Single cell RNA sequencing of human eosinophils from nasal polyps reveals eosinophil heterogeneity in chronic rhinosinusitis tissue.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation in the United States, but the actual roles that eosinophils play in CRSwNP remain largely unclear. OBJECTIVE: To reveal the roles and heterogeneity of eosinophils in nasal polyp (NP) tissue, we performed single cell RNA sequencing (scRNA-Seq) analysis of NP tissue. METHODS: Sinonasal tissues (NP and control sinus tissue) and patient matched peripheral blood (PB) samples were obtained from 5 control patients and 5 patients with CRSwNP. Eosinophils were enriched before processing for scRNA-Seq. The gene expression profiles in eosinophils were determined by microwell-based scRNA-Seq technology (BD Rhapsody platform). We predicted the overall function of NP eosinophils by Gene Ontology (geneontology.org) enrichment and pathway analyses and confirmed expression of selected genes by flow cytometry. RESULTS: After filtering out contaminating cells, we detected 5,542 eosinophils from control PB, 3,883 eosinophils from CRSwNP PB, 101 eosinophils from control sinus tissues (not included in further analyses), and 9,727 eosinophils from NPs by scRNA-Seq. We found that 204 genes were downregulated and 354 genes upregulated in NP eosinophils compared to all PB eosinophils (>1.5-fold, Padj < .05). Upregulated genes in NP eosinophils were associated with activation, cytokine-mediated signaling, growth factor activity, NF-κB signaling, and antiapoptotic molecules. NP eosinophils displayed 4 clusters revealing potential heterogeneity of eosinophils in NP tissue. CONCLUSIONS: Elevated eosinophils in NP tissue appear to exist in several subtypes that may play important pathogenic roles in CRSwNP, in part by controlling inflammation and hyperproliferation of other cells.

SARS-CoV-2 Surveillance of Wild Mice and Rats in North American Cities.

From July 2020 to June 2021, 248 wild house mice (Mus musculus), deer mice (Peromyscus maniculatus), brown rats (Rattus norvegicus), and black rats (Rattus rattus) from Texas and Washington, USA, and British Columbia, Canada, were tested for SARS-CoV-2 exposure and infection. Two brown rats and 11 house mice were positive for neutralizing antibodies using a surrogate virus neutralization test, but negative or indeterminate with the Multiplexed Fluorometric ImmunoAssay COVID-Plex, which targets full-length spike and nuclear proteins. Oro-nasopharyngeal swabs and fecal samples tested negative by RT-qPCR, with an indeterminate fecal sample in one house mouse. Continued surveillance of SARS-CoV-2 in wild rodents is warranted.

Corrigendum: Case Series: Maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequalae of COVID (PASC).

[This corrects the article DOI: 10.3389/fmed.2023.1122529.].

Relative risks of childhood developmental vulnerabilities in three Australian communities with exposure to per- and polyfluoroalkyl substances: data linkage study.

Background: Aqueous film forming foams (AFFF) containing per- and polyfluoroalkyl substances (PFAS) caused local environmental contamination in three Australian residential areas: Katherine in the Northern Territory (NT), Oakey in Queensland (Qld) and Williamtown in New South Wales (NSW). We examined whether children who lived in these areas had higher risks of developmental vulnerabilities than children who lived in comparison areas without known contamination. Methods: All children identified in the Medicare Enrolment File-a consumer directory for Australia's universal healthcare insurance scheme-who ever lived in exposure areas, and a sample of children who ever lived in selected comparison areas, were linked to the Australian Early Development Census (AEDC). The AEDC data were available from four cycles: 2009, 2012, 2015 and 2018. For each exposure area, we estimated relative risks (RRs) of developmental vulnerability on each of five AEDC domains and a summary measure, adjusting for sociodemographic characteristics and other potential confounders. Findings: We included 2,429 children from the NT, 2,592 from Qld and 510 from NSW. We observed lower risk of developmental vulnerability in the Communication skills and general knowledge domain in Katherine (RR = 0.74, 95% confidence interval (CI) 0.57 to 0.97), and higher risks of developmental vulnerability in the same domain (RR = 1.49, 95% CI 1.18 to 1.87) and in the Physical health and wellbeing domain in Oakey (RR = 1.31, 95% CI 1.06 to 1.61). Risks of developmental vulnerabilities on other domains were not different from those in the relevant comparison areas or were uncertain due to small numbers of events. Conclusion: There was inadequate evidence for increased risks of developmental vulnerabilities in children who ever lived in three PFAS-affected areas in Australia.

The Brief Solastalgia Scale: A Psychometric Evaluation and Revision.

Witnessing degradation and loss to one's home environment can cause the negative emotional experience of solastalgia. We review the psychometric properties of the 9-item Solastalgia subscale from the Environmental Distress Scale (Higginbotham et al. (EcoHealth 3:245-254, 2006)). Using data collected from three large, independent, adult samples (N = 4229), who were surveyed soon after the 2019/20 Australian bushfires, factor analyses confirmed the scale's unidimensionality, while analyses derived from Item Response Theory highlighted the poor psychometric performance and redundant content of specific items. Consequently, we recommend a short-form scale consisting of five items. This Brief Solastalgia Scale (BSS) yielded excellent model fit and internal consistency in both the initial and cross-validation samples. The BSS and its parent version provide very similar patterns of associations with demographic, health, life satisfaction, climate emotion, and nature connectedness variables. Finally, multi-group confirmatory factor analysis demonstrated comparable construct architecture (i.e. configural, metric, and scalar invariance) across validation samples, gender categories, and age. As individuals and communities increasingly confront and cope with climate change and its consequences, understanding related emotional impacts is crucial. The BSS promises to aid researchers, decision makers, and practitioners to understand and support those affected by negative environmental change.

The effect of three years of vitamin D supplementation on erectile dysfunction: Results from the randomized placebo-controlled D-Health Trial.

BACKGROUND & AIMS: Erectile dysfunction is common among older men and has been associated with low serum 25-hydroxy vitamin D concentration. However, this association may be due to uncontrolled confounding, and there is a paucity of evidence from interventional studies. We aimed to examine the effect of vitamin D supplementation on the prevalence of erectile dysfunction, in an exploratory analysis using data from a large randomized controlled trial. METHODS: The D-Health Trial recruited Australians aged 60-84 years between January 2014 and May 2015 and randomly assigned them to supplementation with 60,000 IU of vitamin D or placebo per month for up to 5 years. Blood samples were collected annually from randomly selected participants (total N = 3943). We assessed erectile dysfunction at the end of the third year of follow-up. We used log-binomial regression to examine the effect of vitamin D on the prevalence of erectile dysfunction overall, and within sub-groups. RESULTS: Of the 11,530 men enrolled, 8920 (77.4 %) completed the erectile dysfunction question and were included in the analysis. After three years of supplementation, the mean serum 25-hydroxy vitamin D concentration was 76 nmol/L (standard deviation (SD) 24.94) in the placebo group and 106 nmol/L (SD 26.76) in the vitamin D group (p < 0.0001). The prevalence of erectile dysfunction was 58.8 % and 59.0 % in the vitamin D and placebo groups, respectively (prevalence ratio 1.00, 95 % CI 0.97, 1.03); there was no evidence of an effect of vitamin D in any subgroup analyses. CONCLUSION: Supplementing older men with vitamin D is unlikely to prevent or improve erectile dysfunction. CLINICAL TRIALS REGISTRY: (ACTRN12613000743763).

Effect of Bulky N-Dibenzofuranylmethyl Substitution on the 5-HT2 Receptor Affinity and Efficacy of a Psychedelic Phenethylamine.

The introduction of arylmethyl substituents on the amine nitrogen atom of phenethylamines and tryptamines often results in profound increases in their affinity and functional activity at 5-HT2 serotonin receptors. To probe the sensitivity of this effect to substantially larger N-substituents, ten derivatives of the well-characterized psychedelic phenethylamine 2C-B were prepared by appending different dibenzo[b,d]furylmethyl (DBFM) moieties to the basic nitrogen. The DBFM group attached to the amino group through its 1-, -2-, or 3-position decreased affinity and agonist activity at the 5-HT2A/2C receptors. Substitution through the 4-position usually favored affinity for all three 5-HT2 receptor subtypes with compound 5 exhibiting 10- and 40-fold higher affinities at the 5-HT2A and 5-HT2C receptors, respectively, but less than fourfold selectivity among the three receptor subtypes. Nevertheless, all were relatively weak partial 5-HT2AR agonists, mostly in the low micromolar range, but full or nearly full agonists at the 5-HT2C subtype as determined in a calcium mobilization assay. Molecular docking simulations suggested that the dibenzofuryl portion dives more deeply into the orthosteric binding site of the 5-HT2A than the 5-HT2C receptor, interacting with the Trp3366.48 toggle switch associated with its activation, while the phenylamine moiety lies close to the extracellular side of the receptor. In conclusion, a very bulky N-substituent on a phenethylamine 5-HT2 receptor agonist is tolerated and may increase affinity if its orientation is appropriate. However, the Gq protein-mediated potencies are generally low, with low efficacy (relative to 5-HT) at the 5-HT2A receptor, somewhat higher efficacy at the 5-HT2B subtype, and full or nearly full efficacy at the 5-HT2C subtype.

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism.

There is an increased incidence of autism among the children of women who take the anti-epileptic, mood-stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNA-seq data obtained from E12.5 fetal mouse brains 3 hours after VPA administration to the pregnant dam revealed that VPA rapidly and significantly increased or decreased the expression of approximately 7,300 genes. No significant sex differences in VPA-induced gene expression were observed. Expression of 399 autism risk genes was significantly altered by VPA as was expression of 255 genes that have been reported to play fundamental roles in fetal brain development but are not otherwise linked to autism. Expression of genes associated with intracellular signaling pathways, neurogenesis, and excitation-inhibition balance as well as synaptogenesis, neuronal fate determination, axon and dendritic development, neuroinflammation, circadian rhythms, and epigenetic modulation of gene expression was dysregulated by VPA. The goal of this study was to identify mouse genes that are: (a) significantly up- or down-regulated by VPA in the fetal brain and (b) known to be associated with autism and/or to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity and, consequently behavior, in the adult. The set of genes meeting these criteria provides potential targets for future hypothesis-driven studies to elucidate the proximal causes of errors in brain connectivity underlying neurodevelopmental disorders such as autism.

Amniotic fluid embolism: a reappraisal.

OBJECTIVES: Using cases from our own experience and from the published literature on amniotic fluid embolism (AFE), we seek to improve on existing criteria for diagnosis and discern associated risk factors. Additionally, we propose a novel theory of pathophysiology. METHODS: This retrospective case review includes eight cases of AFE from two hospital systems and 21 from the published literature. All cases were evaluated using the modified criteria for research reporting of AFE by Clark et al. in Am J Obstet Gynecol, 2016;215:408-12 as well as our proposed criteria for diagnosis. Additional clinical and demographic characteristics potentially correlated with a risk of AFE were included and analyzed using descriptive analysis. RESULTS: The incidence of AFE was 2.9 per 100,000 births, with five maternal deaths in 29 cases (17.2 %) in our series. None of the cases met Clark's criteria while all met our criteria. 62.1 % of patients were over the age of 32 years and two out of 29 women (6.9 %) conceived through in-vitro fertilization. 6.5 % of cases were complicated by fetal death. Placenta previa occurred in 13.8 %. 86.2 % of women had cesarean sections of which 52.0 % had no acute maternal indication. CONCLUSIONS: Our criteria identify more patients with AFE than others with a low likelihood of false positives. Clinical and demographic associations in our review are consistent with those previously reported. A possible relationship between cesarean birth and risk of AFE was identified using our criteria. Additionally, we propose a new hypothesis of pathophysiology.

Endotypic heterogeneity and pathogenesis in chronic rhinosinusitis.

PURPOSE OF REVIEW: This review aims to provide updates in realms of endotypic heterogeneity, pathogenesis at the molecular level, potential of biomarkers, and cutting-edge scope of biologics in CRS. RECENT FINDINGS: High-dimensional analyses, such as transcriptomes, and machine learning, have significantly enhanced CRS endotyping, uncovering diverse pathogenetic mechanisms contributing to its heterogeneity. The dynamic process of epithelial remodeling in CRS pathogenesis has gained more clarity and support as exemplified by IL-13 and oncostatin M (OSM) that are shown intricately linked to epithelial barrier dysfunction. Moreover, anti-dsDNA autoantibody, BAFF, periostin, and cystatin SN show promise as potentials biomarkers, offering diagnostic and prognostic value for CRS. SUMMARY: The identification of inflammatory molecules involved in endotype specific signaling pathways provides insights into the underlying mechanisms and verifiable biomarkers for diagnosis and prediction of disease severity. More comprehensive clinical studies should be conducted to facilitate biologics from bench to bedside in treating CRS.

Individualized aerosol medicine: Integrating device into the patient.

Pulmonary drug delivery is complex due to several challenges including disease-, patient-, and clinicians-related factors. Although many inhaled medications are available in aerosol medicine, delivering aerosolized medications to patients requires effective disease management. There is a large gap in the knowledge of clinicians who select and provide instructions for the correct use of aerosol devices. Since improper device selection, incorrect inhaler technique, and poor patient adherence to prescribed medications may result in inadequate disease control, individualized aerosol medicine is essential for effective disease management and control. The components of individualized aerosol medicine include: (1) Selecting the right device, (2) Selecting the right interface, (3) Educating the patient effectively, and (4) Increasing patient adherence to therapy. This paper reviews each of these components and provides recommendations to integrate the device and interface into the patient for better clinical outcomes.

Benefits and harms of prostate specific antigen testing according to Australian guidelines.

Guidelines for prostate specific antigen (PSA) testing in Australia recommend that men at average risk of prostate cancer who have been informed of the benefits and harms, and who decide to undergo regular testing, should be offered testing every 2 years from 50 to 69 years. This study aimed to estimate the benefits and harms of regular testing in this context. We constructed Policy1-Prostate, a discrete event microsimulation platform of the natural history of prostate cancer and prostate cancer survival, and PSA testing patterns and subsequent management in Australia. The model was calibrated to pre-PSA (before 1985) prostate cancer incidence and mortality and validated against incidence and mortality trends from 1985 to 2011 and international trials. The model predictions were concordant with trials and Australian observed incidence and mortality data from 1985 to 2011. Out of 1000 men who choose to test according to the guidelines, 36 [21-41] men will die from prostate cancer and 126 [119-133] men will be diagnosed with prostate cancer, compared with 50 [47-54] and 94 [90-98] men who do not test, respectively. During the 20 years of active PSA testing, 32.3% [25.6%-38.8%] of all PSA-test detected cancers are overdiagnosed cases that is, 30 [21-42] out of 94 [83-107] PSA-test detected cancers. Australian men choosing to test with PSA every two years from 50 to 69 will reduce their risk of ever dying from prostate cancer and incur a risk of overdiagnosis: for every man who avoids dying from prostate cancer, two will be overdiagnosed with prostate cancer between 50 and 69 years of age. Australian men, with health professionals, can use these results to inform decision-making about PSA testing.

Predictors of individual mental health and psychological resilience after Australia's 2019-2020 bushfires.

AIMS: We assessed the mental health effects of Australia's 2019-2020 bushfires 12-18 months later, predicting psychological distress and positive psychological outcomes from bushfire exposure and a range of demographic variables, and seeking insights to enhance disaster preparedness and resilience planning for different profiles of people. METHODS: We surveyed 3083 bushfire-affected and non-affected Australian residents about their experiences of bushfire, COVID-19, psychological distress (depression, anxiety, stress, post-traumatic stress disorder) and positive psychological outcomes (resilient coping, wellbeing). RESULTS: We found high rates of distress across all participants, exacerbated by severity of bushfire exposure. For people who were bushfire-affected, being older, having less financial stress, and having no or fewer pre-existing mental disorders predicted both lower distress and higher positive outcomes. Being male or having less income loss also predicted positive outcomes. Severity of exposure, higher education and higher COVID-19-related stressors predicted both higher distress and higher positive outcomes. Pre-existing physical health diagnosis and previous bushfire experience did not significantly predict distress or positive outcomes. RECOMMENDATIONS: To promote disaster resilience, we recommend investment in mental health, particularly for younger adults and for those in rural and remote areas. We also recommend investment in mechanisms to protect against financial distress and the development of a broader definition of bushfire-related impacts than is currently used to capture brushfires' far-reaching effects.

IL-13 and IL-13-induced periostin levels are specifically decreased in patients following endoscopic sinus surgery for chronic rhinosinusitis.

BACKGROUND: Type 2 (T2) inflammation plays a pathogenic role in chronic rhinosinusitis (CRS). The effects of endoscopic sinus surgery (ESS) on T2 inflammation are unknown. OBJECTIVE: The aim of this study was to compare T2 inflammatory biomarkers from middle meatal (MM) mucus for distinguishing patients with CRS from CRS-free patients, identifying major phenotypes (CRS without nasal polyps [CRSsNP] and CRS with nasal polyps [CRSwNP]), assessing endotypic change, and establishing cross-sectional and longitudinal outcomes in patients undergoing ESS. METHODS: MM mucus samples were collected from patients with CRSsNP and patients with CRSwNP before and 6 to 12 months after ESS and compared with samples from CRS-free control patients. T2 biomarkers were evaluated both continuously and using threshold-based definitions of T2 endotype to identify relationships with patient-reported (based on the 22-Item Sinonasal Outcomes Test and Chronic Rhinosinusitis Patient-Reported Outcomes Measure) and clinician-reported (radiographic and endoscopic) severity. Linear mixed models were developed to analyze clinical variables associated with T2 biomarker levels. RESULTS: A total of 154 patients with CRS (89 with CRSsNP and 65 with CRSwNP) were enrolled, with a mean interval of 9 months between ESS and follow-up. An analysis of pre-ESS MM mucus samples revealed elevated levels of T2 mediators in patients with CRSwNP versus in patients with CRSsNP and CRS-free controls. Temporally stable correlations between levels of IL-13 and IL-5, levels of periostin and complement 5a, and levels of eosinophil cationic protein (ECP) and eotaxin-3 were observed. On this basis and on the basis of pathologic significance, levels of IL-13, periostin and ECP were further analyzed. After ESS, levels of IL-13 and periostin decreased significantly, whereas ECP levels remained unchanged. Across pre- and post-ESS evaluation, the T2 endotype was associated with radiographic severity but did not predict outcomes. CRSwNP status and African American race were associated with higher levels of IL-13 and periostin, whereas ECP level was higher in patients undergoing extensive surgery. CONCLUSION: ESS decreased levels of IL-13 and periostin in the middle meatus. T2 inflammation after ESS was correlated with patient- and clinician-reported severity across phenotypes. Pre-ESS T2 inflammation did not predict post-ESS outcomes.

A Bayesian model of the jumping-to-conclusions bias and its relationship to psychopathology.

The mechanisms by which delusion and anxiety affect the tendency to make hasty decisions (Jumping-to-Conclusions bias) remain unclear. This paper proposes a Bayesian computational model that explores the assignment of evidence weights as a potential explanation of the Jumping-to-Conclusions bias using the Beads Task. We also investigate the Beads Task as a repeated measure by varying the key aspects of the paradigm. The Bayesian model estimations from two online studies showed that higher delusional ideation promoted reduced belief updating but the impact of general and social anxiety on evidence weighting was inconsistent. The altered evidence weighting as a result of a psychopathological trait appeared insufficient in contributing to the Jumping-to-Conclusions bias. Variations in Beads Task aspects significantly affected subjective certainty at the point of decisions but not the number of draws to decisions. Repetitions of the Beads Task are feasible if one assesses the Jumping-to-Conclusions bias using number of draws to decisions.

Expanding the Transuranic Metal-Organic Framework Portfolio: The Optical Properties of Americium(III) MOF-76.

Reported is the synthesis, crystal structure, and solid-state characterization of a new americium containing metal-organic framework (MOF), [Am(C9H3O6)(H2O)], MOF-76(Am). This material is constructed from Am3+ metal centers and 1,3,5-tricarboxylic acid (BTC) ligands, forming a porous three-dimensional framework that is isostructural with several known trivalent lanthanide (Ln) analogs (e.g., Ce, Nd, and Sm-Lu). The Am3+ ions have seven coordinates and assume a distorted, capped trigonal prismatic geometry with C1 symmetry. The Am3+-O bonds were studied via infrared spectroscopy and compared to several MOF-76(Ln) analogs, where Ln = Nd3+, Eu3+, Tb3+, and Ho3+. The results show that the strength of the ligand carboxylate stretching and bending modes increase with Nd3+ < Eu3+ < Am3+ < Tb3+ < Ho3+, suggesting the metal-oxygen bonds are predominantly ionic. Optical absorbance spectroscopy measurements reveal strong f-f transitions; some exhibit pronounced crystal field splitting. The photoluminescence spectrum contains weak Am3+-based emission that is achieved through direct and indirect metal center excitation. The weak emissive behavior is somewhat surprising given that ligand-to-metal resonance energy transfer is efficient in the isoelectronic Eu3+ (4f6) and related Tb3+ (4f8) analogs. The optical properties were explored further within a series of heterometallic MOF-76(Tb1-xAmx) (x = 0.8, 0.2, and 0.1) samples, and the results reveal enhanced Am3+ photoluminescence.

Genomic Analysis of Influenza A and B Viruses Carrying Baloxavir Resistance-Associated Substitutions Serially Passaged in Human Epithelial Cells.

Baloxavir marboxil (baloxavir) is an FDA-approved inhibitor of the influenza virus polymerase acidic (PA) protein. Here, we used next-generation sequencing to compare the genomic mutational profiles of IAV H1N1 and H3N2, and IBV wild type (WT) and mutants (MUT) viruses carrying baloxavir resistance-associated substitutions (H1N1-PA I38L, I38T, and E199D; H3N2-PA I38T; and IBV-PA I38T) during passaging in normal human bronchial epithelial (NHBE) cells. We determined the ratio of nonsynonymous to synonymous nucleotide mutations (dN/dS) and identified the location and type of amino acid (AA) substitutions that occurred at a frequency of ≥30%. We observed that IAV H1N1 WT and MUT viruses remained relatively stable during passaging. While the mutational profiles for IAV H1N1 I38L, I38T, and E199D, and IBV I38T MUTs were relatively similar after each passage compared to the respective WTs, the mutational profile of the IAV H3N2 I38T MUT was significantly different for most genes compared to H3N2 WT. Our work provides insight into how baloxavir resistance-associated substitutions may impact influenza virus evolution in natural settings. Further characterization of the potentially adaptive mutations identified in this study is needed.