Vaccine-induced protection against hepatitis B in pediatric solid organ transplant patients.

BACKGROUND: Vaccination against hepatitis B virus (HBV) has led to a worldwide reduction in disease burden and mortality. Vaccine immunogenicity data in transplanted children are limited, and vaccine-induced protection may be reduced. We evaluated HBV vaccination coverage, seroprotection rates, and factors influencing vaccine immunity among pediatric solid organ transplant (SOT) patients. METHODS: We retrospectively identified patients ≤21 years of age evaluated for SOT and/or transplanted at our center between January 1, 2015, and December 31, 2018. A detailed chart review was conducted using a standard questionnaire to gather information on demographic, clinical, and laboratory features of patients' HBV vaccination, and hepatitis B surface antibody (HBsAb) titers. RESULTS: A total of 381 patients undergoing evaluation and/or transplantation were included: 139 (36.5%) liver, 138 (36.2%) kidney, and 104 (27.3%) heart. Overall, HBsAb at evaluation was reactive in 216 (56.7%), indeterminate in 17 (4.5%), non-reactive in 138 (36.2%), and not available in 10 (2.6%). Of those that completed a primary HBV vaccine series (n = 304), HBsAb was reactive in 164 (53.9%), indeterminate in 13 (4.3%), non-reactive in 119 (39.1%), and not available in 8 (2.6%). For those up to date for age on HBV vaccinations with non-reactive/indeterminate titers at evaluation, revaccination and a follow-up HBsAb were available in 45 patients of which 33 (73.3%) seroconverted to a reactive HBsAb titer. CONCLUSION: Vaccine-induced protection against HBV infection among high-risk pediatric SOT recipients can be improved by serology-based intervention. Though the absence of HBsAb does not always indicate loss of protection, boosting or completing primary series is recommended.

Long-term (5-year) clinical evaluation of the Resolute zotarolimus-eluting coronary stent: The RESOLUTE US clinical trial.

OBJECTIVES: To assess the long-term safety and efficacy of the Resolute zotarolimus-eluting stent (R-ZES). BACKGROUND: The R-ZES has been associated with low rates of adverse events over short-intermediate term follow-up. However, reliable assessment of the safety and efficacy of any implanted device requires long-term evaluation. METHODS: The RESOLUTE US trial was a prospective, observational study conducted at 116 U.S. sites and enrolled patients with de novo coronary lesions. Patients were followed clinically for 5 years with independent event adjudication and data monitoring. RESULTS: A total of 1,402 patients (1,573 lesions) were enrolled; 34% had diabetes mellitus and 75% had ACC type B2/C lesions. The 5-year rate of target lesion failure (TLF) was 12.3%, target lesion revascularization was 6.5%, target vessel myocardial infarction was 3.2%, and cardiac death was 4.1%. Dual antiplatelet therapy usage was 94% at 1 year and 47% at 5 years, with a 0.1% and 0.5% respective incidence of definite or probable stent thrombosis. The 5-year rate of TLF was 16.9% among patients with diabetes mellitus and 14.7% in patients with at least one small (≤2.5 mm) vessel treated. Covariates independently associated with 5-year TLF in multivariable analysis included diabetes mellitus (odds ratio [OR] 1.89, p < .001), prior coronary artery bypass grafting (OR 2.28, p < .001), prior myocardial infarction (OR 1.85, p = .002), and smaller reference vessel diameter (OR 1.75, p = .004). CONCLUSIONS: Results from the fully adjudicated and monitored RESOLUTE US trial demonstrate long-term 5-year safety and efficacy of the R-ZES stent among a relatively low-risk population of patients, including a 0.5% rate of stent thrombosis at 5 years.

Cannabis use and treatment resistance in first episode psychosis: a natural language processing study.

BACKGROUND: Cannabis is frequently used among individuals with first episode psychosis and is associated with poor clinical outcomes. However, little is known about the effect of cannabis use on the response to antipsychotic medications and how use could affect outcomes. Using natural language processing on clinical data from a large electronic case register, we sought to investigate whether resistance to antipsychotic treatment mediated poor clinical outcomes associated with cannabis use. METHODS: Data were obtained from 2026 people with first episode psychosis in south London, UK. Cannabis use documented in free text clinical records was identified with natural language processing. Data for age, sex, ethnicity, marital status, psychotic disorder diagnosis, subsequent hospital admission, and number of unique antipsychotic medications prescribed were obtained using the Clinical Record Interactive Search instrument. The association of these variables with cannabis use was analysed with multivariable regression and mediation analysis. FINDINGS: 939 people (46·3%) with first episode psychosis were using cannabis at first presentation. Cannabis use was most strongly associated with being 16-25 years old, male, and single, and was also associated with an increase in number of hospital admissions (incidence rate ratio 1·50, 95% CI 1·25-1·80), compulsory hospital admission (odds ratio 1·55, 1·16-2·08), and number of days spent in hospital (ß coefficient 35·1 days, 12·1-58·1) over 5 years' follow-up. An increase in number of unique antipsychotic medications mediated an increase in number of hospital admissions (natural indirect effect 1·11, 1·04-1·17; total effect 1·41, 1·22-1·64), compulsory hospital admission (1·27, 1·10-1·45; 1·71, 1·05-2·78), and number of days spent in hospital (16·1, 6·7-25·5; 19·9, 2·5-37·3). INTERPRETATION: We showed that a substantial number of people with first episode psychosis used cannabis and that its use was associated with increased likelihood of hospital admission and number of days spent in hospital. These associations were partly mediated by an increase in number of unique antipsychotic medications prescribed. These findings suggest that cannabis might reduce response to conventional antipsychotic treatment and highlight the importance of strategies to reduce its use. FUNDING: National Institute for Health Research, UK Medical Research Council.

Long-term follow-up of the platinum chromium TAXUS Element (ION) stent: The PERSEUS Workhorse and Small Vessel trial five-year results.

BACKGROUND: The TAXUS Element (ION) platinum chromium paclitaxel-eluting stent (PtCr-PES) incorporates a thin (81 µm) strut design with a similar polymer and drug dose density as prior PES. The pivotal PERSEUS trial program consisted of two studies: PERSEUS Workhorse (WH) and PERSEUS Small Vessel (SV). The PERSEUS WH trial demonstrated the PtCr-PES to be non-inferior to the predicate TAXUS Express PES (TE-PES) for target lesion failure (TLF) at 1 year and in-segment angiographic percent diameter stenosis at 9 months. The PERSEUS SV trial demonstrated the PtCr-PES to be superior to a historical bare metal stent (BMS) for angiographic late lumen loss at 9 months. Long-term (5-year) clinical outcomes following PtCr-PES have not been previously reported. METHODS: PERSEUS WH was a prospective, Bayesian, 3:1 randomized (PtCr-PES vs. TE-PES) trial in patients with lesion length ≤28 mm and vessel diameter ≥2.75 to ≤4.0 mm. PERSEUS SV was a prospective, single-arm trial in patients with lesion length ≤20 mm and vessel diameter ≥2.25 to <2.75 mm comparing PtCr-PES to a matched historical BMS control. RESULTS: Among randomized subjects in the PERSEUS WH study, clinical event rates at 5 years were similar between treatment groups, including TLF (12.9% TE-PES vs. 12.1% PtCr-PES; P = 0.66). In the PERSEUS SV study, 5-year rates of MACE, and TLF were significantly lower for PtCr-PES (vs. BMS) following adjustment for baseline characteristics and were primarily due to lower target lesion revascularization rates (27.2% BMS vs. 14.9% PtCr-PES; P = 0.049). CONCLUSIONS: At 5 years, the PtCr-PES provides efficacy and safety that is comparable to the TE-PES and superior efficacy with similar safety when compared with BMS in smaller caliber vessels. Cumulative stent thrombosis rates remained low and similar through 5 years for both DES platforms.

A review on how meditation could be used to comfort the terminally ill.

OBJECTIVE: Our objective was to review how meditation could comfort the terminally ill. METHOD: Our methodology was a literature search, which included books, journals, papers in collections, and online databases. The main search engines employed were Google Scholar and the Durham University Library. The main databases consulted were the Christian Meditation Centre, Project Meditation, and Stress-Related Facts and Well-Being at Monash. We were specifically interested in data acquired from clinical and nonclinical trials. The arguments needed to be based on qualitative and quantitative scientific data. Papers were published between 1985 and 2014. We then subdivided the review into three subcategories: physical, emotional, and self-awareness. When reviewing each category, we put our results into tabular form. In each table, we noted the percentage of terminally ill patients (TIPs) and non-terminally ill patients (NTIPs), and whether meditation had comforted them. RESULTS: Our review demonstrated that there are many areas that have yet to be researched. First, very little work has been done on how meditation affects the physical health of TIPs, including such variables as blood pressure, chronic pain, and sleeping patterns. However, no research has been done on heart disease, hypertension, depression, among others. Second, virtually no research has been conducted on how meditation affects the mental health of TIPs. Notably neglected areas include anxiety, compliance, depression, and stress. Third, no research has been done on whether meditation increases self-awareness in TIPs. In each of these cases, most NTIPs reacted positively; however, no research has been done on why TIPs reacted differently. SIGNIFICANCE OF RESULTS: Our results demonstrate the need for further research on how meditation affects terminally ill patients. In turn, this would enrich the debate on whether meditation should be prescribed for the dying.

Strategies for integrating artificial intelligence into mammography screening programmes: a retrospective simulation analysis.

BACKGROUND: Integrating artificial intelligence (AI) into mammography screening can support radiologists and improve programme metrics, yet the potential of different strategies for integrating the technology remains understudied. We compared programme-level performance metrics of seven AI integration strategies. METHODS: We performed a retrospective comparative evaluation of seven strategies for integrating AI into mammography screening using datasets generated from screening programmes in Germany (n=1 657 068), the UK (n=223 603) and Sweden (n=22 779). The commercially available AI model used was Vara version 2.10, trained from scratch on German data. We simulated the performance of each strategy in terms of cancer detection rate (CDR), recall rate, and workload reduction, and compared the metrics with those of the screening programmes. We also assessed the distribution of the stages and grades of the cancers detected by each strategy and the AI model's ability to correctly localise those cancers. FINDINGS: Compared with the German screening programme (CDR 6·32 per 1000 examinations, recall rate 4·11 per 100 examinations), replacement of both readers (standalone AI strategy) achieved a non-inferior CDR of 6·37 (95% CI 6·10-6·64) at a recall rate of 3·80 (95% CI 3·67-3·93), whereas single reader replacement achieved a CDR of 6·49 (6·31-6·67), a recall rate of 4·01 (3·92-4·10), and a 49% workload reduction. Programme-level decision referral achieved a CDR of 6·85 (6·61-7·11), a recall rate of 3·55 (3·43-3·68), and an 84% workload reduction. Compared with the UK programme CDR of 8·19, the reader-level, programme-level, and deferral to single reader strategies achieved CDRs of 8·24 (7·82-8·71), 8·59 (8·12-9·06), and 8·28 (7·86-8·71), without increasing recall and while reducing workload by 37%, 81%, and 95%, respectively. On the Swedish dataset, programme-level decision referral increased the CDR by 17·7% without increasing recall and while reducing reading workload by 92%. INTERPRETATION: The decision referral strategies offered the largest improvements in cancer detection rates and reduction in recall rates, and all strategies except normal triaging showed potential to improve screening metrics. FUNDING: Vara.

Effects of intraoperative liposomal bupivacaine on postoperative opioid usage in kidney transplant recipients.

This study retrospectively evaluated the use of intraoperative locally infiltrated peri-incisional liposomal bupivacaine in kidney transplant recipients with the primary outcome of oral morphine equivalent reduction during the transplant admission. Secondary outcomes included pain scores, time to first bowel movement and length of stay. Postoperative morphine equivalents were significantly lower in the liposomal bupivacaine group <24 hours (50% reduction, p < 0.05) and 24-48 hours (56.5% reduction, p < 0.05). When accounting for analgesic medication choices, liposomal bupivacaine did not result in a significant reduction in opioid use within 48 hours postoperatively with the exception of a 51% (p = 0.02) median reduction in fentanyl patient-controlled analgesia morphine equivalents <24 hours postoperatively. Morphine equivalence reductions >48 hours, differences in pain scores, time to first bowel movement or length of stay did not reach significance. Intraoperative liposomal bupivacaine reduced kidney transplant recipient's postoperative opioid requirements, but this benefit did not reliably extend past 24 hours postoperatively.

Promising role for pleural vent in pneumothorax following CT-guided biopsy of lung lesions.

OBJECTIVES: To evaluate the safety, effectiveness and cost-benefit of ambulatory pleural vent compared to conventional chest drain for pneumothorax following CT-guided biopsy of lung lesions (CTGB). METHODS: We retrospectively analysed electronic hospital records of patients requiring intervention for pneumothorax following CTGB. All patients treated with pleural vent over a 2-year period (August 2017-July 2019) were included and compared to a control group of all patients treated with chest drain over a previous 2-year period (August 2014-July 2016). RESULTS: Patients managed with a pleural vent had a shorter length of hospital stay compared to the chest drain group (median 0 days vs 4.5 days, p < 0.01). The mean cost of follow-up in the pleural vent group was £530.36 per patient compared to a mean of £2699.38 per patient in the chest drain group (p-value < 0.01). CONCLUSION: Pleural vent can be a safe and effective alternative to conventional chest drain for the management of CTGB-related pneumothorax which allows patients to be managed on an outpatient basis with reduced hospital stays and lower associated healthcare costs. ADVANCES IN KNOWLEDGE: To the best of our knowledge, this is the first study demonstrating the safety and effectiveness of pleural vent for CTGB-related pneumothorax.

A nonimaging catheter for measurement of coronary artery lumen area: a first in man pilot study.

OBJECTIVES: The objective of this human pilot study was to determine the safety and the level of agreement between a novel nonimaging 2.7 Fr. catheter-based system (LumenRECON, LR) that uses electrical conductance for measurement of lumen cross-sectional area (CSA) with intravascular ultrasound (IVUS) and quantitative coronary angiography (QCA). Based on previous animal studies, we hypothesized the level of agreement between LR and IVUS to be 13%. BACKGROUND: Accurate and reproducible vessel sizing is essential for optimal percutaneous coronary intervention (PCI). METHODS: A total of 12 patients were studied to evaluate the safety, accuracy, and reproducibility of the system in comparison with IVUS and QCA. The CSA of coronary arteries was determined by IVUS, QCA, and LR in the distal, proximal, and center of a lesion during standard PCI. RESULTS: A Bland-Altman plot of the LR versus IVUS and QCA show a nonsignificant mean difference between the two measurements of 0.04 and 0.07 mm in diameter, respectively. The root mean square error of LR versus IVUS and QCA was 14.3 and 25.8% of the mean IVUS or QCA diameter, respectively. The mean of the difference between two LR duplicate measurements was nearly zero (0.03 mm) and the repeatability coefficient was within 8.7% of the mean of the two measurements. There were no procedural complications nor were any device-related MACE reported within 30 days of the procedure. CONCLUSIONS: This proof of concept pilot study establishes the safety and accuracy of the conductance technology for a pivotal trial of coronary sizing.

Human periosteum is a source of cells for orthopaedic tissue engineering: a pilot study.

BACKGROUND: Periosteal cells are important in embryogenesis, fracture healing, and cartilage repair and could provide cells for osteochondral tissue engineering. QUESTIONS/PURPOSE: We determined whether a population of cells isolated from human periosteal tissue contains cells with a mesenchymal stem cell (MSC) phenotype and whether these cells can be expanded in culture and used to form tissue in vitro. METHODS: We obtained periosteal tissue from six patients. Initial expression of cell surface markers was assessed using flow cytometry. Cells were cultured over 10 generations and changes in gene expression evaluated to assess phenotypic stability. Phenotype was confirmed using flow cytometry and colony-forming ability assays. Mineral formation was assessed by culturing Stro-1(-) and unsorted cells with osteogenic supplements. Three cell culture samples were used for a reverse transcription-polymerase chain reaction, four for flow cytometry, three for colony-forming assay, and three for mineralization. RESULTS: Primary cultures, containing large numbers of hematopoietic cells were replaced initially by Stro-1 and ALP-expressing immature osteoblastic cell types and later by ALP-expressing cells, which lacked Stro-1 and which became the predominant cell population during subculture. Approximately 10% of the total cell population continued to express markers for Stro1(+)/ALP(-) cells throughout. CONCLUSIONS: These data suggest periosteum contains a large number of undifferentiated cells that can differentiate into neotissue and persist despite culture in noncell-specific media for over 10 passages. CLINICAL RELEVANCE: Cultured periosteal cells may contribute to tissue formation and may be applicable for tissue engineering applications.

ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity.

ONCR-177 is an engineered recombinant oncolytic herpes simplex virus (HSV) with complementary safety mechanisms, including tissue-specific miRNA attenuation and mutant UL37 to inhibit replication, neuropathic activity, and latency in normal cells. ONCR-177 is armed with five transgenes for IL12, FLT3LG (extracellular domain), CCL4, and antagonists to immune checkpoints PD-1 and CTLA-4. In vitro assays demonstrated that targeted miRNAs could efficiently suppress ONCR-177 replication and transgene expression, as could the HSV-1 standard-of-care therapy acyclovir. Although ONCR-177 was oncolytic across a panel of human cancer cell lines, including in the presence of type I IFN, replication was suppressed in human pluripotent stem cell-derived neurons, cardiomyocytes, and hepatocytes. Dendritic cells activated with ONCR-177 tumor lysates efficiently stimulated tumor antigen-specific CD8+ T-cell responses. In vivo, biodistribution analyses suggested that viral copy number and transgene expression peaked approximately 24 to 72 hours after injection and remained primarily within the injected tumor. Intratumoral administration of ONCR-177 mouse surrogate virus, mONCR-171, was efficacious across a panel of syngeneic bilateral mouse tumor models, resulting in partial or complete tumor regressions that translated into significant survival benefits and to the elicitation of a protective memory response. Antitumor effects correlated with local and distant intratumoral infiltration of several immune effector cell types, consistent with the proposed functions of the transgenes. The addition of systemic anti-PD-1 augmented the efficacy of mONCR-171, particularly for abscopal tumors. Based in part upon these preclinical results, ONCR-177 is being evaluated in patients with metastatic cancer (ONCR-177-101, NCT04348916).

Electrochemical quantification of serotonin in the live embryonic zebrafish intestine.

We monitored real-time in vivo levels of serotonin release in the digestive system of intact zebrafish embryos during early development (5 days postfertilization, dpf) using differential pulse voltammetry with implanted carbon fiber microelectrodes modified with carbon nanotubes dispersed in nafion. A detection limit of 1 nM, a linear range between 5 and 200 nM, and a sensitivity of 83.65 nA x microM(-1) were recorded. The microelectrodes were implanted at various locations in the intestine of zebrafish embryos. Serotonin levels of up to 29.9 (+/-1.13) nM were measured in vivo in normal physiological conditions. Measurements were performed in intact live embryos without additional perturbation beyond electrode insertion. The sensor was able to quantify pharmacological alterations in serotonin release and provide the longitudinal distribution of this neurotransmitter along the intestine with high spatial resolution. In the presence of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), concentrations of 54.1 (+/-1.05) nM were recorded while in the presence of p-chloro-phenylalanine (PCPA), a tryptophan hydroxylase inhibitor, the serotonin levels decreased to 7.2 (+/-0.45) nM. The variation of serotonin levels was correlated with immunohistochemical analysis. We have demonstrated the first use of electrochemical microsensors for in vivo monitoring of intestinal serotonin levels in intact zebrafish embryos.

Comparative materials differences revealed in engineered bone as a function of cell-specific differentiation.

An important aim of regenerative medicine is to restore tissue function with implantable, laboratory-grown constructs that contain tissue-specific cells that replicate the function of their counterparts in the healthy native tissue. It remains unclear, however, whether cells used in bone regeneration applications produce a material that mimics the structural and compositional complexity of native bone. By applying multivariate analysis techniques to micro-Raman spectra of mineralized nodules formed in vitro, we reveal cell-source-dependent differences in interactions between multiple bone-like mineral environments. Although osteoblasts and adult stem cells exhibited bone-specific biological activities and created a material with many of the hallmarks of native bone, the 'bone nodules' formed from embryonic stem cells were an order of magnitude less stiff, and lacked the distinctive nanolevel architecture and complex biomolecular and mineral composition noted in the native tissue. Understanding the biological mechanisms of bone formation in vitro that contribute to cell-source-specific materials differences may facilitate the development of clinically successful engineered bone.

Evolution of complex life cycles in helminth parasites.

The fundamental question of how complex life cycles--where there is typically more than one host-evolve in host--parasite systems remains largely unexplored. We suggest that complex cycles in helminths without penetrative infective stages evolve by two essentially different processes, depending on where in the cycle a new host is inserted. In 'upward incorporation', a new definitive host, typically higher up a food web and which preys on the original definitive host, is added. Advantages to the parasite are avoidance of mortality due to the predator, greater body size at maturity and higher fecundity. The original host typically becomes an intermediate host, in which reproduction is suppressed. In 'downward incorporation', a new intermediate host is added at a lower trophic level; this reduces mortality and facilitates transmission to the original definitive host. These two processes should also apply in helminths with penetrative infective stages, although the mathematical conditions differ.

Osteoblasts response to microstructured and nanostructured polyimide film, processed by the use of silica bead microlenses.

The surface of polyimide films was modified by the use of silica microspheres as microlenses to focus radiation emitted by an excimer laser. The resultant surface had both microstructures and nanostructures. Physical and chemical characterization was performed by atomic force and Fourier transform-infrared microscopy. Laser processing resulted in surfaces that had similar roughness but different component frequencies. Chemical changes were not observed with the techniques used. The response of osteoblasts to the surface was assayed by measuring their metabolic activity and the enzyme alkaline phosphatase activity, after 24 hours of growth. Cytoskeleton and expression were both investigated. Metabolic activity was similar on treated and untreated samples. Total cell number and size were increased on microstructured polymer, where specific structures were observed (protrusions). Adhesion was noted, and the actin cytoskeleton showed normal morphology. Cells on nanostructured samples had a diffuse actin network and less mature adhesions as compared with the control. FROM THE CLINICAL EDITOR: Polyimide films with microstructure and nanostructure surface elements were studied from the standpoint of osteoblast response. Total cell number and size were increased on microstructured polymer and protrusions were also observed. Adhesion was noted and the actin cytoskeleton exhibited normal morphology. Cells on nanostructured samples had a diffuse actin network and less mature adhesions.

CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer.

The tumor microenvironment (TME) is an essential contributor to the development and progression of malignancy. Within the TME, tumor associated macrophages (TAMs) mediate angiogenesis, metastasis, and immunosuppression, which inhibits infiltration of tumor-specific cytotoxic CD8+ T cells. In previous work, we demonstrated that the synthetic triterpenoid CDDO-methyl ester (CDDO-Me) converts breast TAMs from a tumor-promoting to a tumor-inhibiting activation state in vitro. We show now that CDDO-Me remodels the breast TME, redirecting TAM activation and T cell tumor infiltration in vivo. We demonstrate that CDDO-Me significantly attenuates IL-10 and VEGF expression but stimulates TNF production, and reduces surface expression of CD206 and CD115, markers of immunosuppressive TAMs. CDDO-Me treatment redirects the TAM transcriptional profile, inducing signaling pathways associated with immune stimulation, and inhibits TAM tumor infiltration, consistent with decreased expression of CCL2. In CDDO-Me-treated mice, both the absolute number and proportion of splenic CD4+ T cells were reduced, while the proportion of CD8+ T cells was significantly increased in both tumors and spleen. Moreover, mice fed CDDO-Me demonstrated significant reductions in numbers of CD4+ Foxp3+ regulatory T cells within tumors. These results demonstrate for the first time that CDDO-Me relieves immunosuppression in the breast TME and unleashes host adaptive anti-tumor immunity.

Profibrotic Activation of Human Macrophages in Systemic Sclerosis.

OBJECTIVE: Genome-wide gene expression studies implicate macrophages as mediators of fibrosis in systemic sclerosis (SSc), but little is known about how these cells contribute to fibrotic activation in SSc. We undertook this study to characterize the activation profile of SSc monocyte-derived macrophages and assessed their interaction with SSc fibroblasts. METHODS: Plasma and peripheral blood mononuclear cells (PBMCs) were obtained from whole blood from SSc patients (n = 24) and age- and sex-matched healthy controls (n = 12). Monocytes were cultured with autologous or allogeneic plasma to differentiate cells into macrophages. For reciprocal activation studies, macrophages were cocultured with fibroblasts using Transwell plates. RESULTS: The gene expression signature associated with blood-derived human SSc macrophages was enriched in SSc skin in an independent cohort and correlated with skin fibrosis. SSc macrophages expressed surface markers associated with activation and released CCL2, interleukin-6, and transforming growth factor ß under basal conditions (n = 8) (P < 0.05). Differentiation of healthy donor monocytes in plasma from SSc patients conferred the immunophenotype of SSc macrophages (n = 13) (P < 0.05). Transwell experiments demonstrated that coculture of SSc macrophages with SSc fibroblasts induced fibroblast activation (n = 3) (P < 0.05). CONCLUSION: These data demonstrate that the activation profile of SSc macrophages is profibrotic. SSc macrophages are activated under basal conditions and release mediators and express surface markers associated with both alternative and inflammatory macrophage activation. These findings also suggest that activation of SSc macrophages arises from soluble factors in local microenvironments. These studies implicate macrophages as likely drivers of fibrosis in SSc and suggest that therapeutic targeting of these cells may be beneficial in ameliorating disease in SSc patients.

Use of Natural Language Processing to identify Obsessive Compulsive Symptoms in patients with schizophrenia, schizoaffective disorder or bipolar disorder.

Obsessive and Compulsive Symptoms (OCS) or Obsessive Compulsive Disorder (OCD) in the context of schizophrenia or related disorders are of clinical importance as these are associated with a range of adverse outcomes. Natural Language Processing (NLP) applied to Electronic Health Records (EHRs) presents an opportunity to create large datasets to facilitate research in this area. This is a challenging endeavour however, because of the wide range of ways in which these symptoms are recorded, and the overlap of terms used to describe OCS with those used to describe other conditions. We developed an NLP algorithm to extract OCS information from a large mental healthcare EHR data resource at the South London and Maudsley NHS Foundation Trust using its Clinical Record Interactive Search (CRIS) facility. We extracted documents from individuals who had received a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder. These text documents, annotated by human coders, were used for developing and refining the NLP algorithm (600 documents) with an additional set reserved for final validation (300 documents). The developed NLP algorithm utilized a rules-based approach to identify each of symptoms associated with OCS, and then combined them to determine the overall number of instances of OCS. After its implementation, the algorithm was shown to identify OCS with a precision and recall (with 95% confidence intervals) of 0.77 (0.65-0.86) and 0.67 (0.55-0.77) respectively. The development of this application demonstrated the potential to extract complex symptomatic data from mental healthcare EHRs using NLP to facilitate further analyses of these clinical symptoms and their relevance for prognosis and intervention response.

Arming oHSV with ULBP3 drives abscopal immunity in lymphocyte-depleted glioblastoma.

Oncolytic viruses induce local tumor destruction and inflammation. Whether virotherapy can also overcome immunosuppression in noninfected tumor areas is under debate. To address this question, we have explored immunologic effects of oncolytic herpes simplex viruses (oHSVs) in a genetically engineered mouse model of isocitrate dehydrogenase (IDH) wild-type glioblastoma, the most common and most malignant primary brain tumor in adults. Our model recapitulates the genomics, the diffuse infiltrative growth pattern, and the extensive macrophage-dominant immunosuppression of human glioblastoma. Infection with an oHSV that was armed with a UL16-binding protein 3 (ULBP3) expression cassette inhibited distant tumor growth in the absence of viral spreading (abscopal effect) and yielded accumulation of activated macrophages and T cells. There was also abscopal synergism of oHSVULBP3 with anti-programmed cell death 1 (anti-PD-1) against distant, uninfected tumor areas; albeit consistent with clinical trials in patients with glioblastoma, monotherapy with anti-PD-1 was ineffective in our model. Arming oHSV with ULBP3 led to upregulation of antigen processing and presentation gene sets in myeloid cells. The cognate ULBP3 receptor NKG2D, however, is not present on myeloid cells, suggesting a noncanonical mechanism of action of ULBP3. Overall, the myeloid-dominant, anti-PD-1-sensitive abscopal effect of oHSVULBP3 warrants further investigation in patients with IDH wild-type glioblastoma.