Folate receptor alpha in ovarian cancer tissue and patient serum is associated with disease burden and treatment outcomes.

BACKGROUND: Survival rates for ovarian cancer remain poor, and monitoring and prediction of therapeutic response may benefit from additional markers. Ovarian cancers frequently overexpress Folate Receptor alpha (FRα) and the soluble receptor (sFRα) is measurable in blood. Here we investigated sFRα as a potential biomarker. METHODS: We evaluated sFRα longitudinally, before and during neo-adjuvant, adjuvant and palliative therapies, and tumour FRα expression status by immunohistrochemistry. The impact of free FRα on the efficacy of anti-FRα treatments was evaluated by an antibody-dependent cellular cytotoxicity assay. RESULTS: Membrane and/or cytoplasmic FRα staining were observed in 52.7% tumours from 316 ovarian cancer patients with diverse histotypes. Circulating sFRα levels were significantly higher in patients, compared to healthy volunteers, specifically in patients sampled prior to neoadjuvant and palliative treatments. sFRα was associated with FRα cell membrane expression in the tumour. sFRα levels decreased alongside concurrent tumour burden in patients receiving standard therapies. High concentrations of sFRα partly reduced anti-FRα antibody tumour cell killing, an effect overcome by increased antibody doses. CONCLUSIONS: sFRα may present a non-invasive marker for tumour FRα expression, with the potential for monitoring patient response to treatment. Larger, prospective studies should evaluate FRα for assessing disease burden and response to systemic treatments.

Depletion of pulmonary intravascular macrophages rescues inflammation-induced delayed neutrophil apoptosis in horses.

The objective of this study was to determine the effect of pulmonary intravascular macrophage depletion on systemic inflammation and ex vivo neutrophil apoptosis using an experimental model of intestinal ischemia and reperfusion injury in horses. Neutrophils were isolated before and after surgery from horses that were randomized to three treatment groups, namely, sham celiotomy (CEL, n = 4), intestinal ischemia and reperfusion (IR, n = 6), and intestinal ischemia and reperfusion with gadolinium chloride treatment to deplete pulmonary intravascular macrophages (PIMs, IRGC, n = 6). Neutrophil apoptosis was assessed with Annexin V and propidium iodide staining quantified with flow cytometry and caspase-3, caspase-8, and caspase-9 activities in neutrophil lysates. All horses experienced a systemic inflammatory response following surgery. Following surgery, ex vivo neutrophil apoptosis was significantly delayed after 12 or 24 h in culture, except in IRGC horses (12 h: CEL: P = 0.03, IR: P = 0.05, IRGC: P = 0.2; 24 h: CEL: P = 0.001, IR: P = 0.004, IRGC: P = 0.3). Caspase-3, caspase-8, and caspase-9 activities were significantly reduced in neutrophils isolated after surgery and cultured for 12 h in IR horses, but not in IRGC horses (IR caspase-3: P = 0.002, IR caspase-8: P = 0.002, IR caspase-9: P = 0.04). Serum TNF-α concentration was increased in IRGC horses for 6-18 h following jejunal ischemia. Following surgery, ex vivo equine neutrophil apoptosis was delayed via downregulation of caspase activity, which was ameliorated by PIM depletion potentially via upregulation of TNF-α.

Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes.

PURPOSE: Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. METHODS: Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. RESULTS: Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype-genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. CONCLUSION: This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes.

Global effects of land use on local terrestrial biodiversity.

Human activities, especially conversion and degradation of habitats, are causing global biodiversity declines. How local ecological assemblages are responding is less clear--a concern given their importance for many ecosystem functions and services. We analysed a terrestrial assemblage database of unprecedented geographic and taxonomic coverage to quantify local biodiversity responses to land use and related changes. Here we show that in the worst-affected habitats, these pressures reduce within-sample species richness by an average of 76.5%, total abundance by 39.5% and rarefaction-based richness by 40.3%. We estimate that, globally, these pressures have already slightly reduced average within-sample richness (by 13.6%), total abundance (10.7%) and rarefaction-based richness (8.1%), with changes showing marked spatial variation. Rapid further losses are predicted under a business-as-usual land-use scenario; within-sample richness is projected to fall by a further 3.4% globally by 2100, with losses concentrated in biodiverse but economically poor countries. Strong mitigation can deliver much more positive biodiversity changes (up to a 1.9% average increase) that are less strongly related to countries' socioeconomic status.

Longitudinal exposure of English primary care patients to pharmacogenomic drugs: An analysis to inform design of pre-emptive pharmacogenomic testing.

AIMS: To investigate the longitudinal exposure of English primary care patients to pharmacogenomic drugs to inform design of pre-emptive testing. METHODS: Sixty-three drugs were identified with dosing guidelines based on variants of 19 pharmacogenes in the Pharmacogenomics Knowledgebase on 01 September 2018. Prescribing of these pharmacogenomic drugs between 1993 and 2017 was summarised for a sample of 648 141 English patients aged 50-99 years on 01 January 2013, registered with Clinical Practice Research Datalink practices during 2011-12. Exposure of patients to pharmacogenomic drugs retrospectively (2, 10, 20 y) and prospectively (5 y) was described. RESULTS: During 2011-12, 58% of patients were prescribed at least 1 pharmacogenomic drug, increasing to 80% over the previous 20 years. Multiple exposure was common, with 47% patients prescribed ≥2 pharmacogenomic drugs and 7% prescribed ≥5 pharmacogenomic drugs over the next 5 years. The likelihood of exposure to pharmacogenomic drugs increased with age, with 89% patients ≥70 years prescribed at least 1 pharmacogenomic drug over the previous 20 years. Even among those aged 50-59 years, 71% were prescribed at least 1 pharmacogenomic drug over the previous 20 years. The pharmacogenomic drugs prescribed to the most patients were for pain relief, gastroprotection, psychiatric and cardiovascular conditions. Three pharmacogenes (CYP2D6, CYP2C19 and SLCO1B1) accounted for >95% pharmacogenomic drugs prescribed. CONCLUSIONS: In primary care patients, exposure to pharmacogenomic drugs is extremely common, multiplicitous and has commenced by relatively early adulthood. A small number of pharmacogenes account for the majority of drugs prescribed. These findings could inform design of pre-emptive pharmacogenomic testing for implementation in primary care.

Systematic review of infant and young child complementary feeding practices in South Asian families: the India perspective.

OBJECTIVE: Suboptimal nutrition among children remains a problem among South Asian (SA) families. Appropriate complementary feeding (CF) practices can greatly reduce this risk. Thus, we undertook a systematic review of studies assessing CF (timing, dietary diversity, meal frequency and influencing factors) in children aged <2 years in India. DESIGN: Searches between January 2000 and June 2016 in MEDLINE, EMBASE, Global Health, Web of Science, OVID Maternity & Infant Care, CINAHL, Cochrane Library, BanglaJOL, POPLINE and WHO Global Health Library. Eligibility criteria: primary research on CF practices in SA children aged 0-2 years and/or their families. Search terms: 'children', 'feeding' and 'Asians' and derivatives. Two researchers undertook study selection, data extraction and quality appraisal (EPPI-Centre Weight of Evidence). RESULTS: From 45 712 abstracts screened, sixty-four cross-sectional, seven cohort, one qualitative and one case-control studies were included. Despite adopting the WHO Infant and Young Child Feeding guidelines, suboptimal CF practices were found in all studies. In twenty-nine of fifty-nine studies, CF was introduced between 6 and 9 months, with eight studies finding minimum dietary diversity was achieved in 6-33 %, and ten of seventeen studies noting minimum meal frequency in only 25-50 % of the study populations. Influencing factors included cultural influences, poor knowledge on appropriate CF practices and parental educational status. CONCLUSIONS: This is the first systematic review to evaluate CF practices in SA in India. Campaigns to change health and nutrition behaviour and revision of nationwide child health nutrition programmes are needed to meet the substantial unmet needs of these children.

Who is distressed? A comparison of psychosocial stress in pregnancy across seven ethnicities.

BACKGROUND: Calgary, Alberta has the fourth highest immigrant population in Canada and ethnic minorities comprise 28 % of its total population. Previous studies have found correlations between minority status and poor pregnancy outcomes. One explanation for this phenomenon is that minority status increases the levels of stress experienced during pregnancy. The aim of the present study was to identify specific types of maternal psychosocial stress experienced by women of an ethnic minority (Asian, Arab, Other Asian, African, First Nations and Latin American). METHODS: A secondary analysis of variables that may contribute to maternal psychosocial stress was conducted using data from the All Our Babies prospective pregnancy cohort (N = 3,552) where questionnaires were completed at < 24 weeks of gestation and between 34 and 36 weeks of gestation. Questionnaires included standardized measures of perceived stress, anxiety, depression, physical and emotional health, and social support. Socio-demographic data included immigration status, language proficiency in English, ethnicity, age, and socio-economic status. RESULTS: Findings from this study indicate that women who identify with an ethnic minority were more likely to report symptoms of depression, anxiety, inadequate social support, and problems with emotional and physical health during pregnancy than women who identified with the White reference group. CONCLUSIONS: This study has identified that women of an ethic minority experience greater psychosocial stress in pregnancy compared to the White reference group.

The Ethics of Organ Donor Registration Policies: Nudges and Respect for Autonomy.

Governments must determine the legal procedures by which their residents are registered, or can register, as organ donors. Provided that governments recognize that people have a right to determine what happens to their organs after they die, there are four feasible options to choose from: opt-in, opt-out, mandated active choice, and voluntary active choice. We investigate the ethics of these policies' use of nudges to affect organ donor registration rates. We argue that the use of nudges in this context is morally problematic. It is disrespectful of people's autonomy to take advantage of their cognitive biases since doing so involves bypassing, not engaging, their rational capacities. We conclude that while mandated active choice policies are not problem free-they are coercive, after all-voluntary active choice, opt-in, and opt-out policies are potentially less respectful of people's autonomy since their use of nudges could significantly affect people's decision making.

Ancestral exposure to stress epigenetically programs preterm birth risk and adverse maternal and newborn outcomes.

BACKGROUND: Chronic stress is considered to be one of many causes of human preterm birth (PTB), but no direct evidence has yet been provided. Here we show in rats that stress across generations has downstream effects on endocrine, metabolic and behavioural manifestations of PTB possibly via microRNA (miRNA) regulation. METHODS: Pregnant dams of the parental generation were exposed to stress from gestational days 12 to 18. Their pregnant daughters (F1) and grand-daughters (F2) either were stressed or remained as non-stressed controls. Gestational length, maternal gestational weight gain, blood glucose and plasma corticosterone levels, litter size and offspring weight gain from postnatal days 1 to 30 were recorded in each generation, including F3. Maternal behaviours were analysed for the first hour after completed parturition, and offspring sensorimotor development was recorded on postnatal day (P) 7. F0 through F2 maternal brain frontal cortex, uterus and placenta miRNA and gene expression patterns were used to identify stress-induced epigenetic regulatory pathways of maternal behaviour and pregnancy maintenance. RESULTS: Progressively up to the F2 generation, stress gradually reduced gestational length, maternal weight gain and behavioural activity, and increased blood glucose levels. Reduced offspring growth and delayed behavioural development in the stress cohort was recognizable as early as P7, with the greatest effect in the F3 offspring of transgenerationally stressed mothers. Furthermore, stress altered miRNA expression patterns in the brain and uterus of F2 mothers, including the miR-200 family, which regulates pathways related to brain plasticity and parturition, respectively. Main miR-200 family target genes in the uterus, Stat5b, Zeb1 and Zeb2, were downregulated by multigenerational stress in the F1 generation. Zeb2 was also reduced in the stressed F2 generation, suggesting a causal mechanism for disturbed pregnancy maintenance. Additionally, stress increased placental miR-181a, a marker of human PTB. CONCLUSIONS: The findings indicate that a family history of stress may program central and peripheral pathways regulating gestational length and maternal and newborn health outcomes in the maternal lineage. This new paradigm may model the origin of many human PTB causes.

A global model of the response of tropical and sub-tropical forest biodiversity to anthropogenic pressures.

Habitat loss and degradation, driven largely by agricultural expansion and intensification, present the greatest immediate threat to biodiversity. Tropical forests harbour among the highest levels of terrestrial species diversity and are likely to experience rapid land-use change in the coming decades. Synthetic analyses of observed responses of species are useful for quantifying how land use affects biodiversity and for predicting outcomes under land-use scenarios. Previous applications of this approach have typically focused on individual taxonomic groups, analysing the average response of the whole community to changes in land use. Here, we incorporate quantitative remotely sensed data about habitats in, to our knowledge, the first worldwide synthetic analysis of how individual species in four major taxonomic groups--invertebrates, 'herptiles' (reptiles and amphibians), mammals and birds--respond to multiple human pressures in tropical and sub-tropical forests. We show significant independent impacts of land use, human vegetation offtake, forest cover and human population density on both occurrence and abundance of species, highlighting the value of analysing multiple explanatory variables simultaneously. Responses differ among the four groups considered, and--within birds and mammals--between habitat specialists and habitat generalists and between narrow-ranged and wide-ranged species.

Effects of training on Feline Grimace Scale scoring for acute pain assessment in cats.

OBJECTIVES: The aim of the study was to determine the effects of training on inter-rater reliability and agreement of Feline Grimace Scale (FGS) scoring by small animal practitioners. METHODS: Seven small animal veterinarians were asked to score a total of 50 images of cats in varying degrees of pain before and after training in FGS scoring. Participant scores were compared with those of an expert rater. Inter-rater reliability was analyzed using the intraclass correlation coefficient (ICC) before and after training (ICC <0.50 = poor reliability, 0.50-0.75 = moderate reliability, 0.76-0.90 = good reliability and >0.90 = excellent reliability). The Bland-Altman method was used to analyze the limits of agreement (LoAs) and bias between participants and the expert rater. RESULTS: After training, the ICC classification improved for each action unit (ear position, orbital tightening, muzzle tension, whiskers change and head position). The inter-rater reliability for the total FGS ratio scores before and after the FGS training session was moderate (ICC = 0.75; 95% confidence interval [CI] 0.66-0.83) and good (ICC = 0.80; 95% CI 0.73-0.87), respectively. Before training, LoAs were -0.277 to 0.310 with a bias of 0.016. After training, LoAs were -0.237 to 0.255 with a bias of 0.008. The bias was low (<0.1) both before and after training and LoAs did not span the FGS analgesic threshold (0.39). CONCLUSIONS AND RELEVANCE: Training in FGS scoring improved inter-rater reliability and agreement among seven small animal veterinarians and the veterinarians' skills in pain assessment.

Profiling UK injectable aesthetic practitioners: A national cohort analysis.

INTRODUCTION: The United Kingdom (UK) injectables market has been growing rapidly with a lack of robust regulation and to date, no information regarding the profile of practitioners has been published. AIM: We aim to provide a descriptive and qualitative analysis of the advertised practitioners in the United Kingdom. METHODS: We performed a systematic search using the internet search engine Google to perform a qualitative descriptive analysis of aesthetic practitioners in the UK. For each contiguous country in the UK: England, Scotland, and Wales, five searches were performed. The list of practitioners was then cross-referenced with professional regulatory bodies, with extraction of registration number, date of registration and presence or absence from the Specialist Register or General Practitioner Register. RESULTS: 3000 websites were visited and evaluated. 1224 independent clinics with 4405 practitioners were identified. 738 were identified as those in business support functions and the remaining 3667 practitioners were undertaking injectable practice. The profile of professions were doctors 32%, nurses 13%, dentists 24% and dental nurses 8%. Of the 1163 doctors identified 481 were on the specialist register (41%) and 219 were on the GP register (19%). 27 specialties were represented in this cohort analysis. Plastic Surgery formed the majority of those who were on the specialist register at 37%, followed by Dermatology at 18%. CONCLUSION: This paper is the first to describe the range of practitioners, their professional backgrounds and experience who perform non-surgical aesthetic interventions. The range of backgrounds may have an impact on the potential risks to patients and will be an important consideration in proposed legislation to introduce licensing to the industry.

Applications and advancements of nanoparticle-based drug delivery in alleviating lung cancer and chronic obstructive pulmonary disease.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are among the leading causes of mortality worldwide. Cigarette smoking is among the main aetiologic factors for both ailments. These diseases share common pathogenetic mechanisms including inflammation, oxidative stress, and tissue remodelling. Current therapeutic approaches are limited by low efficacy and adverse effects. Consequentially, LC has a 5-year survival of < 20%, while COPD is incurable, underlining the necessity for innovative treatment strategies. Two promising emerging classes of therapy against these diseases include plant-derived molecules (phytoceuticals) and nucleic acid-based therapies. The clinical application of both is limited by issues including poor solubility, poor permeability, and, in the case of nucleic acids, susceptibility to enzymatic degradation, large size, and electrostatic charge density. Nanoparticle-based advanced drug delivery systems are currently being explored as flexible systems allowing to overcome these limitations. In this review, an updated summary of the most recent studies using nanoparticle-based advanced drug delivery systems to improve the delivery of nucleic acids and phytoceuticals for the treatment of LC and COPD is provided. This review highlights the enormous relevance of these delivery systems as tools that are set to facilitate the clinical application of novel categories of therapeutics with poor pharmacokinetic properties. This picture was generated with BioRender.

Tritium Air Concentration Calculation Using Passive Monitors.

Passive tritium air monitoring was conducted at Sandia National Laboratories' Z-Machine located in New Mexico. When conducting low-level measurements, indication of the measurement's uncertainty and of the detection limit of the counting technique are important to understand. Therefore, a calculational methodology is presented to enable the determination of the airborne tritium concentration by analysis of the minimum detectible activities for the Passive Tritium Monitoring System and the laboratory counting system used. General discussions of the advantages and disadvantages of the Passive Tritium Monitoring System are provided.

Direct and indirect effects of COVID-19 on perinatal outcomes in low- and middle-income countries.

Similar to previous outbreaks, the coronavirus disease 2019 (COVID-19) pandemic will have both direct and indirect effects on perinatal outcomes, especially in low- and middle-income countries. Limited data on the direct impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy shows women who are Black, obese and with co-morbidities are at higher risk of hospitalisation due to COVID-19. Younger age groups in Africa and South Asia have shown increased COVID-19 mortality. Indigenous pregnant women in Pacific Island countries are likely to be high risk for severe outcomes from COVID-19 due to high rates of diabetes and obesity. It is important to involve pregnant women in research, especially with regards to vaccine development and therapeutics.