'It Makes You Sit Back and Think Where You Wanna Go': Veteran experiences in virtual whole health peer-led groups.

BACKGROUND: The Veterans Health Administration (VHA) is building a Whole Health system of care that aspires to empower and equip each Veteran to pursue a personally meaningful vision of health and well-being. As part of this effort, VHA has developed Taking Charge of My Life and Health (TCMLH), a peer-led, group-based programme that seeks to support Veterans in setting and pursuing health and well-being goals. Prior research showed TCMLH groups to positively impact Veteran outcomes; yet, little is known about Veterans' own experiences and perspectives. METHODS: We completed semi-structured telephone interviews with 15 Veterans across 8 sites who had participated in TCMLH groups offered by the VHA in the virtual format between Summer 2020 and Fall 2021. Inductive thematic analysis was applied to interview transcripts to generate themes. FINDINGS: We identified five themes regarding Veterans' experiences with TCMLH: (1) navigating the virtual format; (2) internalizing the value of health engagement; (3) making healthy lifestyle changes; (4) forging social connections; and (5) taking on a more active role in healthcare. CONCLUSION: Veterans perceived virtual TCMLH groups as meaningful and beneficial, yet also highlighted several challenges. Their perspectives speak to the need to supplement time-limited programmes like TCMLH with ongoing, community-based support. Virtual group-based well-being programmes are a promising innovation. Other healthcare systems may draw on VHA's experience while tailoring format and content to the needs of their patient populations. PATIENT OR PUBLIC CONTRIBUTION: Veterans were involved as evaluation participants. A Veteran consultant, who is a coauthor on this paper, was engaged through the conceptualization of the evaluation, development of data collection materials (interview guide) and writing.

Lessons Learned From VHA's Rapid Implementation of Virtual Whole Health Peer-Led Groups During the COVID-19 Pandemic: Staff Perspectives.

BACKGROUND: Committed to implementing a person-centered, holistic (Whole Health) system of care, the Veterans Health Administration (VHA) developed a peer-led, group-based, multi-session "Taking Charge of My Life and Health" (TCMLH) program wherein Veterans reflect on values, set health and well-being-related goals, and provide mutual support. Prior work has demonstrated the positive impact of these groups. After face-to-face TCMLH groups were disrupted by the COVID-19 pandemic, VHA facilities rapidly implemented virtual (video-based) TCMLH groups. OBJECTIVE: We sought to understand staff perspectives on the feasibility, challenges, and advantages of conducting TCMLH groups virtually. METHODS: We completed semi-structured telephone interviews with 35 staff members involved in the implementation of virtual TCMLH groups across 12 VHA facilities and conducted rapid qualitative analysis of the interview transcripts. RESULTS: Holding TCMLH groups virtually was viewed as feasible. Factors that promoted the implementation included use of standardized technology platforms amenable to delivery of group-based curriculum, availability of technical support, and adjustments in facilitator delivery style. The key drawbacks of the virtual format included difficulty maintaining engagement and barriers to relationship-building among participants. The perceived advantages of the virtual format included the positive influence of being in the home environment on Veterans' reflection, motivation, and self-disclosure, the greater convenience and accessibility of the virtual format, and the virtual group's role as an antidote to isolation during the COVID-19 pandemic. CONCLUSION: Faced with the disruption caused by the COVID-19 pandemic, VHA pivoted by rapidly implementing virtual TCMLH groups. Staff members involved in implementation noted that delivering TCMLH virtually was feasible and highlighted both challenges and advantages of the virtual format. A virtual group-based program in which participants set and pursue personally meaningful goals related to health and well-being in a supportive environment of their peers is a promising innovation that can be replicated in other health systems.

Locust bean gum adsorption onto softwood kraft pulp fibres: isotherms, kinetics and paper strength.

The adsorption of locust bean gum (LBG) onto Northern Bleached Softwood Kraft (NBSK) pulp improved paper tensile and burst strength and lowered refining energy by strengthening inter-fibre bonding. Adsorption kinetics and isotherms were investigated to develop a fundamental understanding of the adsorption mechanism. The adsorption rate followed pseudo-second-order kinetics and the activation energy was 99.34 kJ·mol-1, suggesting chemisorption. The adsorption rate constant increased rapidly with temperature from 25 to 45 °C (k = 1.93 to 24.03 g·mg-1·min-1), but the amount adsorbed at equilibrium decreased (q e = 1.91 to 0.48 mg·g-1 o.d. fibre). LBG adsorption to NBSK at 25 °C was consistent with the Langmuir adsorption model for LBG < 2.1 wt% of o.d. fibre, suggesting reversible, homogenous adsorption to a finite number of sites on the fibre surface. Refining to 3000 rev increased the heterogeneity of the NBSK pulp surface leading to multi-layer Freundlich adsorption with adsorption constant n = 5.00, and the equilibrium constant K f = 2.57 mg·g-1·(mg·L-1)-1/n at 25 °C. Favorable adsorption conditions for negatively charged LBG were identified: 25 °C for 10 min, low dosage level (< 2 wt%), lightly refined (< 3000 rev) NBSK pulp at low fibre consistency (< 0.5 wt%), high agitation rate (> 150 r.p.m.), acidic or neutral conditions (pH 2-7) without salt addition. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10570-021-04133-w.

The kinetics of E-selectin- and P-selectin-induced intermediate activation of integrin αLß2 on neutrophils.

Selectins and integrins are key players in the adhesion and signaling cascade that recruits leukocytes to inflamed tissues. Selectin binding induces ß2 integrin binding to slow leukocyte rolling. Here, a micropipette was used to characterize neutrophil adhesion to E-selectin and intercellular adhesion molecule-1 (ICAM-1) at room temperature. The time-dependent adhesion frequency displayed two-stage kinetics, with an E-selectin-mediated fast increase to a low plateau followed by a slow increase to a high plateau mediated by intermediate-affinity binding of integrin αLß2 to ICAM-1. The αLß2 activation required more than 5 s contact to E-selectin and spleen tyrosine kinase (Syk) activity. A multi-zone channel was used to analyze αLß2 activation by P-selectin in separate zones of receptors or antibodies, finding an inverse relationship between the rolling velocity on ICAM-1 and P-selectin dose, and a P-selectin dose-dependent change from bent to extended conformations with a closed headpiece that was faster at 37°C than at room temperature. Activation of αLß2 exhibited different levels of cooperativity and persistent times depending on the strength and duration of selectin stimulation. These results define the precise timing and kinetics of intermediate activation of αLß2 by E- and P-selectins.

L-SIGN is a receptor on liver sinusoidal endothelial cells for SARS-CoV-2 virus.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a pandemic. Severe disease is associated with dysfunction of multiple organs, but some infected cells do not express ACE2, the canonical entry receptor for SARS-CoV-2. Here, we report that the C-type lectin receptor L-SIGN interacted in a Ca2+-dependent manner with high-mannose-type N-glycans on the SARS-CoV-2 spike protein. We found that L-SIGN was highly expressed on human liver sinusoidal endothelial cells (LSECs) and lymph node lymphatic endothelial cells but not on blood endothelial cells. Using high-resolution confocal microscopy imaging, we detected SARS-CoV-2 viral proteins within the LSECs from liver autopsy samples from patients with COVID-19. We found that both pseudo-typed virus enveloped with SARS-CoV-2 spike protein and authentic SARS-CoV-2 virus infected L-SIGN-expressing cells relative to control cells. Moreover, blocking L-SIGN function reduced CoV-2-type infection. These results indicate that L-SIGN is a receptor for SARS-CoV-2 infection. LSECs are major sources of the clotting factors vWF and factor VIII (FVIII). LSECs from liver autopsy samples from patients with COVID-19 expressed substantially higher levels of vWF and FVIII than LSECs from uninfected liver samples. Our data demonstrate that L-SIGN is an endothelial cell receptor for SARS-CoV-2 that may contribute to COVID-19-associated coagulopathy.

Heightened activation of embryonic megakaryocytes causes aneurysms in the developing brain of mice lacking podoplanin.

During early embryonic development in mammals, including humans and mice, megakaryocytes (Mks) first originate from primitive hematopoiesis in the yolk sac. These embryonic Mks (eMks) circulate in the vasculature with unclear function. Herein, we report that podoplanin (PDPN), the ligand of C-type lectin-like receptor (CLEC-2) on Mks/platelets, is temporarily expressed in neural tissue during midgestation in mice. Loss of PDPN or CLEC-2 resulted in aneurysms and spontaneous hemorrhage, specifically in the lower diencephalon during midgestation. Surprisingly, more eMks/platelets had enhanced granule release and localized to the lower diencephalon in mutant mouse embryos than in wild-type littermates before hemorrhage. We found that PDPN counteracted the collagen-1-induced secretion of angiopoietin-1 from fetal Mks, which coincided with enhanced TIE-2 activation in aneurysm-like sprouts of PDPN-deficient embryos. Blocking platelet activation prevented the PDPN-deficient embryo from developing vascular defects. Our data reveal a new role for PDPN in regulating eMk function during midgestation.

Proximal colon-derived O-glycosylated mucus encapsulates and modulates the microbiota.

Colon mucus segregates the intestinal microbiota from host tissues, but how it organizes to function throughout the colon is unclear. In mice, we found that colon mucus consists of two distinct O-glycosylated entities of Muc2: a major form produced by the proximal colon, which encapsulates the fecal material including the microbiota, and a minor form derived from the distal colon, which adheres to the major form. The microbiota directs its own encapsulation by inducing Muc2 production from proximal colon goblet cells. In turn, O-glycans on proximal colon-derived Muc2 modulate the structure and function of the microbiota as well as transcription in the colon mucosa. Our work shows how proximal colon control of mucin production is an important element in the regulation of host-microbiota symbiosis.

Neutrophils lacking ERM proteins polarize and crawl directionally but have decreased adhesion strength.

Ezrin/radixin/moesin (ERM) proteins are adaptors that link the actin cytoskeleton to the cytoplasmic domains of membrane proteins. Leukocytes express mostly moesin with lower levels of ezrin but no radixin. When leukocytes are activated, ERMs are postulated to redistribute membrane proteins from microvilli into uropods during polarization and to transduce signals that influence adhesion and other responses. However, these functions have not been tested in leukocytes lacking all ERMs. We used knockout (KO) mice with neutrophils lacking ezrin, moesin, or both proteins (double knockout [DKO]) to probe how ERMs modulate cell shape, adhesion, and signaling in vitro and in vivo. Surprisingly, chemokine-stimulated DKO neutrophils still polarized and redistributed ERM-binding proteins such as PSGL-1 and CD44 to the uropods. Selectin binding to PSGL-1 on moesin KO or DKO neutrophils activated kinases that enable integrin-dependent slow rolling but not those that generate neutrophil extracellular traps. Flowing neutrophils of all genotypes rolled normally on selectins and, upon chemokine stimulation, arrested on integrin ligands. However, moesin KO and DKO neutrophils exhibited defective integrin outside-in signaling and reduced adhesion strength. In vivo, DKO neutrophils displayed normal directional crawling toward a chemotactic gradient, but premature detachment markedly reduced migration from venules into inflamed tissues. Our results demonstrate that stimulated neutrophils do not require ERMs to polarize or to move membrane proteins into uropods. They also reveal an unexpected contribution of moesin to integrin outside-in signaling and adhesion strengthening.

Th1 Cells Rolling on Selectins Trigger DAP12-Dependent Signals That Activate Integrin αLß2.

During inflammation, both neutrophils and effector T cells use selectins to roll and integrins to arrest in postcapillary venules. In both cell types, chemokines can transduce signals that convert integrin αLß2 to a high-affinity conformation, which interacts with ICAM-1 to mediate arrest. In neutrophils, selectins also trigger an immunoreceptor-like signaling cascade that converts integrin αLß2 to an intermediate-affinity conformation, which interacts with ICAM-1 to slow rolling. It is not known whether selectins induce similar signaling events in T cells. Ag engagement causes phosphorylation of ITAMs on the TCR; these motifs recruit kinases and adaptors that lead to the activation of αLß2. We found that mouse Th1 cells rolling on P- or E-selectin triggered signals that promoted αLß2-dependent slow rolling on ICAM-1 in vitro and in vivo. The selectin signaling cascade resembled that used by the TCR, except that unexpectedly, Th1 cells employed the ITAM-bearing protein DAP12, which was not known to be expressed in these cells. Importantly, outside-in signaling through ligand-occupied αLß2 also required DAP12. Cooperative selectin and chemokine signaling in Th1 cells promoted αLß2-dependent slow rolling and arrest in vitro and in vivo and migration into Ag-challenged tissues in vivo. Our findings reveal an important function for DAP12 in Th1 cells and a new mechanism to recruit effector T cells to sites of inflammation.

Meningoencephalitis Following Endoscopic Dacryocystorhinostomy.

An 81-year-old man with unilateral nasolacrimal duct obstruction underwent routine endonasal dacryocystorhinostomy and 2 days postoperatively developed a severe headache and rigors. Subsequent CT and MRI imaging demonstrated a defect in the floor of the right anterior cranial fossa, which possibly was damaged during the operation, and meningoencephalitis of the adjacent frontal lobe gyrus. Following intravenous antibiotic treatment, the patient made a full recovery with no ongoing sequelae, and his epiphora completely resolved. To the authors' knowledge, this is the first report of meningoencephalitis following endonasal dacryocystorhinostomy. This complication should be considered in any patient with a febrile septic presentation or headache following endonasal dacryocystorhinostomy.

Endothelial signaling by neutrophil-released oncostatin M enhances P-selectin-dependent inflammation and thrombosis.

In the earliest phase of inflammation, histamine and other agonists rapidly mobilize P-selectin to the apical membranes of endothelial cells, where it initiates rolling adhesion of flowing neutrophils. Clustering of P-selectin in clathrin-coated pits facilitates rolling. Inflammatory cytokines typically signal by regulating gene transcription over a period of hours. We found that neutrophils rolling on P-selectin secreted the cytokine oncostatin M (OSM). The released OSM triggered signals through glycoprotein 130 (gp130)-containing receptors on endothelial cells that, within minutes, further clustered P-selectin and markedly enhanced its adhesive function. Antibodies to OSM or gp130, deletion of the gene encoding OSM in hematopoietic cells, or conditional deletion of the gene encoding gp130 in endothelial cells inhibited neutrophil rolling on P-selectin in trauma-stimulated venules of the mouse cremaster muscle. In a mouse model of P-selectin-dependent deep vein thrombosis, deletion of OSM in hematopoietic cells or of gp130 in endothelial cells markedly inhibited adhesion of neutrophils and monocytes and the rate and extent of thrombus formation. Our results reveal a paracrine-signaling mechanism by which neutrophil-released OSM rapidly influences endothelial cell function during physiological and pathological inflammation.

Cooperative PSGL-1 and CXCR2 signaling in neutrophils promotes deep vein thrombosis in mice.

Inflammation is a major contributor to deep vein thrombosis (DVT). Flow restriction of the inferior vena cava (IVC) in mice induces DVT like that in humans. In this model, P-selectin-dependent adhesion of neutrophils and monocytes leads to release of neutrophil extracellular traps (NETs) and expression of tissue factor. However, it is not known what signals cause myeloid cells to generate these procoagulant effectors. Using ultrasonography and spinning-disk intravital microscopy in genetically engineered mice, we found that engagement of P-selectin glycoprotein ligand-1 (PSGL-1) and the chemokine receptor CXCR2 on rolling neutrophils propagated signals that cooperated to induce ß2 integrin-dependent arrest in flow-restricted IVCs. Unlike previous reports, PSGL-1 signaling in neutrophils did not require L-selectin, and it used tyrosine 145 rather than tyrosines 112 and 128 on the adaptor Src homology domain-containing leukocyte phosphoprotein of 76 kDa. PSGL-1 and CXCR2 signaling cooperated to increase the frequency and size of thrombi, in part by stimulating release of NETs. Unlike in neutrophils, blocking PSGL-1 or CXCR2 signaling in monocytes did not affect their recruitment into thrombi or their expression of tissue factor. Our results demonstrate that neutrophils cooperatively signal through PSGL-1 and CXCR2 to promote DVT.

Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking.

Site-1 protease (S1P), encoded by MBTPS1, is a serine protease in the Golgi. S1P regulates lipogenesis, endoplasmic reticulum (ER) function, and lysosome biogenesis in mice and in cultured cells. However, how S1P differentially regulates these diverse functions in humans has been unclear. In addition, no human disease with S1P deficiency has been identified. Here, we report a pediatric patient with an amorphic and a severely hypomorphic mutation in MBTPS1. The unique combination of these mutations results in a frequency of functional MBTPS1 transcripts of approximately 1%, a finding that is associated with skeletal dysplasia and elevated blood lysosomal enzymes. We found that the residually expressed S1P is sufficient for lipid homeostasis but not for ER and lysosomal functions, especially in chondrocytes. The defective S1P function specifically impairs activation of the ER stress transducer BBF2H7, leading to ER retention of collagen in chondrocytes. S1P deficiency also causes abnormal secretion of lysosomal enzymes due to partial impairment of mannose-6-phosphate-dependent delivery to lysosomes. Collectively, these abnormalities lead to apoptosis of chondrocytes and lysosomal enzyme-mediated degradation of the bone matrix. Correction of an MBTPS1 variant or reduction of ER stress mitigated collagen-trafficking defects. These results define a new congenital human skeletal disorder and, more importantly, reveal that S1P is particularly required for skeletal development in humans. Our findings may also lead to new therapies for other genetic skeletal diseases, as ER dysfunction is common in these disorders.

Selectins and chemokines use shared and distinct signals to activate ß2 integrins in neutrophils.

Rolling neutrophils receive signals while engaging P- and E-selectin and chemokines on inflamed endothelium. Selectin signaling activates ß2 integrins to slow rolling velocities. Chemokine signaling activates ß2 integrins to cause arrest. Despite extensive study, key aspects of these signaling cascades remain unresolved. Using complementary in vitro and in vivo assays, we found that selectin and chemokine signals in neutrophils triggered Rap1a-dependent and phosphatidylinositol-4-phosphate 5-kinase γ (PIP5Kγ90)-dependent pathways that induce integrin-dependent slow rolling and arrest. Interruption of both pathways, but not either pathway alone, blocked talin-1 recruitment to and activation of integrins. An isoform of PIP5Kγ90 lacking the talin-binding domain (PIP5Kγ87) could not activate integrins. Chemokines, but not selectins, used phosphatidylinositol-4,5-bisphosphate 3-kinase γ (PI3Kγ) in cooperation with Rap1a to mediate integrin-dependent slow rolling (at low chemokine concentrations), as well as arrest (at high chemokine concentrations). High levels of chemokines activated ß2 integrins without selectin signals. When chemokines were limiting, they synergized with selectins to activate ß2 integrins.

A classical view on nonclassical nucleation.

Understanding and controlling nucleation is important for many crystallization applications. Calcium carbonate (CaCO3) is often used as a model system to investigate nucleation mechanisms. Despite its great importance in geology, biology, and many industrial applications, CaCO3 nucleation is still a topic of intense discussion, with new pathways for its growth from ions in solution proposed in recent years. These new pathways include the so-called nonclassical nucleation mechanism via the assembly of thermodynamically stable prenucleation clusters, as well as the formation of a dense liquid precursor phase via liquid-liquid phase separation. Here, we present results from a combined experimental and computational investigation on the precipitation of CaCO3 in dilute aqueous solutions. We propose that a dense liquid phase (containing 4-7 H2O per CaCO3 unit) forms in supersaturated solutions through the association of ions and ion pairs without significant participation of larger ion clusters. This liquid acts as the precursor for the formation of solid CaCO3 in the form of vaterite, which grows via a net transfer of ions from solution according to z Ca2+ + z CO32- → z CaCO3 The results show that all steps in this process can be explained according to classical concepts of crystal nucleation and growth, and that long-standing physical concepts of nucleation can describe multistep, multiphase growth mechanisms.

Organic-Silica Interactions in Saline: Elucidating the Structural Influence of Calcium in Low-Salinity Enhanced Oil Recovery.

Enhanced oil recovery using low-salinity solutions to sweep sandstone reservoirs is a widely-practiced strategy. The mechanisms governing this remain unresolved. Here, we elucidate the role of Ca2+ by combining chemical force microscopy (CFM) and molecular dynamics (MD) simulations. We probe the influence of electrolyte composition and concentration on the adsorption of a representative molecule, positively-charged alkylammonium, at the aqueous electrolyte/silica interface, for four electrolytes: NaCl, KCl, MgCl2, and CaCl2. CFM reveals stronger adhesion on silica in CaCl2 compared with the other electrolytes, and shows a concentration-dependent adhesion not observed for the other electrolytes. Using MD simulations, we model the electrolytes at a negatively-charged amorphous silica substrate and predict the adsorption of methylammonium. Our simulations reveal four classes of surface adsorption site, where the prevalence of these sites depends only on CaCl2 concentration. The sites relevant to strong adhesion feature the O- silica site and Ca2+ in the presence of associated Cl-, which gain prevalence at higher CaCl2 concentration. Our simulations also predict the adhesion force profile to be distinct for CaCl2 compared with the other electrolytes. Together, these analyses explain our experimental data. Our findings indicate in general how silica wettability may be manipulated by electrolyte concentration.

Sialylation on O-glycans protects platelets from clearance by liver Kupffer cells.

Most platelet membrane proteins are modified by mucin-type core 1-derived glycans (O-glycans). However, the biological importance of O-glycans in platelet clearance is unclear. Here, we generated mice with a hematopoietic cell-specific loss of O-glycans (HC C1galt1-/- ). These mice lack O-glycans on platelets and exhibit reduced peripheral platelet numbers. Platelets from HC C1galt1-/- mice show reduced levels of α-2,3-linked sialic acids and increased accumulation in the liver relative to wild-type platelets. The preferential accumulation of HC C1galt1-/- platelets in the liver was reduced in mice lacking the hepatic asialoglycoprotein receptor [Ashwell-Morell receptor (AMR)]. However, we found that Kupffer cells are the primary cells phagocytosing HC C1galt1-/- platelets in the liver. Our results demonstrate that hepatic AMR promotes preferential adherence to and phagocytosis of desialylated and/or HC C1galt1-/- platelets by the Kupffer cell through its C-type lectin receptor CLEC4F. These findings provide insights into an essential role for core 1 O-glycosylation of platelets in their clearance in the liver.

Circulating soluble P-selectin must dimerize to promote inflammation and coagulation in mice.

Leukocyte adhesion to P-selectin on activated platelets and endothelial cells induces shedding of the P-selectin ectodomain into the circulation. Plasma soluble P-selectin (sP-selectin) is elevated threefold to fourfold in patients with cardiovascular disease. Circulating sP-selectin is thought to trigger signaling in leukocytes that directly contributes to inflammation and thrombosis. However, sP-selectin likely circulates as a monomer, and in vitro studies suggest that sP-selectin must dimerize to induce signaling in leukocytes. To address this discrepancy, we expressed the entire ectodomain of mouse P-selectin as a monomer (sP-selectin) or as a disulfide-linked dimer fused to the Fc portion of mouse immunoglobulin G (sP-selectin-Fc). Dimeric sP-selectin-Fc, but not monomeric sP-selectin, triggered integrin-dependent adhesion of mouse leukocytes in vitro. Antibody-induced oligomerization of sP-selectin or sP-selectin-Fc was required to trigger formation of neutrophil extracellular traps. Injecting sP-selectin-Fc, but not sP-selectin, into mice augmented integrin-dependent adhesion of neutrophils in venules, generated tissue factor-bearing microparticles, shortened plasma-clotting times, and increased thrombus frequency in the inferior vena cava. Furthermore, transgenic mice that overexpressed monomeric sP-selectin did not exhibit increased inflammation or thrombosis. We conclude that elevated plasma sP-selectin is a consequence rather than a cause of cardiovascular disease.

L-selectin mechanochemistry restricts neutrophil priming in vivo.

Circulating neutrophils must avoid premature activation to prevent tissue injury. The leukocyte adhesion receptor L-selectin forms bonds with P-selectin glycoprotein ligand-1 (PSGL-1) on other leukocytes and with peripheral node addressin (PNAd) on high endothelial venules. Mechanical forces can strengthen (catch) or weaken (slip) bonds between biological molecules. How these mechanochemical processes influence function in vivo is unexplored. Here we show that mice expressing an L-selectin mutant (N138G) have altered catch bonds and prolonged bond lifetimes at low forces. Basal lymphocyte homing and neutrophil recruitment to inflamed sites are normal. However, circulating neutrophils form unstable aggregates and are unexpectedly primed to respond robustly to inflammatory mediators. Priming requires signals transduced through L-selectin N138G after it engages PSGL-1 or PNAd. Priming enhances bacterial clearance but increases inflammatory injury and enlarges venous thrombi. Thus, L-selectin mechanochemistry limits premature activation of neutrophils. Our results highlight the importance of probing how mechanochemistry functions in vivo.

Predictors of functional status at service entry and discharge among young people with first episode psychosis.

OBJECTIVE: Most patients with first episode psychosis (FEP) are neither studying nor employed (have a poor functional status) when first accessing care. Knowledge of the characteristics of patients with poor functioning and the features influencing functional status over time may pave the way to better treatment. METHOD: A medical file audit was used to collect data on premorbid, entry, treatment and 18-month outcome characteristics on 661 FEP patients who consecutively attended the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia, between 1998 and 2000. Functional status was ascertained using the modified vocational status index and was rated at baseline (poor or good) and according to its evolution over the treatment period (stable good, stable poor, deteriorating or improved functional status). RESULTS: 52.0% of patients had a poor functional status at service entry. They were more likely to be male with a non-affective psychosis. They also had lower levels of premorbid global functioning and education, and were more likely to have self-reported histories of learning disability, forensic issues, traumatic experiences and substance use. At service entry, they had more severe symptoms and poorer global functioning. 37% of these patients maintained a poor functional status at discharge, and 18% of those with a good functional status at service entry experienced a decline. CONCLUSIONS: Although psychosocial interventions might assist a young person with FEP with working towards functional goals, for some, the impact of factors such as ongoing substance use and forensic issues on functional status needs to be addressed.