Cellular anatomy of the mouse primary motor cortex.

An essential step toward understanding brain function is to establish a structural framework with cellular resolution on which multi-scale datasets spanning molecules, cells, circuits and systems can be integrated and interpreted1. Here, as part of the collaborative Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based anatomical description of one exemplar brain structure, the mouse primary motor cortex, upper limb area (MOp-ul). Using genetic and viral labelling, barcoded anatomy resolved by sequencing, single-neuron reconstruction, whole-brain imaging and cloud-based neuroinformatics tools, we delineated the MOp-ul in 3D and refined its sublaminar organization. We defined around two dozen projection neuron types in the MOp-ul and derived an input-output wiring diagram, which will facilitate future analyses of motor control circuitry across molecular, cellular and system levels. This work provides a roadmap towards a comprehensive cellular-resolution description of mammalian brain architecture.

Stem cell dynamics and cellular heterogeneity across lineage subtypes of castrate-resistant prostate cancer.

To resist lineage-dependent therapies such as androgen receptor inhibition, prostate luminal epithelial adenocarcinoma cells often adopt a stem-like state resulting in lineage plasticity and phenotypic heterogeneity. Castrate-resistant prostate adenocarcinoma can transition to neuroendocrine (NE) and occasionally to amphicrine, co-expressed luminal and NE, phenotypes. We developed castrate-resistant prostate cancer (CRPC) patient-derived organoid models that preserve heterogeneity of the originating tumor, including an amphicrine model displaying a range of luminal and NE phenotypes. To gain biological insight and to identify potential treatment targets within heterogeneous tumor cell populations, we assessed the lineage hierarchy and molecular characteristics of various CRPC tumor subpopulations. Transcriptionally similar stem/progenitor (St/Pr) cells were identified for all lineage populations. Lineage tracing in amphicrine CRPC showed that heterogeneity originated from distinct subclones of infrequent St/Pr cells that produced mainly quiescent differentiated amphicrine progeny. By contrast, adenocarcinoma CRPC progeny originated from St/Pr cells and self-renewing differentiated luminal cells. Neuroendocrine prostate cancer (NEPC) was composed almost exclusively of self-renewing St/Pr cells. Amphicrine subpopulations were enriched for secretory luminal, mesenchymal, and enzalutamide treatment persistent signatures that characterize clinical progression. Finally, the amphicrine St/Pr subpopulation was specifically depleted with an AURKA inhibitor, which blocked tumor growth. These data illuminate distinct stem cell (SC) characteristics for subtype-specific CRPC in addition to demonstrating a context for targeting differentiation-competent prostate SCs.

Reproducible preclinical models of androgen receptor driven human prostate cancer bone metastasis.

BACKGROUND: Preclinical models recapitulating the metastatic phenotypes are essential for developing the next-generation therapies for metastatic prostate cancer (mPC). We aimed to establish a cohort of clinically relevant mPC models, particularly androgen receptor positive (AR+) bone metastasis models, from LuCaP patient-derived xenografts (PDX) that reflect the heterogeneity and complexity of mPC. METHODS: PDX tumors were dissociated into single cells, modified to express luciferase, and were inoculated into NSG mice via intracardiac injection. The progression of metastases was monitored by bioluminescent imaging. Histological phenotypes of metastases were characterized by immunohistochemistry and immunofluorescence staining. Castration responses were further investigated in two AR-positive models. RESULTS: Our PDX-derived metastasis (PDM) model collection comprises three AR+ adenocarcinomas (ARPC) and one AR- neuroendocrine carcinoma (NEPC). All ARPC models developed bone metastases with either an osteoblastic, osteolytic, or mixed phenotype, while the NEPC model mainly developed brain metastasis. Different mechanisms of castration resistance were observed in two AR+ PDM models with distinct genotypes, such as combined loss of TP53 and RB1 in one model and expression of AR splice variant 7 (AR-V7) expression in another model. Intriguingly, the castration-resistant tumors displayed inter- and intra-tumor as well as organ-specific heterogeneity in lineage specification. CONCLUSION: Genetically diverse PDM models provide a clinically relevant system for biomarker identification and personalized medicine in metastatic castration-resistant prostate cancer.

Using patient-derived tumor organoids from common epithelial cancers to analyze personalized T-cell responses to neoantigens.

Adoptive cell transfer of tumor-infiltrating lymphocytes (TIL) can mediate durable complete responses in some patients with common epithelial cancers but does so infrequently. A better understanding of T-cell responses to neoantigens and tumor-related immune evasion mechanisms requires having the autologous tumor as a reagent. We investigated the ability of patient-derived tumor organoids (PDTO) to fulfill this need and evaluated their utility as a tool for selecting T-cells for adoptive cell therapy. PDTO established from metastases from patients with colorectal, breast, pancreatic, bile duct, esophageal, lung, and kidney cancers underwent whole exomic sequencing (WES), to define mutations. Organoids were then evaluated for recognition by autologous TIL or T-cells transduced with cloned T-cell receptors recognizing defined neoantigens. PDTO were also used to identify and clone TCRs from TIL targeting private neoantigens and define those tumor-specific targets. PDTO were successfully established in 38/47 attempts. 75% were available within 2 months, a timeframe compatible with screening TIL for clinical administration. These lines exhibited good genetic fidelity with their parental tumors, especially for mutations with higher clonality. Immunologic recognition assays demonstrated instances of HLA allelic loss not found by pan-HLA immunohistochemistry and in some cases WES of fresh tumor. PDTO could also be used to show differences between TCRs recognizing the same antigen and to find and clone TCRs recognizing private neoantigens. PDTO can detect tumor-specific defects blocking T-cell recognition and may have a role as a selection tool for TCRs and TIL used in adoptive cell therapy.

Interleukin-4 treatment reduces leukemia burden in acute myeloid leukemia.

Interleukin-4 (IL-4) is a signature cytokine pivotal in Type 2 helper T cell (Th2) immune response, particularly in allergy and hypersensitivity. Interestingly, IL-4 increases endogenous levels of prostaglandin D2 (PGD2 ) and its metabolites, Δ12 -prostaglandin J2 (Δ12 -PGJ2 ) and 15-deoxy-Δ12,14 -prostaglandin J2 (15d-PGJ2 ), collectively called cyclopentenone PGs (CyPGs). However, the therapeutic role of IL-4 in hematologic malignancies remains unclear. Here, we employed a murine model of acute myeloid leukemia (AML), where human MLL-AF9 fusion oncoprotein was expressed in hematopoietic progenitor cells, to test the effect of IL-4 treatment in vivo. Daily intraperitoneal treatment with IL-4 at 60 µg/kg/d significantly alleviated the severity of AML, as seen by decreased leukemia-initiating cells (LICs). The effect of IL-4 was mediated, in part, by the enhanced expression of hematopoietic- PGD2  synthase (H-PGDS) to effect endogenous production of CyPGs, through autocrine and paracrine signaling mechanisms. Similar results were seen with patient-derived AML cells cultured ex vivo with IL-4. Use of GW9662, a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, suggested endogenous CyPGs-PPARγ axis mediated p53-dependent apoptosis of LICs by IL-4. Taken together, our results reveal a beneficial role of IL-4 treatment in AML suggesting a potential therapeutic regimen worthy of clinical trials in patients with AML.

Assessment of the soluble proteins HMGB1, CD40L and CD62P during various platelet preparation processes and the storage of platelet concentrates: The BEST collaborative study.

BACKGROUND: Structural and biochemical changes in stored platelets are influenced by collection and processing methods. This international study investigates the effects of platelet (PLT) processing and storage conditions on HMGB1, sCD40L, and sCD62P protein levels in platelet concentrate supernatants (PCs). STUDY DESIGN/METHODS: PC supernatants (n = 3748) were collected by each international centre using identical centrifugation methods (n = 9) and tested centrally using the ELISA/Luminex platform. Apheresis versus the buffy coat (BC-PC) method, plasma storage versus PAS and RT storage versus cold (4°C) were investigated. We focused on PC preparation collecting samples during early (RT: day 1-3; cold: day 1-5) and late (RT: day 4-7; cold: day 7-10) storage time points. RESULTS: HMGB1, sCD40L, and sCD62P concentrations were similar during early storage periods, regardless of storage solution (BC-PC plasma and BC-PC PAS-E) or temperature. During storage and without PAS, sCD40L and CD62P in BC-PC supernatants increased significantly (+33% and +41%, respectively) depending on storage temperature (22 vs. 4°C). However, without PAS-E, levels decreased significantly (-31% and -20%, respectively), depending on storage temperature (22 vs. 4°C). Contrastingly, the processing method appeared to have greater impact on HMGB1 release versus storage duration. These data highlight increases in these parameters during storage and differences between preparation methods and storage temperatures. CONCLUSIONS: The HMGB1 release mechanism/intracellular pathways appear to differ from sCD62P and sCD40L. The extent to which these differences affect patient outcomes, particularly post-transfusion platelet increment and adverse events, warrants further investigation in clinical trials with various therapeutic indications.

Community empowerment: A concept analysis.

AIM: To report an analysis of the concept of community empowerment. DESIGN: Concept analysis. DATA SOURCES: Literature published in the CINAHL, PubMed, Scopus and Medline electronic databases from 2016 to 2022 were systematically searched from 30 July to 1 October 2022. METHOD: The amended guideline from Walker and Avant's approach (2011) to concept analysis was performed in nine stages: choosing a concept, determining the purpose of analysis, identifying definitions of the concept, defining attributes, identifying a model case, identifying antecedents, identifying consequences, defining empirical referents and applying the concept to nursing practice. RESULTS: Community empowerment is a fundamental idea in health promotion that may assist communities in defining priorities, making choices, developing strategies and executing them to improve health and minimize inequalities in health. Community empowerment is an effective tool that advanced practice nurses (APNs) may employ to eliminate health inequities and promote community health. CONCLUSION: This concept analysis is one step towards broadening nurses' understanding of one of the ideas of health promotion. Additionally, the concept of community empowerment represents an opportunity for additional research in nursing that is applicable to communities. IMPACT: Community empowerment has served as a guiding paradigm for both theory and practice in health promotion. Also, it is recognized that social, economic and environmental elements have a direct effect on health status. However, community empowerment research in advanced nursing practices is limited. This paper will guide future nursing research on community empowerment that goes beyond involvement and engagement, for this is an effective strategy APNs can use to address health disparities and improve community health.

Androgen receptor function and targeted therapeutics across breast cancer subtypes.

Despite significant progress in breast cancer (BC) therapy, it is globally the most commonly diagnosed cancer and leads to the death of over 650,000 women annually. Androgen receptor (AR) is emerging as a potential new therapeutic target in BC. While the role of AR is well established in prostate cancer (PCa), its function in BC remains incompletely understood. Emerging data show that AR's role in BC is dependent on several factors including, but not limited to, disease subtype, tumour microenvironment, and levels of circulating oestrogens and androgens. While targeting AR in PCa is becoming increasingly effective, these advances have yet to make any significant impact on the care of BC patients. However, this approach is increasingly being evaluated in BC and it is clear that improvements in our understanding of AR's role in BC will increase the likelihood of success for AR-targeted therapies. This review summarizes our current understanding of the function of AR across BC subtypes. We highlight limitations in our current knowledge and demonstrate the importance of categorizing BC subtypes effectively, in relation to determining AR activity. Further, we describe the current state of the art regarding AR-targeted approaches for BC as monotherapy or in combination with radiotherapy.

Evaluation of Commercially Available High-Throughput SARS-CoV-2 Serologic Assays for Serosurveillance and Related Applications.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurveys can estimate cumulative incidence for monitoring epidemics, requiring assessment of serologic assays to inform testing algorithm development and interpretation of results. We conducted a multilaboratory evaluation of 21 commercial high-throughput SARS-CoV-2 serologic assays using blinded panels of 1,000 highly characterized specimens. Assays demonstrated a range of sensitivities (96%-63%), specificities (99%-96%), and precision (intraclass correlation coefficient 0.55-0.99). Durability of antibody detection was dependent on antigen and immunoglobulin targets; antispike and total Ig assays demonstrated more stable longitudinal reactivity than antinucleocapsid and IgG assays. Assays with high sensitivity, specificity, and durable antibody detection are ideal for serosurveillance, but assays demonstrating waning reactivity are appropriate for other applications, including correlation with neutralizing activity and detection of anamnestic boosting by reinfections. Assay performance must be evaluated in context of intended use, particularly in the context of widespread vaccination and circulation of SARS-CoV-2 variants.

Hyperbaric treatment of platelets extends in vitro storage to 14 days.

BACKGROUND: Platelets for transfusion have a storage time of 5-7 days at 22°C-24°C, which results in a strain on the supply chain and supply shortages. We describe a novel method to extend platelet storage using xenon (Xe) gas under high pressure and refrigeration. STUDY DESIGN AND METHODS: Apheresis platelets (APU) prepared in 65% platelet additive solution (PAS) were stored under standard conditions (SC) at 20°C-24°C to Day 5. Paired APUs were prepared with Xe and stored to Day 14 at 2°C-6°C under hyperbaric conditions (XHC). A standard panel of in vitro assays was conducted. RESULTS: XHC platelets were viable out to Day 14. The average pH of Day 14 platelets was 6.58, and 86% maintained some degree of swirl compared with 7.02 and 100% swirl for Day 5 SC platelets. The rate of glycolysis was reduced under XHC storage with less glucose consumption and lactate generation. Activation levels for Day 14 platelets, while increased, did not prevent response to agonists in vitro, including epinephrine + Adenosine 5-Diphosphate (EPI/ADP) and thrombin receptor-activating peptide (TRAP) aggregation. Thromboelastogram (TEG) assessment showed 80% or greater conservation of platelet function for Day 14 xenon stored platelets compared with Day 5 SC platelets. DISCUSSION: Platelet storage with the Xe/hyperbaric/cold method is a feasible candidate for extension of storage to 14 days based on in vitro characteristics. In vivo recovery and survival studies are indicated. The capability to extend platelet storage to 14 days would make large strides toward resolving issues of platelet outdating for prophylactic use.

Cryopreservation of rare pediatric red blood cells for support following bone marrow transplant.

BACKGROUND: A 2-year-old, 10.8 kg male pediatric patient with X-linked chronic granulomatous disease (CGD) with McLeod syndrome (MLS) was scheduled for a hematopoietic stem cell transplant (HSCT). Identification of allogenic red blood cells (RBC) for post-transplant support was unsuccessful prompting the development of a customized method to collect and freeze rare autologous pediatric cells. STUDY DESIGN AND METHODS: A protocol was developed for the collection of small volume pediatric whole blood (WB) via peripheral venipuncture with collection into 10 ml syringes containing anticoagulants. Additionally, a closed system RBC glycerolization and deglycerolization instrument was adapted to process small volume, non-leukoreduced WB. Both collection and WB processes were validated. In total 4 approximately 100 ml autologous units were collected and frozen. Two units were thawed, deglycerolized, and used for clinical transfusion support. To appreciate processing impacts on RBC rigidity, ektacytometry was performed on pre-processed and post-deglycerolization samples. RESULTS: Free hemoglobin (HGB) of validation units after thawing/deglycerolization was <150 mg/dL with an average red cell recovery of 85%. These units also showed little difference between pre-and post-processing Lorrca deformability curves or membrane rigidity. Two pediatric units were thawed and deglycerolized for transfusion. Free HGB was 70 mg/dL and 50 mg/dL post-thaw, and these RBCs had a slight decrease in deformability and increased membrane rigidity. DISCUSSION: Customized WB collection, glycerolization, freezing, and deglycerolization processes were developed to successfully support a pediatric patient with CGD and MLS after autologous HSCT. Both pediatric units showed increased membrane rigidity post-deglycerolization which may be a consequence of the CGD and MLS genetic background.

Hormones, age, and sex affect platelet responsiveness in vitro.

BACKGROUND: Female sex confers a survival advantage following severe injury in the setting of trauma-induced coagulopathy, with female platelets having heightened responsiveness likely due to estrogen. The effects of testosterone on platelet biology are unknown, and platelets express both estradiol and androgen receptors on the plasma membrane. We hypothesize testosterone decreases platelet responses in vitro, and there are baseline differences in platelet function and metabolism stratified by sex/age. STUDY DESIGN AND METHODS: Apheresis platelets were collected from: older males (OM) ≥45 years, younger males (YM) <45 years, older females (OF) ≥54 years, and younger females (YF) <54 years, and testosterone and estradiol were measured. Platelets were incubated with testosterone (5.31 ng/ml), estradiol (105 pg/ml) or vehicle and stimulated with buffer, adenosine diphosphate (20 µM), platelet activating factor (2 µM), or thrombin (0.3 U/ml). Aggregation, CD62P surface expression, fibrinogen receptor surface expression, and platelet mitochondrial metabolism were measured. RESULTS: Testosterone significantly inhibited aggregation in OF and OM (p < .05), inhibited CD41a expression in YF, YM, and OM (p < .05), and affected a few of the baseline amounts of CD62P surface expression but not platelet activation to platelet-activating factor and adenosine diphosphate, and variably changed platelet metabolism. DISCUSSION: Platelets have sex- and age-specific aggregation, receptor expression, and metabolism. Testosterone decreases platelet function dependent on the stimulus, age, and sex. Similarly, platelet metabolism has varying responses to sex hormones with baseline metabolic differences dependent upon sex and age.

Safety and Biodistribution Profile of Poly(styrenyl acetal trehalose) and Its Granulocyte Colony Stimulating Factor Conjugate.

Poly(styrenyl acetal trehalose) (pSAT), composed of trehalose side chains linked to a polystyrene backbone via acetals, stabilizes a variety of proteins and enzymes against fluctuations in temperature. A promising application of pSAT is conjugation of the polymer to therapeutic proteins to reduce renal clearance. To explore this possibility, the safety of the polymer was first studied. Investigation of acute toxicity of pSAT in mice showed that there were no adverse effects of the polymer at a high (10 mg/kg) concentration. The immune response (antipolymer antibody and cytokine production) in mice was also studied. No significant antipolymer IgG was detected for pSAT, and only a transient and low level of IgM was elicited. pSAT was also safe in terms of cytokine response. The polymer was then conjugated to a granulocyte colony stimulating factor (GCSF), a therapeutic protein that is approved by the Federal Drug Administration, in order to study the biodistribution of a pSAT conjugate. A site-selective, two-step synthesis approach was developed for efficient conjugate preparation for the biodistribution study resulting in 90% conjugation efficiency. The organ distribution of GCSF-pSAT was measured by positron emission tomography and compared to controls GCSF and GCSF-poly(ethylene glycol), which confirmed that the trehalose polymer conjugate improved the in vivo half-life of the protein by reducing renal clearance. These findings suggest that trehalose styrenyl polymers are promising for use in therapeutic protein-polymer conjugates for reduced renal clearance of the biomolecule.

Myocardial protein aggregates in pet guinea pigs.

A retrospective study of guinea pigs submitted for necropsy revealed intracytoplasmic inclusions in the cardiomyocytes of 26 of 30 animals. The inclusions were found with approximately the same frequency in male and female guinea pigs and were slightly more common in older animals. In most cases, the animals did not have clinical signs or necropsy findings suggestive of heart failure, and the cause of death or reason for euthanasia was attributed to concurrent disease processes. However, the 4 guinea pigs with the highest inclusion body burden all had pulmonary edema, sometimes with intra-alveolar hemosiderin-laden macrophages, suggestive of heart failure. The inclusions were found in both the left and right ventricular myocardium, mainly in the papillary muscles, but were most common in the right ventricular free wall. No inclusions were detected in the atrial myocardium or in skeletal muscle. The inclusions did not stain with Congo red or periodic acid-Schiff. Electron microscopy revealed dense aggregates of disorganized myofilaments and microtubules that displaced and compressed the adjacent organelles. By immunohistochemistry, there was some scattered immunoreactivity for desmin and actin at the periphery of the inclusions and punctate actin reactivity within the aggregates. The inclusions did not react with antibodies to ubiquitin or cardiac myosin, but were variably reactive for alpha B crystallin, a small heat shock chaperone protein. The inclusions were interpreted as evidence of impaired proteostasis.

Myocardial Iba1, MHC class II, and CD3 are diffusely increased in canine myocarditis: A step toward antemortem myocarditis diagnostics.

Canine myocarditis is a rare but serious health concern, potentially causing heart failure and death. Antemortem diagnosis is hampered by the numerous causes, nonspecific course, and dearth of diagnostic criteria. Currently, definitive diagnosis can only be made after death. The current human diagnostic gold standard is endomyocardial biopsy pairing cardiac histopathology with immunohistology to enhance detection of often-multifocal disease. We evaluated immune response markers in the canine heart to establish similar immunohistologic criteria. We hypothesized that myocardial major histocompatibility complex class II (MHCII), cluster of differentiation 3 (CD3), and ionized calcium binding adapter molecule 1 (Iba1), markers increased in human myocarditis, would be increased in canine myocarditis cases. Archived paraffin-embedded myocardial tissue from 22 histopathologically confirmed cases of adult and juvenile myocarditis and 23 controls was analyzed by immunohistochemistry for MHCII, CD3, and Iba1, and the fraction of myocardium with labeling was determined. All 3 markers were significantly increased compared with controls across the entire section: Iba1, 10.1× (P < .0001, Mann-Whitney U test); MHCII, 3.04× (P = .0019); and CD3, 4.4× (P = .0104). To mimic off-target biopsy, samples from 2 mm2 outside of inflammatory foci were analyzed, and these showed significant increases in Iba1 by 3.2× (P = .0036, Mann-Whitney U test) and CD3 by 1.2× (P = .0026). These data show diffusely increased immune response markers with canine myocarditis, with detection potentially independent of tissue sampling. Thus, endomyocardial biopsy and immunohistochemical detection of MHCII, CD3, and Iba1 may permit sensitive antemortem diagnosis of canine myocarditis.

Hepatocyte p53 ablation induces metabolic dysregulation that is corrected by food restriction and vertical sleeve gastrectomy in mice.

P53 has been implicated in the pathogenesis of obesity and diabetes; however, the mechanisms and tissue sites of action are incompletely defined. Therefore, we investigated the role of hepatocyte p53 in metabolic homeostasis using a hepatocyte-specific p53 knockout mouse model. To gain further mechanistic insight, we studied mice under two complementary conditions of restricted weight gain: vertical sleeve gastrectomy (VSG) or food restriction. VSG or sham surgery was performed in high-fat diet-fed male hepatocyte-specific p53 wild-type and knockout littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Hepatocyte-specific p53 ablation in sham-operated ad libitum-fed mice impaired glucose homeostasis, increased body weight, and decreased energy expenditure without changing food intake. The metabolic deficits induced by hepatocyte-specific p53 ablation were corrected, in part by food restriction, and completely by VSG. Unlike food restriction, VSG corrected the effect of hepatocyte p53 ablation to lower energy expenditure, resulting in a greater improvement in glucose homeostasis compared with food restricted mice. These data reveal an important new role for hepatocyte p53 in the regulation of energy expenditure and body weight and suggest that VSG can improve alterations in energetics associated with p53 dysregulation.

SARS-CoV-2 antibody persistence in COVID-19 convalescent plasma donors: Dependency on assay format and applicability to serosurveillance.

BACKGROUND: Antibody response duration following severe acute respiratory syndrome coronavirus 2 infection tends to be variable and depends on severity of disease and method of detection. STUDY DESIGN AND METHODS: COVID-19 convalescent plasma from 18 donors was collected longitudinally for a maximum of 63-129 days following resolution of symptoms. All the samples were initially screened by the Ortho total Ig test to confirm positivity and subsequently tested with seven additional direct sandwich or indirect binding assays (Ortho, Roche, Abbott, Broad Institute) directed against a variety of antigen targets (S1, receptor binding domain, and nucleocapsid [NC]), along with two neutralization assays (Broad Institute live virus PRNT and Vitalant Research Institute [VRI] Pseudovirus reporter viral particle neutralization [RVPN]). RESULTS: The direct detection assays (Ortho total Ig total and Roche total Ig) showed increasing levels of antibodies over the time period, in contrast to the indirect IgG assays that showed a decline. Neutralization assays also demonstrated declining responses; the VRI RVPN pseudovirus had a greater rate of decline than the Broad PRNT live virus assay. DISCUSSION: These data show that in addition to variable individual responses and associations with disease severity, the detection assay chosen contributes to the heterogeneous results in antibody stability over time. Depending on the scope of the research, one assay may be preferable over another. For serosurveillance studies, direct, double Ag-sandwich assays appear to be the best choice due to their stability; in particular, algorithms that include both S1- and NC-based assays can help reduce the rate of false-positivity and discriminate between natural infection and vaccine-derived seroreactivity.

Role of Environmental Air Pollution in Chronic Rhinosinusitis.

PURPOSE OF REVIEW: Chronic rhinosinusitis (CRS) is a highly prevalent disease with large social and financial burdens. The pathophysiology is multifactorial. Environmental pollutants have been suggested to play a role in the inflammatory component of the disease process. RECENT FINDINGS: Recent work has focused on exposure to various pollutants, primarily particulate matter (PM). Exposure to environmental pollutants leads to upregulation of inflammatory markers and ciliary dysfunction at the cellular level. Mouse models suggest a role for epithelial barrier dysfunction contributing to inflammatory changes after pollutant exposure. Clinical studies support the role of pollutants contributing to disease severity in certain populations, but the role in CRS incidence or prevalence is less clear. Research is limited by the retrospective nature of most studies. This review focuses on recent advancements in our understanding of the impact of environmental pollutants in CRS, limitations of the available data, and potential opportunities for future studies.

Emerging models and trends in mental health crisis care in England: a national investigation of crisis care systems.

BACKGROUND: Inpatient psychiatric care is unpopular and expensive, and development and evaluation of alternatives is a long-standing policy and research priority around the world. In England, the three main models documented over the past fifty years (teams offering crisis assessment and treatment at home; acute day units; and residential crisis services in the community) have recently been augmented by several new service models. These are intended to enhance choice and flexibility within catchment area acute care systems, but remain largely undocumented in the research literature. We therefore aimed to describe the types and distribution of crisis care models across England through a national survey. METHODS: We carried out comprehensive mapping of crisis resolution teams (CRTs) using previous surveys, websites and multiple official data sources. Managers of CRTs were invited to participate as key informants who were familiar with the provision and organisation of crisis care services within their catchment area. The survey could be completed online or via telephone interview with a researcher, and elicited details about types of crisis care delivered in the local catchment area. RESULTS: We mapped a total of 200 adult CRTs and completed the survey with 184 (92%). Of the 200 mapped adult CRTs, there was a local (i.e., within the adult CRT catchment area) children and young persons CRT for 84 (42%), and an older adults CRT for 73 (37%). While all but one health region in England provided CRTs for working age adults, there was high variability regarding provision of all other community crisis service models and system configurations. Crisis cafes, street triage teams and separate crisis assessment services have all proliferated since a similar survey in 2016, while provision of acute day units has reduced. CONCLUSIONS: The composition of catchment area crisis systems varies greatly across England and popularity of models seems unrelated to strength of evidence. A group of emerging crisis care models with varying functions within service systems are increasingly prevalent: they have potential to offer greater choice and flexibility in managing crises, but an evidence base regarding impact on service user experiences and outcomes is yet to be established.

Be under your own influence: Effectiveness of a Culturally-Adapted drug prevention campaign targeting Reservation-Dwelling American Indian youth.

Be Under Your Own Influence (BUYOI) is a previously validated school-based intervention designed to delay adolescent substance use (SU) initiation. This study examined the effectiveness of a culturally-adapted version of BUYOI in delaying SU initiation among reservation-dwelling American Indian (AI) youth. Five reservation-based middle schools participated. Three schools were randomly assigned to receive BUYOI-AI (N = 321), and two schools served as controls (N = 176). Beginning in 7th grade, all participating students completed four assessments over the study period. Discrete time hazard models estimated the effects of BUYOI on students' risk of initiating alcohol, alcohol intoxication and marijuana before the end of 8th grade. AI students exposed to BUYOI had a lower risk of initiating alcohol use or intoxication, though sex moderated the effect on intoxication. These findings provide preliminary support for the effectiveness of a culturally-adapted version of BUYOI in delaying AI youth's first-time alcohol use and intoxication.