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.

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.

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.

Prevalence and longitudinal trends of food allergy during childhood and adolescence: Results of the Isle of Wight Birth Cohort study.

BACKGROUND: The prevalence and time trends of food allergy change during childhood depending on the age of the child and the type of food. OBJECTIVE: To study prevalence and longitudinal trends in food allergy from birth to 18 years in an unselected birth cohort in the Isle of Wight. METHOD: Information on food allergy was collected at ages 1, 2, 4, 10 and 18 years from the Isle of Wight Birth Cohort (n = 1456). Skin prick testing (SPT) was performed at the age of 1 and 2 years in symptomatic children. At 4, 10 and 18 years of age, participants were tested to a panel of food and aeroallergens. Food allergy was diagnosed based on the criteria: symptoms suggestive of a typical IgE-mediated reaction and reaction <4 hours following exposure to a known food allergen. McNemar's test was used to determine significance of changes in prevalence over time. RESULTS: The prevalence of food allergy remained relatively constant in early childhood (5.3%, 4.4% and 5.0% at 1, 2 and 4 years, respectively), with significant decline at 10 years (2.3%, P < .001 vs 4 years) followed by significant rise at 18 years (4%, P = .02 vs 10 years). Cow's milk (1.6%-3.5%) and egg (1.1%-1.4%) were the most common allergens in the first 10 years with peanut (1%) and tree nuts (0.5%) becoming more prevalent beyond 10 years. Fruit and wheat allergy were less common at 10 years, and shellfish and kiwi emerged during adolescence. The prevalence of food allergy plus positive SPT was 1.3%, 0.8%, 0.8%, 0.9% and 2.2% at 1, 2, 4, 10 and 18 years, respectively. CONCLUSION: Food allergy is highly prevalent in infancy with partial resolution during late childhood. However, a number of children acquire new food allergy during adolescence resulting in a relatively higher prevalence at 18 years.

Observations and Modelling of the Pre-flare Period of the 29 March 2014 X1 Flare.

On 29 March 2014, NOAA Active Region (AR) 12017 produced an X1 flare that was simultaneously observed by an unprecedented number of observatories. We have investigated the pre-flare period of this flare from 14:00 UT until 19:00 UT using joint observations made by the Interface Region Imaging Spectrometer (IRIS) and the Hinode Extreme Ultraviolet Imaging Spectrometer (EIS). Spectral lines providing coverage of the solar atmosphere from the chromosphere to the corona were analysed to investigate pre-flare activity within the AR. The results of the investigation have revealed evidence of strongly blue-shifted plasma flows, with velocities up to 200 km s - 1 , being observed 40 minutes prior to flaring. These flows are located along the filament present in the active region and are both spatially discrete and transient. In order to constrain the possible explanations for this activity, we undertake non-potential magnetic field modelling of the active region. This modelling indicates the existence of a weakly twisted flux rope along the polarity inversion line in the region where a filament and the strong pre-flare flows are observed. We then discuss how these observations relate to the current models of flare triggering. We conclude that the most likely drivers of the observed activity are internal reconnection in the flux rope, early onset of the flare reconnection, or tether-cutting reconnection along the filament.

Use of multiplex PCR to rapidly diagnose febrile patients during a gastroenteritis outbreak among Ebola virus treatment unit workers.

Multiplex PCR can provide rapid diagnosis for patients presenting with an acute undifferentiated febrile illness. Such technology is useful in deployed settings, where access to conventional microbiological diagnosis is limited. It was used in Sierra Leone to guide management of febrile healthcare workers, in whom Ebola virus disease was a possible cause. In particular, it informed appropriate antibiotic treatment while minimising the risk to clinicians of exposure to the causative organism.

The Pan-University Network for Global Health: framework for collaboration and review of global health needs.

In the current United Nations efforts to plan for post 2015-Millennium Development Goals, global partnership to address non-communicable diseases (NCDs) has become a critical goal to effectively respond to the complex global challenges of which inequity in health remains a persistent challenge. Building capacity in terms of well-equipped local researchers and service providers is a key to bridging the inequity in global health. Launched by Penn State University in 2014, the Pan University Network for Global Health responds to this need by bridging researchers at more than 10 universities across the globe. In this paper we outline our framework for international and interdisciplinary collaboration, as well the rationale for our research areas, including a review of these two themes. After its initial meeting, the network has established two central thematic priorities: 1) urbanization and health and 2) the intersection of infectious diseases and NCDs. The urban population in the global south will nearly double in 25 years (approx. 2 billion today to over 3.5 billion by 2040). Urban population growth will have a direct impact on global health, and this growth will be burdened with uneven development and the persistence of urban spatial inequality, including health disparities. The NCD burden, which includes conditions such as hypertension, stroke, and diabetes, is outstripping infectious disease in countries in the global south that are considered to be disproportionately burdened by infectious diseases. Addressing these two priorities demands an interdisciplinary and multi-institutional model to stimulate innovation and synergy that will influence the overall framing of research questions as well as the integration and coordination of research.

Gender differences in the association between stop-signal reaction times, body mass indices and/or spontaneous food intake in pre-school children: an early model of compromised inhibitory control and obesity.

BACKGROUND: Poor inhibitory control is associated with overeating and/or obesity in school-age children, adolescents and adults. The current study examined whether an objective and reliable marker of response inhibition, the stop-signal reaction time (SSRT), is associated with body mass index (BMI) z-scores and/or food intake during a snack test in pre-school children. METHODS: The current sample consisted of 193 pre-school children taking part in a longitudinal study of early brain development (Maternal Adversity, Vulnerability and Neurodevelopment (the MAVAN project)). Linear mixed-effect models were used to examine whether the SSRT measured at age 48 months associated with BMI z-scores and/or dietary intake during a laboratory-based snack test. RESULTS: After controlling for significant covariates including maternal BMI, there was a significant gender by SSRT interaction effect in predicting 48-month BMI z-scores. Post-hoc analysis revealed an association between longer SSRTs (poor response inhibition) and higher BMIs in girls but not boys. Across both girls and boys, longer SSRTs were associated with greater intake of carbohydrates and sugars during the snack test. The association between SSRT scores and BMI z-scores in girls was not statistically mediated by carbohydrate or sugar intake. CONCLUSIONS: At 48 months of age, slower response inhibition on the Stop-Signal Task associates with higher BMI z-scores in girls, and with higher intake of carbohydrates and sugars during a snack test across both genders. Ongoing follow-up of these children will help clarify the implications of these associations for longer term macronutrient intake, eating-related pathology and/or pathological weight gain over time.

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.

Health of adults living with a clinically significant haemoglobinopathy in New South Wales, Australia.

AIM: To comprehensively review the health needs of patients living with clinically significant haemoglobinopathies (thalassaemia and sickle-cell disease (SCD)) in New South Wales, Australia. METHODS: A survey-based health needs assessment was undertaken in outpatients cared for at five tertiary institutions in metropolitan and regional centres. Sixty-three of 121 adults (approximately 80-90% of adult patients with transfusion-requiring haemoglobinopathies in New South Wales) completed an in-house and commercial health-related quality assessment survey (SF-36v2). RESULTS: Subjects came from more than eight world regions, with those with SCD being more likely to be born outside of Australia than subjects with thalassaemia (P < 0.001, likelihood ratio 20.64) as well as more likely to have been refugees (26% vs 2%). The population contained socially disadvantaged subjects with 13 subjects (20.6%) having incomes below the Australian poverty line. Complications of thalassaemia were comparable to previous international reports although our subjects had a high rate of secondary amenorrhea (>12 months = 27%) and surgical splenectomy (55.6%). Use of hydroxyurea in SCD was less than expected with only 46.6% of subjects having prior use. Lack of universal access to magnetic resonance imaging-guided chelation (international best practice) was evident, although 65.5% had been able to access magnetic resonance imaging through clinical trial, or self-funding. CONCLUSIONS: Patients with SCD and thalassaemia experience considerable morbidity and mortality and require complex, multidisciplinary care. This study revealed both variance from international best practice and between specialist units. The results of this research may provide the impetus for the development of clinical and research networks to enable the uniform delivery of health services benchmarked against international standards.

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.

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.

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.

Trends in cutaneous sensitization in the first 18 years of life: results from the 1989 Isle of Wight birth cohort study.

BACKGROUND: Skin prick testing (SPT) is fundamental to the practice of clinical allergy identifying relevant allergens and predicting the clinical expression of disease. There are only limited data on the natural history of SPT results over childhood and adolescence. OBJECTIVE: We aimed to describe the natural history of SPT and patterns of sensitization over childhood and adolescence. METHODS: The 1989 Isle of Wight birth cohort (1456 participants) was followed up at 1, 2, 4, 10 and 18 years. SPT was undertaken from 4 years. RESULTS: SPT was performed on 980 (80%), 1036 (75%) and 853 (65%) of participants at 4, 10 and 18 years. The prevalence of sensitization to any allergen at these time-points was 19.7%, 26.9% and 41.3% respectively. At each time-point, boys were significantly more likely to be sensitized (P < 0.016) and sensitization significantly increased over childhood and adolescence (average annual increase of 7%). Some children outgrew their sensitization. The rate of sensitization to most individual allergens increased over childhood and adolescence. A configural frequency analysis showed that whether an individual was sensitizated was relatively fixed over childhood and adolescence. Cluster analysis at 4 years demonstrated four major groups of individuals with similar co-sensitization to specific allergens. Children who were sensitized at age 4 years generally went onto become sensitized to additional allergens at 10 and 18 years. CONCLUSIONS AND CLINICAL RELEVANCE: Allergic sensitization continues to increase over childhood into adolescence although the majority of children who were not sensitized at 4 years remain non-sensitized throughout childhood and adolescence. The presence of sensitization at 4 years predicted later sensitization to additional allergens.

Incidental focal colonic lesions found on (18)Fluorodeoxyglucose positron emission tomography/computed tomography scan: further support for a national guideline on definitive management.

AIM: (18)Fluorodeoxyglucose ((18)FDG) positron emission tomography/computed tomography (PET/CT) is an established part of staging in a wide variety of malignancies. Incidental abnormal uptake of (18)FDG of unknown significance is frequently encountered. Therefore, we investigated patients with abnormal colonic uptake of (18)FDG, determined by PET/CT images, using colonoscopy. METHOD: The radiology reports of all patients referred to a tertiary referral centre for a PET/CT scan were reviewed retrospectively. Patients with abnormal colonic uptake of (18)FDG were identified and the PET/CT findings were correlated with colonoscopic findings. RESULTS: Of 555 consecutive patients identified over a 26-month period, 53 had abnormal colonic uptake of (18)FDG, as determined by PET/CT images. Twenty-nine were not investigated following discussion in a specialist multidisciplinary (MDT) meeting, according to local protocol. Twenty out of 24 patients investigated by endoscopy had a colonic lesion correlating to the site identified on the PET/CT image: 16 patients had tubulovillous adenomas (nine of which were > 10 mm), two had invasive adenocarcinomas, two had diverticular disease and one had collagenous colitis; no colonic lesion was detected in three. These findings were incidental and not related to the primary diagnosis for which the scan was being performed. Accordingly, a positive predictive value of 83% is associated with the finding of abnormal uptake of (18)FDG on PET/CT images. CONCLUSION: Incidental abnormal colonic uptake of (18)FDG, determined by a PET/CT scan requires definitive colonic investigation in patients suitable for further treatment because significant colonic pathology is frequently identified. The benefit of this approach should be discussed in specialist MDT meetings and tailored to each patient; however, national guidelines for management are required.

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.

The influence of gender and atopy on the natural history of rhinitis in the first 18 years of life.

BACKGROUND: Longitudinal studies of the natural history of childhood and adolescent rhinitis are lacking. OBJECTIVES: To investigate the natural history of rhinitis up to 18 years of age, and how that is influenced by gender and atopy. METHODS: The Isle of Wight birth cohort was recruited in 1989 (n=1456). Questionnaire data on nasal symptoms (rhinitis) were collected at 1, 2, 4, 10 and 18 years of age. To define atopy, skin prick tests were conducted at 4, 10 and 18 years. The 12-month period prevalence plus positive and negative transitions (defined as change in disease status in two consecutive study assessments) were stratified by gender and atopic status. RESULTS: Overall rhinitis prevalence increased from 5.4% at 4 years to 35.8% at 18 years (P<0.001), without gender difference. Atopic rhinitis prevalence increased steadily from 3.4% at 4 years to 27.3% at 18 years (P<0.001), was commoner in boys at 18 years (P=0.02) and associated with greater positive transition in boys from 10 to 18 years (P=0.01). Prevalence of non-atopic rhinitis also increased from 4 to 18 years (P=0.003) and was greater in girls at 18 years (P<0.001) reflecting higher female positive transition from 10 to 18 years (P<0.001). Non-atopic rhinitis negative transition (remission) was highest in early life and reduced in later childhood/adolescence. CONCLUSION: Atopic rhinitis becomes increasingly common as children grow into adolescents, with stronger associations to male gender. Non-atopic rhinitis shows a female predominance at 18 years as girls 'grow into' it more during adolescence. Our findings suggest differential gender effects on the increasing prevalence of both atopic and non-atopic rhinitis in adolescence. CLINICAL RELEVANCE: A better understanding of how gender and atopic status influence rhinitis during adolescence emerges from this study. Application of such knowledge could help to improve clinical recognition, judge prognosis and ultimately improve management of this common condition.