions, environment, and substance use on health and developmental outcomes in children and adolescents.