Ethnic and age differences in right-left breast asymmetry in a large population-based screening population

OBJECTIVE: Exposure to sex hormones is important in the pathogenesis of breast cancer and inability to tolerate such exposure may be reflected in increased asymmetrical growth of the breasts. This study aims to characterize, for the first time, asymmetry in breast volume (BV) and radiodense volume (DV) in a large ethnically diverse population. METHODS: Automated measurements from digital raw mammographic images of 54,591 cancer-free participants (aged 47-73) in a UK breast screening programme were used to calculate absolute (cm3) and relative asymmetry in BV and DV. Logistic regression models were fitted to assess asymmetry associations with age and ethnicity. RESULTS: BV and DV absolute asymmetry were positively correlated with the corresponding volumetric dimension (BV or DV). BV absolute asymmetry increased, whilst DV absolute asymmetry decreased, with increasing age (P-for-linear-trend <0.001 for both). Relative to Whites, Blacks had statistically significantly higher, and Chinese lower, BV and DV absolute asymmetries. However, after adjustment for the corresponding underlying volumetric dimension the age and ethnic differences were greatly attenuated. Median relative (fluctuating) BV and DV asymmetry were 2.34 and 3.28% respectively. CONCLUSION: After adjusting for the relevant volumetric dimension (BV or DV), age and ethnic differences in absolute breast asymmetry were largely resolved. ADVANCES IN KNOWLEDGE: Previous small studies have reported breast asymmetry-breast cancer associations. Automated measurements of asymmetry allow the conduct of large-scale studies to further investigate these associations

To what extent are objectively measured mammographic imaging techniques associated with compression outcomes

OBJECTIVE: To describe the association between objectively measurable imaging techniques and the resulting compression thickness and dose. METHODS: The study included 80,495 routine screens from the South-West London Breast Screening Service between March 2013 and July 2017. Average compression force, paddle tilt and dose were calculated. The Volpara® DensityTM algorithm was used to estimate pressure, breast volume and density.Linear regression models, using generalized estimating equations (GEEs) to account for clustering by practitioner, assessed the strength of the associations between the imaging compression outcomes, (thickness, dose) and imaging techniques (force, pressure and paddle tilt), adjusting for the subject's characteristics (age, ethnicity, breast volume and percent mammographic density). RESULTS: Fully adjusted linear regression models showed that compression thickness decreased by ~1 mm (~2% of mean thickness) for every 1daN increase in force and decreased by ~0.8 mm with an increase of 1 kPa of pressure (at median pressure). Increasing pressure above 15 kPa resulted in minimal reduction in thickness. Dose increased with increased force but decreased by ~1% of mean dose with every increase in 1 kPa of pressure. For 1o increase in paddle tilt, the compression thickness increased by ~1.5 mm (~2.5%) and dose increased by ~2.5%, (Pt <0.001 in all cases). CONCLUSION: Differences in imaging technique are associated with imaging outcome measures (thickness and dose). A better understanding of the association between objective image acquisition parameters and tumour conspicuity could lead to clearer guidelines for practitioners. ADVANCES IN KNOWLEDGE: Increased paddle tilt is associated with increased compression thickness and increased dose after adjustment for breast volume and force applied

A diffuse reflectance comparative study of benzil inclusion within microcrystalline cellulose and beta-cyclodextrin

Diffuse reflectance and laser-induced techniques were used to study photochemical and photophysical processes of benzil adsorbed on two solid powdered supports, microcrystalline cellulose and beta-cyclodextrin. In both substrates, a distribution of ground-state benzil conformers exists, largely dominated by skew conformations where the carbonyl groups are twisted one to the other. Room temperature phosphorescence was observed in air-equilibrated samples in both cases. The decay times vary greatly and the largest lifetime was obtained for benzil/beta-cyclodextrin, showing that this host's cavity accommodates benzil well, enhancing its room temperature phosphorescence. Triplet - triplet absorption of benzil entrapped in cellulose was detected and benzil ketyl radical formation also occurred. With benzil included into beta-cyclodextrin, and following laser excitation, benzoyl radicals were detected on the millisecond timescale. Product analysis and identification of laser-irradiated benzil samples in the two hosts clearly showed that the main degradation photoproducts were benzoic acid and benzaldehyde. The main differences were a larger benzoic acid/benzaldehyde ratio in the case of cellulose and the formation of benzyl alcohol in this support

The Impact of Rainfall Variability on Diets and Undernutrition of Young Children in Rural Burkina Faso

Background: Climate change and consequent increases in rainfall variability may have negative consequences for the food production of subsistence farmers in West Africa with adverse impacts on nutrition and health. We explored the pathway from rainfall through diet up to child undernutrition for rural Burkina Faso. Methods: The study used data of a dynamic cohort with 1,439 children aged 7-60 months from the Nouna Health and Demographic Surveillance Site (HDSS) for 2017 to 2019. We assessed data on diets, height, weight, household characteristics, and daily precipitation (from 1981 to 2019). Principal component analysis was used to identify distinct child dietary patterns (Dietary Pattern Scores, DPS). These were related to 15 rainfall indicators by area to obtain a precipitation variability score (PVS) through reduced rank regression (RRR). Associations between the PVS and anthropometric measures, height-for-age (HAZ), and weight-for-height (WHZ), were examined using multi-level regression analysis. Results: Stunting (HAZ < -2) and wasting (WHZ < -2) were seen in 24 and 6% of the children. Three main dietary patterns were identified (market-based, vegetable-based, and legume-based diets) and showed mixed evidence for associations with child undernutrition. The RRR-derived PVS explained 14% of the total variance in these DPS. The PVS was characterized by more consecutive dry days during the rainy season, higher cumulative rainfall in July and more extremely wet days. A 1-point increase in the PVS was associated with a reduction of 0.029 (95% CI: -0.06, 0.00, p < 0.05) in HAZ in the unadjusted, and an increase by 0.032 (95% CI: 0.01, 0.06, p < 0.05) in WHZ in the fully adjusted model. Conclusion: Rainfall variability was associated with dietary patterns in young children of a rural population of Burkina Faso. Increased rainfall variability was associated with an increase in chronic undernutrition, but not in acute undernutrition among young children

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Malaria remains a major global health problem. Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Here we explore the potential of the aminoacyl-tRNA synthetase (ARS) family as a source of antimalarial drug targets. First, a battery of known and novel ARS inhibitors was tested against Plasmodium falciparum cultures, and their activities were compared. Borrelidin, a natural inhibitor of threonyl-tRNA synthetase (ThrRS), stands out for its potent antimalarial effect. However, it also inhibits human ThrRS and is highly toxic to human cells. To circumvent this problem, we tested a library of bioengineered and semisynthetic borrelidin analogs for their antimalarial activity and toxicity. We found that some analogs effectively lose their toxicity against human cells while retaining a potent antiparasitic activity both in vitro and in vivo and cleared malaria from Plasmodium yoelii-infected mice, resulting in 100% mice survival rates. Our work identifies borrelidin analogs as potent, selective, and unexplored scaffolds that efficiently clear malaria both in vitro and in vivo.Human Frontier Science Program (Strasbourg, France) (Postdoctoral Fellowship LT000307/2013

Delivering transformative action in paediatric pain: a <i>Lancet Child &amp; Adolescent Health</i> Commission

Every infant, child, and adolescent will experience pain at times throughout their life. Childhood pain ranges from acute to chronic, and includes procedural, disease-related, breakthrough, and other types of pain. Despite its ubiquity, pain is a major challenge for individuals, families, health-care professionals, and societies. As a private mental experience, pain is often hidden and can go undiscussed or ignored. Undertreated, unrecognised, or poorly managed pain in childhood leads to important and long-lasting negative consequences that continue into adulthood, including continued chronic pain, disability, and distress. This undertreatment of pain should not continue, as there are available tools, expertise, and evidence to provide better treatment for childhood pain

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Reduced free asparagine in wheat grain resulting from a natural deletion of TaASN-B2: investigating and exploiting diversity in the asparagine synthetase gene family to improve wheat quality

Background: Understanding the determinants of free asparagine concentration in wheat grain is necessary to reduce levels of the processing contaminant acrylamide in baked and toasted wheat products. Although crop management strategies can help reduce asparagine concentrations, breeders have limited options to select for genetic variation underlying this trait. Asparagine synthetase enzymes catalyse a critical step in asparagine biosynthesis in plants and, in wheat, are encoded by five homeologous gene triads that exhibit distinct expression profiles. Within this family, TaASN2 genes are highly expressed during grain development but TaASN-B2 is absent in some varieties. Results: Natural genetic diversity in the asparagine synthetase gene family was assessed in different wheat varieties revealing instances of presence/absence variation and other polymorphisms, including some predicted to affect the function of the encoded protein. The presence and absence of TaASN-B2 was determined across a range of UK and global common wheat varieties and related species, showing that the deletion encompassing this gene was already present in some wild emmer wheat genotypes. Expression profiling confirmed that TaASN2 transcripts were only detectable in the grain, while TaASN3.1 genes were highly expressed during the early stages of grain development. TaASN-A2 was the most highly expressed TaASN2 homeologue in most assayed wheat varieties. TaASN-B2 and TaASN-D2 were expressed at similar, lower levels in varieties possessing TaASN-B2. Expression of TaASN-A2 and TaASN-D2 did not increase to compensate for the absence of TaASN-B2, so total TaASN2 expression was lower in varieties lacking TaASN-B2. Consequently, free asparagine concentrations in field-produced grain were, on average, lower in varieties lacking TaASN-B2, although the effect was lost when free asparagine accumulated to very high concentrations as a result of sulphur deficiency. Conclusions: Selecting wheat genotypes lacking the TaASN-B2 gene may be a simple and rapid way for breeders to reduce free asparagine concentrations in commercial wheat grain

A Novel Phase Variation Mechanism in the Meningococcus Driven by a Ligand-Responsive Repressor and Differential Spacing of Distal Promoter Elements

Phase variable expression, mediated by high frequency reversible changes in the length of simple sequence repeats, facilitates adaptation of bacterial populations to changing environments and is frequently important in bacterial virulence. Here we elucidate a novel phase variable mechanism for NadA, an adhesin and invasin of Neisseria meningitidis. The NadR repressor protein binds to operators flanking the phase variable tract and contributes to the differential expression levels of phase variant promoters with different numbers of repeats likely due to different spacing between operators. We show that IHF binds between these operators, and may permit looping of the promoter, allowing interaction of NadR at operators located distally or overlapping the promoter. The 4-hydroxyphenylacetic acid, a metabolite of aromatic amino acid catabolism that is secreted in saliva, induces NadA expression by inhibiting the DNA binding activity of the repressor. When induced, only minor differences are evident between NadR-independent transcription levels of promoter phase variants and are likely due to differential RNA polymerase contacts leading to altered promoter activity. Our results suggest that NadA expression is under both stochastic and tight environmental-sensing regulatory control, both mediated by the NadR repressor, and may be induced during colonization of the oropharynx where it plays a major role in the successful adhesion and invasion of the mucosa. Hence, simple sequence repeats in promoter regions may be a strategy used by host-adapted bacterial pathogens to randomly switch between expression states that may nonetheless still be induced by appropriate niche-specific signals

Mechanisms of leukocyte migration across the blood–retina barrier

Immune-mediated inflammation in the retina is regulated by a combination of anatomical, physiological and immuno-regulatory mechanisms, referred to as the blood–retina barrier (BRB). The BRB is thought to be part of the specialised ocular microenvironment that confers protection or “immune privilege” by deviating or suppressing destructive inflammation. The barrier between the blood circulation and the retina is maintained at two separate anatomical sites. These are the endothelial cells of the inner retinal vasculature and the retinal pigment epithelial cells on Bruch’s membrane between the fenestrated choroidal vessels and the outer retina. The structure and regulation of the tight junctions forming the physical barrier are described. For leukocyte migration across the BRB to occur, changes are needed in both the leukocytes themselves and the cells forming the barrier. We review how the blood–retina barrier is compromised in various inflammatory diseases and discuss the mechanisms controlling leukocyte subset migration into the retina in uveoretinitis in more detail. In particular, we examine the relative roles of selectins and integrins in leukocyte interactions with the vascular endothelium and the pivotal role of chemokines in selective recruitment of leukocyte subsets, triggering adhesion, diapedesis and migration of inflammatory cells into the retinal tissue