A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study.

BACKGROUND: Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy. FINDINGS: We performed a genome-wide association analysis in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated. CONCLUSIONS: The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

Plant-pollinator network architecture does not impact intraspecific microbiome variability.

Variation in how individuals interact with food resources can directly impact, and be affected by, their microbial interactions due to the potential for transmission. The degree to which this transmission occurs, however, may depend on the structure of forager networks, which determine the community-scale transmission opportunities. In particular, how the community-scale opportunity for transfer balances individual-scale barriers to transmission is unclear. Examining the bee-flower and bee-microbial interactions of over 1000 individual bees, we tested (1) the degree to which individual floral visits predicted microbiome composition and (2) whether plant-bee networks with increased opportunity for microbial transmission homogenized the microbiomes of bees within that network. The pollen community composition carried by bees was associated with microbiome composition at some sites, suggesting that microbial transmission at flowers occurred. Contrary to our predictions, however, microbiome variability did not differ based on transfer opportunity: bee microbiomes in asymmetric networks with high opportunity for microbial transfer were similarly variable compared to microbiomes in networks with more evenly distributed links. These findings suggest that microbial transmission at flowers is frequent enough to be observed at the community level, but that community network structure did not substantially change the dynamics of this transmission, perhaps due to filtering processes in host guts.

How school policies, strategies, and relational factors contribute to teacher victimization and school safety.

In this study, we examined how school policies and strategies (i.e., positive discipline, hardening strategies, and positive behavioral strategies) affect teacher relational factors and teacher reports of victimization and safety. Specifically, we examined the mediational roles of teacher support of student learning, maltreatment of students by teachers, and teachers' differential treatment of students in schools. Using a sample of 6643 pre-K-12th-grade teachers, path analysis results revealed that positive behavior strategies, hardening strategies, and positive discipline were indirectly associated with teacher victimization and sense of safety. Additionally, teachers' perceptions of other teachers maltreating students had the greatest contributions to their sense of safety and victimization by students. Positive discipline was directly and indirectly associated with teacher victimization and safety. Implications and directions for future studies are discussed.

Association of Breast Cancer Odds with Background Parenchymal Enhancement Quantified Using a Fully Automated Method at MRI: The IMAGINE Study.

Background Background parenchymal enhancement (BPE) at breast MRI has been associated with increased breast cancer risk in several independent studies. However, variability of subjective BPE assessments have precluded its use in clinical practice. Purpose To examine the association between fully objective measures of BPE at MRI and odds of breast cancer. Materials and Methods This prospective case-control study included patients who underwent a bilateral breast MRI examination and were receiving care at one of three centers in the United States from November 2010 to July 2017. Breast volume, fibroglandular tissue (FGT) volume, and BPE were quantified using fully automated software. Fat volume was defined as breast volume minus FGT volume. BPE extent was defined as the proportion of FGT voxels with enhancement of 20% or more. Spearman rank correlation between quantitative BPE extent and Breast Imaging Reporting and Data System (BI-RADS) BPE categories assigned by an experienced board-certified breast radiologist was estimated. With use of multivariable logistic regression, breast cancer case-control status was regressed on tertiles (low, moderate, and high) of BPE, FGT volume, and fat volume, with adjustment for covariates. Results In total, 536 case participants with breast cancer (median age, 48 years [IQR, 43-55 years]) and 940 cancer-free controls (median age, 46 years [IQR, 38-55 years]) were included. BPE extent was positively associated with BI-RADS BPE (rs = 0.54; P < .001). Compared with low BPE extent (range, 2.9%-34.2%), high BPE extent (range, 50.7%-97.3%) was associated with increased odds of breast cancer (odds ratio [OR], 1.74 [95% CI: 1.23, 2.46]; P for trend = .002) in a multivariable model also including FGT volume (OR, 1.39 [95% CI: 0.97, 1.98]) and fat volume (OR, 1.46 [95% CI: 1.04, 2.06]). The association of high BPE extent with increased odds of breast cancer was similar for premenopausal and postmenopausal women (ORs, 1.75 and 1.83, respectively; interaction P = .73). Conclusion Objectively measured BPE at breast MRI is associated with increased breast cancer odds for both premenopausal and postmenopausal women. Clinical trial registration no. NCT02301767 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bokacheva in this issue.

Astrocytic deletion of protein kinase R-like ER kinase (PERK) does not affect learning and memory in aged mice but worsens outcome from experimental stroke.

Aging is associated with cognitive decline and is the main risk factor for a myriad of conditions including neurodegeneration and stroke. Concomitant with aging is the progressive accumulation of misfolded proteins and loss of proteostasis. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and activation of the unfolded protein response (UPR). The UPR is mediated, in part, by the eukaryotic initiation factor 2α (eIF2α) kinase protein kinase R-like ER kinase (PERK). Phosphorylation of eIF2α reduces protein translation as an adaptive mechanism but this also opposes synaptic plasticity. PERK, and other eIF2α kinases, have been widely studied in neurons where they modulate both cognitive function and response to injury. The impact of astrocytic PERK signaling in cognitive processes was previously unknown. To examine this, we deleted PERK from astrocytes (AstroPERKKO ) and examined the impact on cognitive functions in middle-aged and old mice of both sexes. Additionally, we tested the outcome following experimental stroke using the transient middle cerebral artery occlusion (MCAO) model. Tests of short-term and long-term learning and memory as well as of cognitive flexibility in middle-aged and old mice revealed that astrocytic PERK does not regulate these processes. Following MCAO, AstroPERKKO had increased morbidity and mortality. Collectively, our data demonstrate that astrocytic PERK has limited impact on cognitive function and has a more prominent role in the response to neural injury.

Children endorse deterrence motivations for third-party punishment but derive higher enjoyment from compensating victims.

Children's punishment behavior may be driven by both retribution and deterrence, but the potential primacy of either motive is unknown. Moreover, children's punishment enjoyment and compensation enjoyment have never been directly contrasted. Here, British, Colombian, and Italian 7- to 11-year-old children (N = 123) operated a Justice System in which they viewed different moral transgressions in Minecraft, a globally popular video game, either face-to-face with an experimenter or over the internet. Children could respond to transgressions by punishing transgressors and compensating victims. The purpose of the system was framed in terms of retribution, deterrence, or compensation between participants. Children's performance, endorsement, and enjoyment of punishment and compensation were measured, along with their endorsement of retribution versus deterrence as punishment justifications, during and/or after justice administration. Children overwhelmingly endorsed deterrence over retribution as their punishment justification irrespective of age. When asked to reproduce the presented frame in their own words, children more reliably reproduced the deterrence frame rather than the retribution frame. Punishment enjoyment decreased while compensation enjoyment increased over time. Despite enjoying compensation more, children preferentially endorsed punishment over compensation, especially with increasing age and transgression severity. Reported deterrent justifications, superior reproduction of deterrence framing, lower enjoyment of punishment than of compensation, and higher endorsement of punishment over compensation together suggest that children felt that they ought to mete out punishment as a means to deter future transgressions. Face-to-face and internet-mediated responses were not distinguishable, supporting a route to social psychology research with primary school-aged children unable to physically visit labs.

The role of endoplasmic reticulum stress in astrocytes.

Astrocytes are glial cells that support neurological function in the central nervous system (CNS), in part, by providing structural support for neuronal synapses and blood vessels, participating in electrical and chemical transmission, and providing trophic support via soluble factors. Dysregulation of astrocyte function contributes to neurological decline in CNS diseases. Neurological diseases are highly heterogeneous but share common features of cellular stress including the accumulation of misfolded proteins. Endoplasmic reticulum (ER) stress has been reported in nearly all neurological and neurodegenerative diseases. ER stress occurs when there is an accumulation of misfolded proteins in the ER lumen and the protein folding demand of the ER is overwhelmed. ER stress initiates the unfolded protein response (UPR) to restore homeostasis by abating protein translation and, if the cell is irreparably damaged, initiating apoptosis. Although protein aggregation and misfolding in neurological disease has been well described, cell-specific contributions of ER stress and the UPR in physiological and disease states are poorly understood. Recent work has revealed a role for active UPR signaling that may drive astrocytes toward a maladaptive phenotype in various model systems. In response to ER stress, astrocytes produce inflammatory mediators, have reduced trophic support, and can transmit ER stress to other cells. This review will discuss the current known contributions and consequences of activated UPR signaling in astrocytes.

Association of contralateral breast cancer risk with mammographic density defined at higher-than-conventional intensity thresholds.

Mammographic dense area (MDA) is an established predictor of future breast cancer risk. Recent studies have found that risk prediction might be improved by redefining MDA in effect at higher-than-conventional intensity thresholds. We assessed whether such higher-intensity MDA measures gave stronger prediction of subsequent contralateral breast cancer (CBC) risk using the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based CBC case-control study of ≥1 year survivors of unilateral breast cancer diagnosed between 1990 and 2008. Three measures of MDA for the unaffected contralateral breast were made at the conventional intensity threshold ("Cumulus") and at two sequentially higher-intensity thresholds ("Altocumulus" and "Cirrocumulus") using the CUMULUS software and mammograms taken up to 3 years prior to the first breast cancer diagnosis. The measures were fitted separately and together in multivariable-adjusted logistic regression models of CBC (252 CBC cases and 271 unilateral breast cancer controls). The strongest association with CBC was MDA defined using the highest intensity threshold, Cirrocumulus (odds ratio per adjusted SD [OPERA] 1.40, 95% CI 1.13-1.73); and the weakest association was MDA defined at the conventional threshold, Cumulus (1.32, 95% CI 1.05-1.66). In a model fitting the three measures together, the association of CBC with Cirrocumulus was unchanged (1.40, 95% CI 0.97-2.05), and the lower brightness measures did not contribute to the CBC model fit. These results suggest that MDA defined at a high-intensity threshold is a better predictor of CBC risk and has the potential to improve CBC risk stratification beyond conventional MDA measures.

Does Operative Management of Epidural Abscesses Increase Healthcare Expenditures up to 1 Year After Treatment?

BACKGROUND: The incidence of spinal epidural abscesses is increasing. What is more, they are associated with high rates of morbidity and mortality. Advances in diagnostic imaging and antibiotic therapies have made earlier diagnosis and nonoperative management feasible in appropriately selected patients. Nonoperative treatment also has the advantage of lower immediate healthcare charges; however, it is unknown whether initial nonoperative care leads to higher healthcare charges long term. QUESTIONS/PURPOSES: (1) Does operative intervention generate higher charges than nonoperative treatment over the course of 1 year after the initial treatment of spinal epidural abscesses? (2) Does the treatment of spinal epidural abscesses in people who actively use intravenous drugs generate higher charges than management in people who do not? METHODS: This retrospective comparative study at two tertiary academic centers compared adult patients with spinal epidural abscesses treated operatively and nonoperatively from January 2016 through December 2017. Ninety-five patients were identified, with four excluded for lack of billing data and one excluded for concomitant intracranial abscess. Indications for operative management included new or progressive motor deficit, lack of response to nonoperative treatment including persistent or progressive systemic illness, or initial sepsis requiring urgent source control. Of the included patients, 52% (47 of 90) received operative treatment with no differences in age, gender, BMI, and Charlson comorbidity index between groups, nor any difference in 30-day all-cause readmission rate, 1-year reoperation rate, or 2-year mortality. Furthermore, 29% (26 of 90) of patients actively used intravenous drugs and were younger, with a lower BMI and lower Charlson comorbidity index, with no differences in 30-day all-cause readmission rate, 1-year reoperation rate, or 2-year mortality. Cumulative charges at the index hospital discharge and 90 days and 1 year after discharge were compared based on operative or nonoperative management and secondarily by intravenous drug use status. Medical records, laboratory results, and hospital billing data were reviewed for data extraction. Demographic factors including age, gender, region of abscess, intravenous drug use, and comorbidities were extracted, along with clinical factors such as symptoms and ambulatory function at presentation, spinal instability, intensive care unit admission, and complications. The primary outcome was charges associated with care at the index hospital discharge and 90 days and 1 year after discharge. All covariates extracted were included in this analysis using negative binomial regression that accounted for confounders and the nonparametric nature of charge data. Results are presented as an incidence rate ratio with 95% confidence intervals. RESULTS: After adjusting for demographic and clinical variables such as age, gender, BMI, ambulatory status, presence of mechanical instability, and intensive care unit admission among others, we found higher charges for the group treated with surgery compared with those treated nonoperatively at the index admission (incidence rate ratio [IRR] 1.62 [95% CI 1.35 to 1.94]; p < 0.001) and at 1 year (IRR 1.36 [95% CI 1.10 to 1.68]; p = 0.004). Adjusted analysis also showed that active intravenous drug use was also associated with higher charges at the index admission (IRR 1.57 [95% CI 1.16 to 2.14]; p = 0.004) but no difference at 1 year (IRR 1.11 [95% CI 0.79 to 1.57]; p = 0.55). CONCLUSION: Multidisciplinary teams caring for patients with spinal epidural abscesses should understand that the decreased charges associated with selecting nonoperative management during the index admission persist at 1 year with no difference in 30-day readmission rates, 1-year reoperation rates, or 2-year mortality. On the other hand, patients with active intravenous drug use have higher index admission charges that do not persist at 1 year, with no difference in 30-day readmission rates, 1-year reoperation rates, or 2-year mortality. These results suggest possible economic benefit to nonoperative management of epidural abscesses without increases in readmission or mortality rates, further tipping the scale in an evolving framework of clinical decision-making. Future studies should investigate if these economic implications are mirrored on the patient-facing side to determine whether any financial burden is shifted onto patients and their families in nonoperative management. LEVEL OF EVIDENCE: Level III, therapeutic study.

Integrating science, technology, engineering, and math (STEM) and music: Putting the arts in science, technology, engineering, arts, and math (STEAM) through acoustics.

Music is an important part of education and most students are ardent fans. However, the students are not necessarily aware of the artistic and technical details it takes to create what they hear. These details are what necessitate music and technology coming together. Part of science, technology, engineering, and math (STEM) education should be to help students appreciate the practical applications that come from each of the entities in STEM, namely, science, technology, engineering, and math. Music provides the connection of these elements with a topic that interests the students and motivates their learning. This paper outlines ways for educators to integrate music with STEM topics and put the "A" in "STEAM" (science, technology, engineering, arts, and math).

Positive school climate for school staff? The roles of administrators, staff beliefs, and school organization in high and low resource school districts.

Despite continued calls for positive school climate, school staff members are rarely included in school climate research or theories. This qualitative case study explored how socioeconomic status (SES), school districts, leadership, and school contexts combine to create school climate. Four schools were selected from a sample of positive and negative climate schools in one high and one low-SES district. Data collection involved key informant interviews and observation. District and school SES did not directly dictate the quality of climate. Organizational variables such as the principal's decisions and vision were key influences on the quality of climate for staff members. Staff members often prioritize student experiences of climate above their own experiences. School organization and the influence of the principal are critical for the quality of school climate staff members experience; these along with staff voice are critical ongoing contributions to school climate research, theory, and practice.

Race, ethnicity and risk of second primary contralateral breast cancer in the United States.

Breast cancer survivors have a high risk of a second primary contralateral breast cancer (CBC), but there are few studies of CBC risk in racial/ethnic minority populations. We examined whether the incidence and risk factors for CBC differed by race/ethnicity in the United States. Women with a first invasive Stage I-IIB breast cancer diagnosis at ages 20-74 years between 2000 and 2015 in the Surveillance, Epidemiology, and End Results Program (SEER) 18 registries were followed through 2016 for a diagnosis of invasive CBC ≥1 year after the first breast cancer diagnosis. We used cause-specific Cox proportional hazards models to test the association between race/ethnicity and CBC, adjusting for age, hormone receptor status, radiation therapy, chemotherapy and stage at first diagnosis, and evaluated the impact of contralateral prophylactic mastectomy, socioeconomic status, and insurance status on the association. After a median follow-up of 5.9 years, 9247 women (2.0%) were diagnosed with CBC. Relative to non-Hispanic (NH) White women, CBC risk was increased in NH Black women (hazard ratio = 1.44, 95% CI 1.35-1.54) and Hispanic women (1.11, 95% CI 1.02-1.20), with the largest differences among women diagnosed at younger ages. Adjustment for contralateral prophylactic mastectomy, socioeconomic status and health insurance did not explain the associations. Therefore, non-Hispanic Black and Hispanic women have an increased risk of CBC that is not explained by clinical or socioeconomic factors collected in SEER. Large studies of diverse breast cancer survivors with detailed data on treatment delivery and adherence are needed to inform interventions to reduce this disparity.

Mass-flowering monoculture attracts bees, amplifying parasite prevalence.

As the global agricultural footprint expands, it is increasingly important to address the link between the resource pulses characteristic of monoculture farming and wildlife epidemiology. To understand how mass-flowering crops impact host communities and subsequently amplify or dilute parasitism, we surveyed wild and managed bees in a monoculture landscape with varying degrees of floral diversification. We screened 1509 bees from 16 genera in sunflower fields and in non-crop flowering habitat across 200 km2 of the California Central Valley. We found that mass-flowering crops increase bee abundance. Wild bee abundance was subsequently associated with higher parasite presence, but only in sites with a low abundance of non-crop flowers. Bee traits related to higher dispersal ability (body size) and diet breadth (pollen lecty) were also positively related to parasite presence. Our results highlight the importance of non-crop flowering habitat for supporting bee communities. We suggest monoculture alone cannot support healthy bees.

The chameleon rash: a review of the polyphenotypic dermatoses of dermatomyositis.

Dermatomyositis (DM) is an autoimmune connective tissue disease that is included in the idiopathic inflammatory myopathies. Cutaneous manifestations are a prominent part of the condition: some skin signs in DM are common to most patients, while other signs are encountered infrequently. A number of features are pathognomic for DM. The demonstration of myositis-specific antibodies (MSAs) in DM has extended the ability to define phenotypic subgroups. It appears that the presence of certain MSAs confers susceptibility to specific clinical features, an association which reveals a serotype-phenotype relationship. In this review article we have provided a detailed summary of common and under-recognized cutaneous manifestations of DM.

Poplar phyllosphere harbors disparate isoprene-degrading bacteria.

The climate-active gas isoprene (2-methyl-1,3-butadiene) is released to the atmosphere in huge quantities, almost equaling that of methane, yet we know little about the biological cycling of isoprene in the environment. Although bacteria capable of growth on isoprene as the sole source of carbon and energy have previously been isolated from soils and sediments, no microbiological studies have targeted the major source of isoprene and examined the phyllosphere of isoprene-emitting trees for the presence of degraders of this abundant carbon source. Here, we identified isoprene-degrading bacteria in poplar tree-derived microcosms by DNA stable isotope probing. The genomes of isoprene-degrading taxa were reconstructed, putative isoprene metabolic genes were identified, and isoprene-related gene transcription was analyzed by shotgun metagenomics and metatranscriptomics. Gram-positive bacteria of the genus Rhodococcus proved to be the dominant isoprene degraders, as previously found in soil. However, a wider diversity of isoprene utilizers was also revealed, notably Variovorax, a genus not previously associated with this trait. This finding was confirmed by expression of the isoprene monooxygenase from Variovorax in a heterologous host. A Variovorax strain that could grow on isoprene as the sole carbon and energy source was isolated. Analysis of its genome confirmed that it contained isoprene metabolic genes with an identical layout and high similarity to those identified by DNA-stable isotope probing and metagenomics. This study provides evidence of a wide diversity of isoprene-degrading bacteria in the isoprene-emitting tree phyllosphere and greatly enhances our understanding of the biodegradation of this important metabolite and climate-active gas.

Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis.

Liver kinase B1 (LKB1) is a ubiquitously expressed kinase involved in the regulation of cell metabolism, growth, and inflammatory activation. We previously reported that a single nucleotide polymorphism in the gene encoding LKB1 is a risk factor for multiple sclerosis (MS). Since astrocyte activation and metabolic function have important roles in regulating neuroinflammation and neuropathology, we examined the serine/threonine kinase LKB1 in astrocytes in a chronic experimental autoimmune encephalomyelitis mouse model of MS. To reduce LKB1, a heterozygous astrocyte-selective conditional knockout (het-cKO) model was used. While disease incidence was similar, disease severity was worsened in het-cKO mice. RNAseq analysis identified Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched in het-cKO mice relating to mitochondrial function, confirmed by alterations in mitochondrial complex proteins and reductions in mRNAs related to astrocyte metabolism. Enriched pathways included major histocompatibility class II genes, confirmed by increases in MHCII protein in spinal cord and cerebellum of het-cKO mice. We observed increased numbers of CD4+ Th17 cells and increased neuronal damage in spinal cords of het-cKO mice, associated with reduced expression of choline acetyltransferase, accumulation of immunoglobulin-γ, and reduced expression of factors involved in motor neuron survival. In vitro, LKB1-deficient astrocytes showed reduced metabolic function and increased inflammatory activation. These data suggest that metabolic dysfunction in astrocytes, in this case due to LKB1 deficiency, can exacerbate demyelinating disease by loss of metabolic support and increase in the inflammatory environment.

Association of breast cancer with MRI background parenchymal enhancement: the IMAGINE case-control study.

BACKGROUND: Background parenchymal enhancement (BPE) on breast magnetic resonance imaging (MRI) may be associated with breast cancer risk, but previous studies of the association are equivocal and limited by incomplete blinding of BPE assessment. In this study, we evaluated the association between BPE and breast cancer based on fully blinded assessments of BPE in the unaffected breast. METHODS: The Imaging and Epidemiology (IMAGINE) study is a multicenter breast cancer case-control study of women receiving diagnostic, screening, or follow-up breast MRI, recruited from three comprehensive cancer centers in the USA. Cases had a first diagnosis of unilateral breast cancer and controls had no history of or current breast cancer. A single board-certified breast radiologist with 12 years' experience, blinded to case-control status and clinical information, assessed the unaffected breast for BPE without view of the affected breast of cases (or the corresponding breast laterality of controls). The association between BPE and breast cancer was estimated by multivariable logistic regression separately for premenopausal and postmenopausal women. RESULTS: The analytic dataset included 835 cases and 963 controls. Adjusting for fibroglandular tissue (breast density), age, race/ethnicity, BMI, parity, family history of breast cancer, BRCA1/BRCA2 mutations, and other confounders, moderate/marked BPE (vs minimal/mild BPE) was associated with breast cancer among premenopausal women [odds ratio (OR) 1.49, 95% CI 1.05-2.11; p = 0.02]. Among postmenopausal women, mild/moderate/marked vs minimal BPE had a similar, but statistically non-significant, association with breast cancer (OR 1.45, 95% CI 0.92-2.27; p = 0.1). CONCLUSIONS: BPE is associated with breast cancer in premenopausal women, and possibly postmenopausal women, after adjustment for breast density and confounders. Our results suggest that BPE should be evaluated alongside breast density for inclusion in models predicting breast cancer risk.

A large multicentre, randomized, double-blind, cross-over study in healthy volunteers to compare pharmacokinetics, pharmacodynamics and safety of a pegfilgrastim biosimilar with its US- and EU-reference biologics.

AIMS: Recombinant PEGylated human granulocyte colony-stimulating factor (pegfilgrastim) is indicated for the reduction of chemotherapy-induced neutropenia and prevention of febrile neutropenia. Biosimilar pegfilgrastim is expected to reduce the financial burden of this complication of chemotherapy. The aim of this study was to demonstrate biosimilarity between Sandoz biosimilar pegfilgrastim and its US- and EU-approved reference biologics. METHODS: Phase I, randomized, double-blind, single-dose, 3-period, 6-sequence cross-over, multicentre study to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of Sandoz biosimilar pegfilgrastim with US- and EU-references in healthy adults. RESULTS: Pharmacokinetic and pharmacodynamic similarity was demonstrated between the 3 biologics, as the 90% confidence interval for all primary pharmacokinetic and pharmacodynamic endpoint comparisons were contained within the predefined similarity margins of 0.80-1.25. Safety, immunogenicity and tolerability were also similar. CONCLUSIONS: Sandoz biosimilar pegfilgrastim demonstrated pharmacokinetic and pharmacodynamic similarity to both US- and EU-reference biologics. No meaningful differences in safety, local tolerability and immunogenicity were identified.

A Grand Challenge. 3. Unbiased Phenotypic Function of Metabolites from Australia Plants Gloriosa superba and Alangium villosum against Parkinson's Disease.

As part of a continuing research program aiming to identify chemical probes to interrogate Parkinson's disease (PD), we have investigated the Australian plants Gloriosa superba and Alangium villosum. The chemical investigations of G. superba resulted in the isolation of four new alkaloids, ß-lumicolchicosides A-C (1-3) and γ-lumicolchicoside A (4), together with four lumicolchicine derivatives (5-8) and six colchicine analogues (9-14) as known structures. The chemical investigations of A. villosum resulted in the isolation of four new benzoquinolizidine N-oxides, tubulosine Nß5-oxide (15), isotubulosine Nα5-oxide (16), 9-demethyltubulosine Nß5-oxide (17), and 9-demethylisotubulosine Nα5-oxide (18), together with five known benzoquinolizidine alkaloids (19-23). The chemical structures of the new compounds (1-4 and 15-18) were characterized unambiguously by extensive analysis of their NMR and MS data. Unbiased multidimensional profiling was used to investigate the phenotypic profiles of all of the metabolites. The results show that the lead probes have different effects on cellular organelles that are implicated in PD in patient-derived cells.

Keep your (social) distance: Pathogen concerns and social perception in the time of COVID-19.

Previous research suggests that individual differences in pathogen disgust sensitivity and social anxiety predict avoidance behavior, especially of pathogen cues, and reduced tolerance for social ambiguity. Conversely, generalized social trust is associated with approach behavior and a greater tolerance for social ambiguity. We conducted an online study (N = 1078) to test these predictions in the context of the COVID-19 global pandemic. Specifically, we assessed whether individual differences in pathogen disgust sensitivity, social anxiety and generalized social trust predicted judgments of trustworthiness, desired social distance and perceptions of sickness of target faces wearing surgical masks. Our results showed that (a) high sensitivity to pathogen disgust predicted lower judgments of trustworthiness and lower social desirability; (b) high social anxiety predicted higher perceptions of illness and lower judgments of trustworthiness; and (c) generalized social trust predicted higher judgments of trustworthiness and lower perceptions of illness of target faces. Further, we found that mask wearers were perceived as more likely to be ill, more trustworthy and more socially desirable than the same faces presented to a control group, without the surgical mask superimposed. Results are discussed in terms of perceived compliance with an emerging social norm overriding the intrinsic untrustworthiness of masked faces.