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Abstract Background Many women with hyperglycaemia in pregnancy do not receive care during and after pregnancy according to standards recommended in international guidelines. The burden of hyperglycaemia in pregnancy falls disproportionately upon Indigenous peoples worldwide, including Aboriginal and Torres Strait Islander women in Australia. The remote and regional Australian context poses additional barriers to delivering healthcare, including high staff turnover and a socially disadvantaged population with a high prevalence of diabetes. Methods A complex health systems intervention to improve care for women during and after a pregnancy complicated by hyperglycaemia will be implemented in remote and regional Australia (the Northern Territory and Far North Queensland). The Theoretical Domains Framework was used during formative work with stakeholders to identify intervention components: (1) increasing workforce capacity, skills and knowledge and improving health literacy of health professionals and women; (2) improving access to healthcare through culturally and clinically appropriate pathways; (3) improving information management and communication; (4) enhancing policies and guidelines; (5) embedding use of a clinical register as a quality improvement tool. The intervention will be evaluated utilising the RE-AIM framework at two timepoints: firstly, a qualitative interim evaluation involving interviews with stakeholders (health professionals, champions and project implementers); and subsequently a mixed-methods final evaluation of outcomes and processes: interviews with stakeholders; survey of health professionals; an audit of electronic health records and clinical register; and a review of operational documents. Outcome measures include changes between pre- and post-intervention in: proportion of high risk women receiving recommended glucose screening in early pregnancy; diabetes-related birth outcomes; proportion of women receiving recommended postpartum care including glucose testing; health practitioner confidence in providing care, knowledge and use of relevant guidelines and referral pathways, and perception of care coordination and communication systems; changes to health systems including referral pathways and clinical guidelines. Discussion This study will provide insights into the impact of health systems changes in improving care for women with hyperglycaemia during and after pregnancy in a challenging setting. It will also provide detailed information on process measures in the implementation of such health system changes.

Is anthropogenic soil erosion a sink or source of atmospheric carbon? The answer depends on factors beyond hillslope erosion alone because the probable fate of mobilized soil carbon evolves as it traverses the fluvial system. The transit path, residence times, and the resulting mechanisms of C-loss or gain change significantly down-basin and are currently difficult to predict as soils erode and floodplains evolve – this should be a key focus of future research.

Chronic inflammation and lipometabolism share many causal genes and possibly pathways. Here, the authors use a multi-trait GWAS approach to study shared genetic determinants of low-grade inflammation, measured by C-reactive protein (CRP), and closely linked lipid and metabolic pathways.

External perturbations can induce 3D charge order in cuprates, but the 3D correlation length is limited and the mechanism is not well understood. Ruiz et al. show that Pr substitution in YBa2Cu3O7 enhances interplanar orbital coupling and stabilizes coherent 3D charge order that coexists with superconductivity.

Despite being key drivers of protective antibodies against malaria, little is known regarding the host and parasite factors that influence CD4 T-follicular helper cell and antibody development. Authors utilise samples from a study of children living in an area of high malaria transmission in Uganda, to characterize Tfh cells and functional antibodies to multiple parasites stages.

Abstract Background There is a clear need for novel approaches to malaria vaccine development. We aimed to develop a genetically attenuated blood-stage vaccine and test its safety, infectivity, and immunogenicity in healthy volunteers. Our approach was to target the gene encoding the knob-associated histidine-rich protein (KAHRP), which is responsible for the assembly of knob structures at the infected erythrocyte surface. Knobs are required for correct display of the polymorphic adhesion ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1), a key virulence determinant encoded by a repertoire of var genes. Methods The gene encoding KAHRP was deleted from P. falciparum 3D7 and a master cell bank was produced in accordance with Good Manufacturing Practice. Eight malaria naïve males were intravenously inoculated (day 0) with 1800 (2 subjects), 1.8 × 105 (2 subjects), or 3 × 106 viable parasites (4 subjects). Parasitemia was measured using qPCR; immunogenicity was determined using standard assays. Parasites were rescued into culture for in vitro analyses (genome sequencing, cytoadhesion assays, scanning electron microscopy, var gene expression). Results None of the subjects who were administered with 1800 or 1.8 × 105 parasites developed parasitemia; 3/4 subjects administered 3× 106 parasites developed significant parasitemia, first detected on days 13, 18, and 22. One of these three subjects developed symptoms of malaria simultaneously with influenza B (day 17; 14,022 parasites/mL); one subject developed mild symptoms on day 28 (19,956 parasites/mL); and one subject remained asymptomatic up to day 35 (5046 parasites/mL). Parasitemia rapidly cleared with artemether/lumefantrine. Parasitemia induced a parasite-specific antibody and cell-mediated immune response. Parasites cultured ex vivo exhibited genotypic and phenotypic properties similar to inoculated parasites, although the var gene expression profile changed during growth in vivo. Conclusions This study represents the first clinical investigation of a genetically attenuated blood-stage human malaria vaccine. A P. falciparum 3D7 kahrp– strain was tested in vivo and found to be immunogenic but can lead to patent parasitemia at high doses. Trial registration Australian New Zealand Clinical Trials Registry (number: ACTRN12617000824369 ; date: 06 June 2017).

Background Remote monitoring (RM) of cardiac implantable electronic devices (CIEDs) is now the standard of care, but whether the demonstrated benefits of RM translate into improvements in heart failure (HF) management is controversial. This systematic review addresses the role of RM in patients with HF with a CIED.Methods and results A systematic search of the literature for randomised clinical trials in patients with HF and a CIED assessing efficacy/effectiveness of RM was performed using MEDLINE, PubMed and Embase. Meta-analysis was performed on the effects of RM of CIEDs in patients with HF on mortality and readmissions. Effects on implantable cardiac defibrillator (ICD) therapy, healthcare costs and clinic presentations were also assessed.607 articles were identified and refined to 10 studies with a total of 6579 patients. Implementation of RM was not uniform with substantial variation in methodology across the studies. There was no reduction in mortality or hospital readmission rates, while ICD therapy findings were inconsistent. There was a reduction in patient-associated healthcare costs and reduction in healthcare presentations.Conclusion RM for patients with CIEDs and HF was not uniformly performed. As currently implemented, RM does not provide a benefit on overall mortality or the key metric of HF readmission. It does provide a reduction in healthcare costs and healthcare presentations.PROSPERO REGISTRATION NUMBER CRD42019129270.

Abstract Background Oxygen therapy is routinely administered to mechanically ventilated patients. However, there remains uncertainty about the optimal oxygen titration target in patients with the acute respiratory distress syndrome (ARDS). Methods Prospectively identified adult patients meeting the Berlin definition of ARDS between 1st January 2014 and 13th December 2016 were analyzed. Oxygen exposure variables were collected at 6-hourly intervals. The primary exposure was the average time-weighted partial pressure of arterial oxygen (PaO2) calculated over a maximum of 7 days from meeting ARDS criteria. The primary outcome was ICU mortality. Univariable and multivariable logistic regression analyses were performed to assess the impact of exposure variables on clinical outcomes. Results are presented as odds ratio [95% confidence interval]. Results 202 patients were included in the final analysis. Overall ICU mortality was 31%. The average time-weighted PaO2 during the first 7 days of ARDS was similar between non-survivors and survivors (11.3 kPa [10.2, 12.5] (84.8 mmHg [76.5, 93.8]) vs. 11.9 kPa [10.9, 12.6] (89.3 mmHg [81.8, 94.5]); p = 0.08). In univariable and multivariable analysis, average time-weighted PaO2 demonstrated a U-shaped relationship with ICU mortality. There was a similar relationship identified with hospital mortality. Conclusions In patients with ARDS, the predicted probability of both ICU and hospital mortality was lowest when the average time-weighted PaO2 was between 12.5 and 14 kPa (93.8–105.0 mmHg), suggesting this is a reasonable oxygenation target for clinicians to aim for.

Abstract Background The pathogenesis of malaria in pregnancy (MiP) involves accumulation of P. falciparum-infected red blood cells (pRBCs) in the placenta, contributing to poor pregnancy outcomes. Parasite accumulation is primarily mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1). Magnitude of IgG to pRBCs has been associated with reduced risk of MiP in some studies, but associations have been inconsistent. Further, antibody effector mechanisms are poorly understood, and the role of antibody complement interactions is unknown. Methods Studying a longitudinal cohort of pregnant women (n=302) from a malaria-endemic province in Papua New Guinea (PNG), we measured the ability of antibodies to fix and activate complement using placental binding pRBCs and PfEMP1 recombinant domains. We determined antibody-mediated complement inhibition of pRBC binding to the placental receptor, chondroitin sulfate A (CSA), and associations with protection against placental parasitemia. Results Some women acquired antibodies that effectively promoted complement fixation on placental-binding pRBCs. Complement fixation correlated with IgG1 and IgG3 antibodies, which dominated the response. There was, however, limited evidence for membrane attack complex activity or pRBC lysis or killing. Importantly, a higher magnitude of complement fixing antibodies was prospectively associated with reduced odds of placental infection at delivery. Using genetically modified P. falciparum and recombinant PfEMP1 domains, we found that complement-fixing antibodies primarily targeted a specific variant of PfEMP1 (known as VAR2CSA). Furthermore, complement enhanced the ability of antibodies to inhibit pRBC binding to CSA, which was primarily mediated by complement C1q protein. Conclusions These findings provide new insights into mechanisms mediating immunity to MiP and reveal potential new strategies for developing malaria vaccines that harness antibody-complement interactions.

Abstract Background The aim of the current study is to assess the natural history and prognostic value of elevated left ventricular end-diastolic pressure (LVEDP) in patients with ST-segment elevation myocardial infarction (STEMI) after reperfusion with thrombolysis; we utilize data from the Thrombolysis in Myocardial Infarction (TIMI) II study. Methods A total of 3339 patients were randomized to either an invasive (n = 1681) or a conservative (n = 1658) strategy in the TIMI II study following thrombolysis. To make the current cohort as relevant as possible to modern pharmaco-invasively managed cohorts, patients in the invasive arm with TIMI flow grade ≥ 2 (N = 1201) at initial catheterization are included in the analysis. Of these, 259 patients had a second catheterization prior to hospital discharge, and these were used to define the natural history of LVEDP in reperfused STEMI. Results The median LVEDP for the whole cohort was 18 mmHg (IQR: 12–23). Patients were divided into quartiles by LVEDP measured during the first cardiac catheterization. During a median follow up of 3 (IQR: 2.1–3.2) years, quartile 4 (highest LVEDP) had the highest incidence of mortality and heart failure admissions. In the cohort with paired catheterization data, the LVEDP dropped slightly from 18 mmHg (1QR: 12–22) to 15 mmHg (IQR: 10–20) (p = 0.01) from the first to the pre-hospital discharge catheterization. Conclusions LVEDP remains largely stable during hospitalisation post-STEMI. Elevated LVEDP is a predictor of death and heart failure hospitalization in STEMI patients undergoing successful thrombolysis. Graphic abstract

Antibodies plays critical roles in the adaptive immune response to infectious agents including malaria. Here the authors defined antibody interactions with -Fcγ-receptors expressed on immune cells with sporozoites of Plasmodium falciparum, and identified specific target epitopes of antibodies.

Abstract Background Plasmodium falciparum malaria increases plasma levels of the cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), a haematopoietic factor associated with dendritic cell (DC) expansion. It is unknown if the zoonotic parasite Plasmodium knowlesi impacts Flt3L or DC in human malaria. This study investigated circulating DC and Flt3L associations in adult malaria and in submicroscopic experimental infection. Methods Plasma Flt3L concentration and blood CD141+ DC, CD1c+ DC and plasmacytoid DC (pDC) numbers were assessed in (i) volunteers experimentally infected with P. falciparum and in Malaysian patients with uncomplicated (ii) P. falciparum or (iii) P. knowlesi malaria. Results Plasmodium knowlesi caused a decline in all circulating DC subsets in adults with malaria. Plasma Flt3L was elevated in acute P. falciparum and P. knowlesi malaria with no increase in a subclinical experimental infection. Circulating CD141+ DCs, CD1c+ DCs and pDCs declined in all adults tested, for the first time extending the finding of DC subset decline in acute malaria to the zoonotic parasite P. knowlesi. Conclusions In adults, submicroscopic Plasmodium infection causes no change in plasma Flt3L but does reduce circulating DCs. Plasma Flt3L concentrations increase in acute malaria, yet this increase is insufficient to restore or expand circulating CD141+ DCs, CD1c+ DCs or pDCs. These data imply that haematopoietic factors, yet to be identified and not Flt3L, involved in the sensing/maintenance of circulating DC are impacted by malaria and a submicroscopic infection. The zoonotic P. knowlesi is similar to other Plasmodium spp in compromising DC in adult malaria.

Healthcare is a major global industry accounting for a significant proportion of government spending. Drug and medical device manufacturers are publicly traded companies with a responsibility to their shareholders to maximise profits by increasing sales. In order to achieve this, industry exerts influence over every part of healthcare including academic research, medical education, clinical guideline development, physician prescribing and through direct interactions with patients. In contrast, healthcare services seek to provide effective, safe and evidence-based treatments. This article examines interactions with industry across these domains and seeks to identify mutually beneficial relationships and potential conflict leading to patient harms. Case studies are used to illustrate these interactions. There is no single solution for improving healthcare's relationship with industry, although increased transparency has raised awareness of this issue. We briefly discuss some successful interventions that have been tried at national and regulatory level. While industry influence is widespread in healthcare and this has benefits for shareholders, healthcare practitioners have an ethical obligation to prioritise their patients’ best interests. Industry interactions with healthcare professionals have a valid role in product development and distribution, but industry sponsorship of healthcare education and practice, guideline development or regulatory decision-making can have harmful consequences for patients. Healthcare practitioners need to carefully consider these issues when deciding whether to collaborate with industry.Educational aims To explore the many areas where industry influences healthcare and the subsequent effects on patient care. Case studies are used to illustrate examples of beneficial and harmful effects of this influence. To raise awareness of the effects of industry influence and for readers to consider their own potential conflicts of interest. To suggest potential ways to improve the current system with a focus on solutions which have successfully been trialled already.

Aims This study aims to (1) define the characteristics of patients with a first admission for heart failure (HF), stratified by type (reduced (HFrEF) vs preserved (HFpEF) ejection fraction) in a regional Australian setting; (2) compare the outcomes in terms of mortality and rehospitalisation and (3) assess adherence to the treatment guidelines.Methods We identified all index hospitalisations with HF to John Hunter Hospital and Tamworth Rural Referral Hospital in the Hunter New England Local Health District over a 12 months. We used the recent Australian HF guidelines to classify HFrEF and HFpEF and assess adherence to guideline-directed therapy. The primary outcome of the study was to compare short-term (1 year) and long-term all-cause mortality and the composite of all-cause hospitalisation or all-cause mortality of patients with HFrEF and HFpEF.Results There were 664 patients who had an index HF admission to John Hunter and Tamworth hospitals in 2014. The median age was 80 years, 47% were female and 22 (3%) were Aboriginal. In terms of HF type, 29% had HFrEF, 37% had HFpEF, while the remainder (34%) did not have an echocardiogram within 1 year of admission and could not be classified. The median follow-up was 3.3 years. HFrEF patients were predominantly male (64%) and in 48% the aetiology was ischaemic heart disease. The 1-year all-cause mortality was 23% in HFpEF subgroup and 29% in HFrEF subgroup (p=0.15). Five-year mortality was 61% in HFpEF and HFrEF patients. Of the HFrEF patients, only 61% were on renin-angiotensin-aldosterone blockers, 74% were on β-blockers and 39% were on aldosterone antagonist.Conclusion HF patients are elderly and about evenly split between HFrEF and HFpEF. In this regional cohort, both HF types are associated with similar 1-year and 5-year mortality following incident HF hospitalisation. Echocardiography and guideline-directed therapies were underused.

Purpose: MR-linacs (MRLs) have enabled the use of stereotactic magnetic resonance (MR) guided online adaptive radiotherapy (SMART) across many cancers. As data emerges to support SMART, uncertainty remains regarding optimal technical parameters, such as optimal patient positioning, immobilization, image quality, and contouring protocols. Prior to clinical implementation of SMART, we conducted a prospective study in healthy volunteers (HVs) to determine optimal technical parameters and to develop and practice a multidisciplinary SMART workflow. Methods: HVs 18 years or older were eligible to participate in this IRB-approved study. Using a 0.35 T MRL, simulated adaptive treatments were performed by a multi-disciplinary treatment team in HVs. For each scan, image quality parameters were assessed on a 5-point scale (5 = extremely high, 1 = extremely poor). Adaptive recontouring times were compared between HVs and subsequent clinical cases with a t-test. Results: 18 simulated treatments were performed in HVs on MRL. Mean parameters for visibility of target, visibility of nearby organs, and overall image quality were 4.58, 4.62, and 4.62, respectively (range of 4–5 for all measures). In HVs, mean ART was 15.7 min (range 4–35), comparable to mean of 16.1 (range 7–33) in the clinical cases (p = 0.8963). Using HV cases, optimal simulation and contouring guidelines were developed across a range of disease sites and have since been implemented clinically. Conclusions: Prior to clinical implementation of SMART, scans of HVs on an MRL resulted in acceptable image quality and target visibility across a range of organs with similar ARTs to clinical SMART. We continue to utilize HV scans prior to clinical implementation of SMART in new disease sites and to further optimize target tracking and immobilization. Further study is needed to determine the optimal duration of HV scanning prior to clinical implementation.

Summary: Background: Protective malarial antibodies are acquired more rapidly in adults than children, independently of cumulative exposure, however the cellular responses mediating these differences are unknown. CD4 T-follicular helper (Tfh) cells have key roles in inducing antibodies, with Th2-Tfh cell activation associated with antibody development in malaria. Whether Tfh cell activation in malaria is age dependent is unknown and no studies have compared Tfh cell activation in children and adults with malaria. Methods: We undertook a comprehensive study of Tfh cells, along with B cells and antibody induction in children and adults with malaria. Activation and proliferation of circulating Tfh (cTfh) cell subsets was measured ex vivo and parasite-specific Tfh cell frequencies and functions studied with Activation Induced Marker (AIM) assays and intracellular cytokine staining. Findings: During acute malaria, the magnitude of cTfh cell activation was higher in adults than in children and occurred across all cTfh cell subsets in adults but was restricted only to the Th1-cTfh subset in children. Further, adults had higher levels of parasite-specific cTfh cells, and cTfh cells which produced more Th2-Tfh associated cytokine IL-4. Consistent with a role of higher Tfh cell activation in rapid immune development in adults, adults had higher activation of B cells during infection and higher induction of antibodies 7 and 28 days after malaria compared to children. Interpretation: Our data provide evidence that age impacts Tfh cell activation during malaria, and that these differences may influence antibody induction after treatment. Findings have important implications for vaccine development in children. Funding: This word was supported by the National Health and Medical Research Council of Australia, Wellcome Trust, Charles Darwin University Menzies School of Health Research, Channel 7 Children's Research Foundation, and National Health Institute.

Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[18F]FDF) targets the fructose-preferred facilitative hexose transporter GLUT5, which is expressed predominantly in brain microglia and activated in response to inflammatory stimuli. We hypothesize that 6-[18F]FDF will specifically image microglia following neuroinflammatory insult. 6-[18F]FDF and, for comparison, [18F]FDG were evaluated in unilateral intra-striatal lipopolysaccharide (LPS)-injected male and female rats (50 µg/animal) by longitudinal dynamic PET imaging in vivo. In LPS-injected rats, increased accumulation of 6-[18F]FDF was observed at 48 h post-LPS injection, with plateaued uptake (60–120 min) that was significantly higher in the ipsilateral vs. contralateral striatum (0.985 ± 0.047 and 0.819 ± 0.033 SUV, respectively; p = 0.002, n = 4M/3F). The ipsilateral–contralateral difference in striatal 6-[18F]FDF uptake expressed as binding potential (BPSRTM) peaked at 48 h (0.19 ± 0.11) and was significantly decreased at one and two weeks. In contrast, increased [18F]FDG uptake in the ipsilateral striatum was highest at one week post-LPS injection (BPSRTM = 0.25 ± 0.06, n = 4M). Iba-1 and GFAP immunohistochemistry confirmed LPS-induced activation of microglia and astrocytes, respectively, in ipsilateral striatum. This proof-of-concept study revealed an early response of 6-[18F]FDF to neuroinflammatory stimuli in rat brain. 6-[18F]FDF represents a potential PET radiotracer for imaging microglial GLUT5 density in brain with applications in neuroinflammatory and neurodegenerative diseases.

Designing organic thermoelectric materials with high electrical conductivity and Seebeck coefficient is challenging due to the direct relationship between these two properties. Here, the authors explore the role of dopant spatial distribution on thermoelectric performance in conjugated polymers.

Abstract Background The Scalidophora (Kinorhyncha, Loricifera and Priapulida) have an important phylogenetic position as early branching ecdysozoans, yet the architecture of their nervous organ systems is notably underinvestigated. Without such information, and in the absence of a stable phylogenetic context, we are inhibited from producing adequate hypotheses about the evolution and diversification of ecdysozoan nervous systems. Here, we utilize confocal laser scanning microscopy to characterize serotonergic, tubulinergic and FMRFamidergic immunoreactivity patterns in a comparative neuroanatomical study with three species of Echinoderes, the most speciose, abundant and diverse genus within Kinorhyncha. Results Neuroanatomy in Echinoderes as revealed by acetylated α-tubulin immunoreactivity includes a circumpharyngeal brain and ten neurite bundles in the head region that converge into five longitudinal nerves within the trunk. The ventral nerve cord is ganglionated, emerging from the brain with two connectives that converge in trunk segments 2–3, and diverge again within segment 8. The longitudinal nerves and ventral nerve cord are connected by two transverse neurites in segments 2–9. Differences among species correlate with the number, position and innervation of cuticular structures along the body. Patterns of serotoninergic and FMRFamidergic immunoreactivity correlate with the position of the brain neuropil and the ventral nerve cord. Distinct serotonergic and FMRFamidergic somata are associated with the brain neuropil and specific trunk segments along the ventral nerve cord. Conclusions Neural architecture is highly conserved across all three species, suggesting that our results reveal a pattern that is common to more than 40% of the species within Kinorhyncha. The nervous system of Echinoderes is segmented along most of the trunk; however, posterior trunk segments exhibit modifications that are likely associated with sensorial, motor or reproductive functions. Although all kinorhynchs show some evidence of an externally segmented trunk, it is unclear whether external segmentation matches internal segmentation of nervous and muscular organ systems across Kinorhyncha, as we observed in Echinoderes. The neuroanatomical data provided in this study not only expand the limited knowledge on kinorhynch nervous systems but also establish a comparative morphological framework within Scalidophora that will support broader inferences about the evolution of neural architecture among the deepest branching lineages of the Ecdysozoa.

Antibodies against Plasmodium falciparum merozoites that fix complement can inhibit blood-stage replication. Here, Reiling et al. show that complement-fixing antibodies strongly correlate with protective immunity in children, identify the merozoite targets, and predict antigen combinations that should result in strong protection.

Introduction Sex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methods This is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.Results ILS resulted in significantly higher increases (postmenopausal women: p

Abstract Objectives Malaria, caused by Plasmodium infection, remains a major global health problem. Monocytes are integral to the immune response, yet their transcriptional and functional responses in primary Plasmodium falciparum infection and in clinical malaria are poorly understood. Methods The transcriptional and functional profiles of monocytes were examined in controlled human malaria infection with P. falciparum blood stages and in children and adults with acute malaria. Monocyte gene expression and functional phenotypes were examined by RNA sequencing and flow cytometry at peak infection and compared to pre‐infection or at convalescence in acute malaria. Results In subpatent primary infection, the monocyte transcriptional profile was dominated by an interferon (IFN) molecular signature. Pathways enriched included type I IFN signalling, innate immune response and cytokine‐mediated signalling. Monocytes increased TNF and IL‐12 production upon in vitro toll‐like receptor stimulation and increased IL‐10 production upon in vitro parasite restimulation. Longitudinal phenotypic analyses revealed sustained significant changes in the composition of monocytes following infection, with increased CD14+CD16− and decreased CD14−CD16+ subsets. In acute malaria, monocyte CD64/FcγRI expression was significantly increased in children and adults, while HLA‐DR remained stable. Although children and adults showed a similar pattern of differentially expressed genes, the number and magnitude of gene expression change were greater in children. Conclusions Monocyte activation during subpatent malaria is driven by an IFN molecular signature with robust activation of genes enriched in pathogen detection, phagocytosis, antimicrobial activity and antigen presentation. The greater magnitude of transcriptional changes in children with acute malaria suggests monocyte phenotypes may change with age or exposure.

Families of quasiracemic materials constructed from 3- and 4-substituted chiral diarylamide molecular frameworks were prepared, where the imposed functional group differences systematically varied from H to CF3–9 unique components for each isomeric framework. Cocrystallization from the melt via hot stage thermomicroscopy using all possible racemic and quasiracemic combinations probed the structural boundaries of quasiracemate formation. The crystal structures and lattice energies (differential scanning calorimetry and lattice energy calculations) for many of these systems showed that quasienantiomeric components organize with near inversion symmetry and lattice energetics closely resembling those found in the racemic counterparts. This study also compared the shape space of pairs of quasienantiomers using an in silico alignment-based method to approximate the differences in molecular shape and provide a diagnostic tool for quasiracemate prediction. Comparing these results to our recent report on related 2-substituted diarylamide quasiracemates shows that functional group position can have a marked effect on quasiracemic behavior and provide critical insight to a more complete shape space, essential for defining molecular recognition processes.

The thermal and radiation stability of free-standing ceramic nanoparticles that are under consideration as potential fillers for the improved thermal and radiation stability of polymeric matrices were investigated by a set of transmission electron microscopy (TEM) studies. A series of lanthanide-doped ceria (Ln:CeOx; Ln = Nd, Er, Eu, Lu) nanocubes/nanoparticles was characterized as synthesized prior to inclusion into the polymers. The Ln:CeOx were synthesized from different solution precipitation (oleylamine (ON), hexamethylenetetramine (HMTA) and solvothermal (t-butylamine (TBA)) routes. The dopants were selected to explore the impact that the cation has on the final properties of the resultant nanoparticles. The baseline CeOx and the subsequent Ln:CeOx particles were isolated as: (i) ON-Ce (not applicable), Nd (34.2 nm), Er (27.8 nm), Eu (42.4 nm), and Lu (287.4 nm); (ii) HMTA-Ce (5.8 nm), Nd (6.6 nm), Er (370.0 nm), Eu (340.6 nm), and Lu (287.4 nm); and (iii) TBA-Ce (4.1 nm), Nd (5.0 nm), Er (3.8 nm), Eu (7.3 nm), and Lu (3.8 nm). The resulting Ln:CeOx nanomaterials were characterized using a variety of analytical tools, including: X-ray fluorescence (XRF), powder X-ray diffraction (pXRD), TEM with selected area electron diffraction (SAED), and energy dispersive X-ray spectroscopy (EDS) for nanoscale elemental mapping. From these samples, the Eu:CeOx (ON, HMTA, and TBA) series were selected for stability studies due to the uniformity of the nanocubes. Through the focus on the nanoparticle properties, the thermal and radiation stability of these nanocubes were determined through in situ TEM heating and ex situ TEM irradiation. These results were coupled with data analysis to calculate the changes in size and aerial density. The particles were generally found to exhibit strong thermal stability but underwent amorphization as a result of heavy ion irradiation at high fluences.

Abstract Background Atopic eczema (AE) is a common skin problem that impairs quality of life and is associated with the development of other atopic diseases including asthma, food allergy and allergic rhinitis. AE treatment is a significant cost burden for health care providers. The purpose of the trial is to investigate whether daily application of emollients for the first year of life can prevent AE developing in high-risk infants (first-degree relative with asthma, AE or allergic rhinitis). Methods This is a protocol for a pragmatic, two-arm, randomised controlled, multicentre trial. Up to 1400 term infants at high risk of developing AE will be recruited through the community, primary and secondary care in England. Participating families will be randomised in a 1:1 ratio to receive general infant skin-care advice, or general skin-care advice plus emollients with advice to apply daily to the infant for the first year of life. Families will not be blinded to treatment allocation. The primary outcome will be a blinded assessment of AE at 24 months of age using the UK Working Party Diagnostic Criteria for Atopic Eczema. Secondary outcomes are other definitions of AE, time to AE onset, severity of AE (EASI and POEM), presence of other allergic diseases including food allergy, asthma and hay fever, allergic sensitisation, quality of life, cost-effectiveness and safety of the emollients. Subgroup analyses are planned for the primary outcome according to filaggrin genotype and the number of first-degree relatives with AE and other atopic diseases. Families will be followed up by online and postal questionnaire at 3, 6, 12 and 18 months with a face-to-face visit at 24 months. Long-term follow-up until 60 months will be via annual questionnaires. Discussion This trial will demonstrate whether skin-barrier enhancement through daily emollient for the first year of life can prevent AE from developing in high-risk infants. If effective, this simple and cheap intervention has the potential to result in significant cost savings for health care providers throughout the world by preventing AE and possibly other associated allergic diseases. Trial registration ISRCTN registry; ID: ISRCTN21528841 . Registered on 25 July 2014.

Machine learning (ML) algorithms have found increasing utility in the medical imaging field and numerous applications in the analysis of digital biomarkers within positron emission tomography (PET) imaging have emerged. Interest in the use of artificial intelligence in PET imaging for the study of neurodegenerative diseases and oncology stems from the potential for such techniques to streamline decision support for physicians providing early and accurate diagnosis and allowing personalized treatment regimens. In this review, the use of ML to improve PET image acquisition and reconstruction is presented, along with an overview of its applications in the analysis of PET images for the study of Alzheimer's disease and oncology.

The development of effective malaria vaccines remains a global health priority. Currently, the most advanced vaccine, known as RTS,S, has only shown modest efficacy in clinical trials. Thus, the development of more efficacious vaccines by improving the formulation of RTS,S for increased efficacy or to interrupt malaria transmission are urgently needed. The RTS,S vaccine is based on the presentation of a fragment of the sporozoite antigen on the surface of virus-like particles (VLPs) based on human hepatitis B virus (HBV). In this study, we have developed and evaluated a novel VLP platform based on duck HBV (known as Metavax) for malaria vaccine development. This platform can incorporate large and complex proteins into VLPs and is produced in a Hansenula cell line compatible with cGMP vaccine production. Here, we have established the expression of leading P. falciparum malaria vaccine candidates as VLPs. This includes Pfs230 and Pfs25, which are candidate transmission-blocking vaccine antigens. We demonstrated that the VLPs effectively induce antibodies to malaria vaccine candidates with minimal induction of antibodies to the duck-HBV scaffold antigen. Antibodies to Pfs230 also recognised native protein on the surface of gametocytes, and antibodies to both Pfs230 and Pfs25 demonstrated transmission-reducing activity in standard membrane feeding assays. These results establish the potential utility of this VLP platform for malaria vaccines, which may be suitable for the development of multi-component vaccines that achieve high vaccine efficacy and transmission-blocking immunity.

When immobile or neuropathic patients are supported by beds or chairs, their soft tissues undergo deformations that can cause pressure ulcers. Current support surfaces that redistribute under-body pressures at vulnerable body sites have not succeeded in reducing pressure ulcer prevalence. Here we show that adding a supporting lateral pressure can counter-act the deformations induced by under-body pressure, and that this 'pressure equalisation' approach is a more effective way to reduce ulcer-inducing deformations than current approaches based on redistributing under-body pressure. A finite element model of the seated pelvis predicts that applying a lateral pressure to the soft tissue reduces peak von Mises stress in the deep tissue by a factor of 2.4 relative to a standard cushion (from 113 kPa to 47 kPa)-a greater effect than that achieved by using a more conformable cushion, which reduced von Mises stress to 75 kPa. Combining both a conformable cushion and lateral pressure reduced peak von Mises stresses to 25 kPa. The ratio of peak lateral pressure to peak under-body pressure was shown to regulate deep tissue stress better than under-body pressure alone. By optimising the magnitude and position of lateral pressure, tissue deformations can be reduced to that induced when suspended in a fluid. Our results explain the lack of efficacy in current support surfaces and suggest a new approach to designing and evaluating support surfaces: ensuring sufficient lateral pressure is applied to counter-act under-body pressure.