Notes

Computational study new all-natural substance agonists of dopamine receptor.
Despite strong evidence that it is efficacious, chemoprevention has been underused in eligible women. Reasons offered not to adopt and initiate strategies to reduce the risk of breast cancer include the fear of adverse effects, medication costs, lack of reasonably accurate and feasible methods for assessing an individual's personal risk, and lack of established risk thresholds that maximize benefit and minimize harms. The article by Macdonald and colleagues remind us that the problem of lack of uptake of risk-reducing medications for breast cancer remains a worldwide clinical challenge despite endorsements from national and international organizations that recommend the use of risk-reducing medications for breast cancer with level I evidence. Several strategies are suggested to improve uptake and utilization of safe and effective chemoprevention medications with high therapeutic indices.See related article by Macdonald et al., p. xxx.
To assess the accuracy of the AbC-19 Rapid Test lateral flow immunoassay for the detection of previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Test accuracy study.

Laboratory based evaluation.

2847 key workers (healthcare staff, fire and rescue officers, and police officers) in England in June 2020 (268 with a previous polymerase chain reaction (PCR) positive result (median 63 days previously), 2579 with unknown previous infection status); and 1995 pre-pandemic blood donors.

AbC-19 sensitivity and specificity, estimated using known negative (pre-pandemic) and known positive (PCR confirmed) samples as reference standards and secondly using the Roche Elecsys anti-nucleoprotein assay, a highly sensitive laboratory immunoassay, as a reference standard in samples from key workers.

Test result bands were often weak, with positive/negative discordance by three trained laboratory staff for 3.9% of devices. Using consensus readings, for known positive and negative samples sef the tested population have had SARS-CoV-2 infection, around one in five key workers testing positive with AbC-19 would be false positives.

ISRCTN 56609224.
ISRCTN 56609224.
To evaluate the Edinburgh Postnatal Depression Scale (EPDS) for screening to detect major depression in pregnant and postpartum women.

Individual participant data meta-analysis.

Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, and Web of Science (from inception to 3 October 2018).

Eligible datasets included EPDS scores and major depression classification based on validated diagnostic interviews. Bivariate random effects meta-analysis was used to estimate EPDS sensitivity and specificity compared with semi-structured, fully structured (Mini International Neuropsychiatric Interview (MINI) excluded), and MINI diagnostic interviews separately using individual participant data. One stage meta-regression was used to examine accuracy by reference standard categories and participant characteristics.

Individual participant data were obtained from 58 of 83 eligible studies (70%; 15 557 of 22 788 eligible participants (68%), 2069 with major depression). Combined sensitivity and specificitSPERO (CRD42015024785).
PROSPERO (CRD42015024785).The capacity for sensory systems to encode relevant information that is invariant to many stimulus changes is central to normal, real-world, cognitive function. This invariance is thought to be reflected in the complex spatiotemporal activity patterns of neural populations, but our understanding of population-level representational invariance remains coarse. Applied topology is a promising tool to discover invariant structure in large datasets. Here, we use topological techniques to characterize and compare the spatiotemporal pattern of coactive spiking within populations of simultaneously recorded neurons in the secondary auditory region caudal medial neostriatum of European starlings (Sturnus vulgaris). We show that the pattern of population spike train coactivity carries stimulus-specific structure that is not reducible to that of individual neurons. We then introduce a topology-based similarity measure for population coactivity that is sensitive to invariant stimulus structure and show that this measure captures invariant neural representations tied to the learned relationships between natural vocalizations. This demonstrates one mechanism whereby emergent stimulus properties can be encoded in population activity, and shows the potential of applied topology for understanding invariant representations in neural populations.SIGNIFICANCE STATEMENT Information in neural populations is carried by the temporal patterns of spikes. We applied novel mathematical tools from the field of algebraic topology to quantify the structure of these temporal patterns. We found that, in a secondary auditory region of a songbird, these patterns reflected invariant information about a learned stimulus relationship. These results demonstrate that topology provides a novel approach for characterizing neural responses that is sensitive to invariant relationships that are critical for the perception of natural stimuli.Loss of auditory-nerve (AN) afferent cochlear innervation is a prevalent human condition that does not affect audiometric thresholds and therefore remains largely undetectable with standard clinical tests. AN loss is widely expected to cause hearing difficulties in noise, known as "hidden hearing loss," but support for this hypothesis is controversial. Here, we used operant conditioning procedures to examine the perceptual impact of AN loss on behavioral tone-in-noise (TIN) sensitivity in the budgerigar (Melopsittacus undulatus; of either sex), an avian animal model with complex hearing abilities similar to humans. Bilateral kainic acid (KA) infusions depressed compound AN responses by 40-70% without impacting otoacoustic emissions or behavioral tone sensitivity in quiet. Surprisingly, animals with AN damage showed normal thresholds for tone detection in noise (0.1 ± 1.0 dB compared to control animals; mean difference ± SE), even under a challenging roving-level condition with random stimulus variation acrossl tone sensitivity in noise. Surprisingly, AN-lesioned animals showed no difference in hearing performance in noise or detection strategy compared with controls. These results show that perceptual deficits from AN damage are smaller than generally expected, and potentially minor compared with those caused by sensorineural hearing loss (SNHL).The classical role of Vitellogenin (Vg) is providing energy reserves for developing embryos, but its roles appear to extend beyond this nutritional function, and its importance in host immune defense is garnering increasing research attention. However, Vg-regulated immunological functions are dependent on three different domains within different species and remain poorly understood. In the present study, we confirmed three conserved VG domains - LPD_N, DUF1943 and VWD - in the Chinese mitten crab (Eriocheir sinensis), highlighting functional similarities of Vg in vertebrates and invertebrates. Of these three domains, DUF1943 and VWD showed definitive bacterial binding activity via interaction with the signature components on microbial surfaces, but this activity was s not exhibited by the LPD_N domain. Antibacterial assays indicated that only the VWD domain inhibits bacterial proliferation, and this function may be conserved between different species due to the conserved amino acid residues. To further explore the relationship between Vg and polymeric immunoglobulin receptor (pIgR), we expressed EspIgR and the three Eriocheir sinensis-Vg (EsVg) domains in HEK293T cells, and co-immunoprecipitation assay demonstrated that only the DUF1943 domain interacts with EspIgR. Subsequent experiments demonstrated that EsVg regulates hemocyte phagocytosis by binding with EspIgR through the DUF1943 domain, thus promoting bacterial clearance and protecting the host from bacterial infection. To the best of our knowledge, our work is the first to report distinct domains in Vg inducing different immunological outcomes in invertebrates, providing new evidence that pIgR acts as a phagocytic receptor for Vg.The tumor microenvironment (TME) promotes tumor development via complex intercellular signaling, aiding tumor growth and suppressing immunity. Eph receptors (Eph) and their ephrin ligands control cell interactions during normal development, and reemerge in tumors and the TME, where they are implicated in invasion, metastasis, and angiogenesis. Recent studies also indicate roles for Ephs in suppressing immune responses by controlling tumor interactions with innate and adaptive immune cells within the TME. Accordingly, inhibiting these functions can promote immune response and efficacy of immune checkpoint inhibition. This research highlights Ephs as potential targets to enhance efficacy of immune-based therapies in patients with cancer.New treatments are needed to address persistent unmet clinical needs for diffuse large B-cell lymphoma (DLBCL). Overexpression of transferrin receptor 1 (TFR1) is common across cancer and permits cell-surface targeting of specific therapies in preclinical and clinical studies of various solid tumors. Here, we developed novel nanocarrier delivery of chemotherapy via TFR1-mediated endocytosis, assessing this target for the first time in DLBCL. Analysis of published datasets showed novel association of increased TFR1 expression with high-risk DLBCL cases. Carbon-nitride dots (CND) are emerging nanoparticles with excellent in vivo stability and distribution and are adaptable to covalent conjugation with multiple substrates. In vitro, linking doxorubicin (Dox) and transferrin (TF) to CND (CND-Dox-TF, CDT) was 10-100 times more potent than Dox against DLBCL cell lines. Gain- and loss-of-function studies and fluorescent confocal microscopy confirmed dependence of these effects on TFR1-mediated endocytosis. In contrast with previous therapeutics directly linking Dox and TF, cytotoxicity of CDT resulted from nuclear entry by Dox, promoting double-stranded DNA breaks and apoptosis. CDT proved safe to administer in vivo, and when incorporated into standard frontline chemoimmunotherapy in place of Dox, it improved overall survival by controlling patient-derived xenograft tumors with greatly reduced host toxicities. Nanocarrier-mediated Dox delivery to cell-surface TFR1, therefore, warrants optimization as a potential new therapeutic option in DLBCL. buy LC-2 SIGNIFICANCE Targeted nanoparticle delivery of doxorubicin chemotherapy via the TRF1 receptor presents a new opportunity against high-risk DLBCL tumors using potency and precision.
System learning from major incidents is a crucial element of improving preparedness for response to any future incidents. Sharing good practice and limitations stimulates further actions to improve preparedness and prevents duplicating mistakes.

This convergent parallel mixed methods study comprises data from responses to an online survey and individual interviews with healthcare staff who took part in the responses to three terrorist incidents in the UK in 2017 (Westminster Bridge attack, Manchester Arena Bombing and London Bridge attack) to understand limitations in the response and share good practices.

The dedication of NHS staff, staff availability and effective team work were the most frequently mentioned enabling factors in the response. Effective coordination between teams and a functional major incident plan facilitated an effective response. Rapid access to blood products, by positioning the blood bank in the ED, treating children and parents together and sharing resources between trauma centres were recognised as very effective innovative practices.
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