Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

The endocytic Ashwell-Morell receptor (AMR) of hepatocytes detects pathogen remodeling of host glycoproteins by neuraminidase in the bloodstream and mitigates the lethal coagulopathy of sepsis. We have investigated the mechanism of host protection by the AMR during the onset of sepsis and in response to the desialylation of blood glycoproteins by the NanA neuraminidase of Streptococcus pneumoniae. We find that the AMR selects among potential glycoprotein ligands unmasked by microbial neuraminidase activity in pneumococcal sepsis to eliminate from blood circulation host factors that contribute to coagulation and thrombosis. This protection is attributable in large part to the rapid induction of a moderate thrombocytopenia by the AMR. We further show that neuraminidase activity in the blood can be manipulated to induce the clearance of AMR ligands including platelets, thereby preactivating a protective response in pneumococcal sepsis that moderates the severity of disseminated intravascular coagulation and enables host survival.Fil: Grewal, Prabhjit K.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados UnidosFil: Aziz, Peter V.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados UnidosFil: Uchiyama, Satoshi. University of California at San Diego; Estados UnidosFil: Rubio, Gabriel R.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados UnidosFil: Lardone, Ricardo Dante. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Le, Dzung. University of California at San Diego; Estados UnidosFil: Varki, Nissi M.. University of California at San Diego; Estados UnidosFil: Nizet, Victor. University of California at San Diego; Estados UnidosFil: Marth, Jamey D.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados Unido

Writing : A Versatile Resource in the Treatment of the Clients’ Proposals

This chapter investigates how writing serves as a resource in decision-making at the Clubhouse and how writing activities relate to professionals’ responses to clients. The ideology of the Clubhouse is one of interaction, and in accordance with this perspective, support workers and clients should be treated equally in decision-making processes related to the activity of the Clubhouse. However, as demonstrated in previous research, encouraging clients in mental health rehabilitation to participate actively in interaction and decision-making can be difficult. Therefore, support workers carry a substantial responsibility for promoting clients’ participation in interactions; this responsibility is supported by how they respond to clients. The focus in this chapter is on a certain type of participation-encouraging response—that is, a response that promotes the documentation of vaguely expressed ideas in written documents and encourages a dialogue between support workers and Clubhouse clients around the formulations in a text-in-production.This chapter investigates how writing serves as a resource in decision-making at the Clubhouse and how writing activities relate to professionals’ responses to clients. The ideology of the Clubhouse is one of interaction, and in accordance with this perspective, support workers and clients should be treated equally in decision-making processes related to the activity of the Clubhouse. However, as demonstrated in previous research, encouraging clients in mental health rehabilitation to participate actively in interaction and decision-making can be difficult. Therefore, support workers carry a substantial responsibility for promoting clients’ participation in interactions; this responsibility is supported by how they respond to clients. The focus in this chapter is on a certain type of participation-encouraging response—that is, a response that promotes the documentation of vaguely expressed ideas in written documents and encourages a dialogue between support workers and Clubhouse clients around the formulations in a text-in-production.Peer reviewe

First histological observations on the incorporation of a novel nanocrystalline hydroxyapatite paste OSTIM(® )in human cancellous bone

BACKGROUND: A commercially available nanocrystalline hydroxyapatite paste Ostim(® )has been reported in few recent studies to surpass other synthetic bone substitutes with respect to the observed clinical results. However, the integration of this implantable material has been histologically evaluated only in animal experimental models up to now. This study aimed to evaluate the tissue incorporation of Ostim(® )in human cancellous bone after reconstructive bone surgery for trauma. METHODS: Biopsy specimens from 6 adult patients with a total of 7 tibial, calcaneal or distal radial fractures were obtained at the time of osteosynthesis removal. The median interval from initial operation to tissue sampling was 13 (range 3–15) months. Samples were stained with Masson-Goldner, von Kossa, and toluidine blue. Osteoid volume, trabecular width and bone volume, and cortical porosity were analyzed. Samples were immunolabeled with antibodies against CD68, CD56 and human prolyl 4-hydroxylase to detect macrophages, osteoblasts, and fibroblasts, respectively. TRAP stainings were used to identify osteoclasts. RESULTS: Histomorphometric data indicated good regeneration with normal bone turnover: mean osteoid volume was 1.93% of the trabecular bone mass, trabecular bone volume – 28.4%, trabecular width – 225.12 μm, and porosity index – 2.6%. Cortical and spongious bone tissue were well structured. Neither inflammatory reaction, nor osteofibrosis or osteonecrosis were observed. The implanted material was widely absorbed. CONCLUSION: The studied nanocrystalline hydroxyapatite paste showed good tissue incorporation. It is highly biocompatible and appears to be a suitable bone substitute for juxtaarticular comminuted fractures in combination with a stable screw-plate osteosynthesis

Protection Effect of Admixed Melaleuca alternifolia and Citrus paradisi Macf. Oil Extracts on High Carbon and 3310 Low Grade Alloy Steels in HCl Solution

Protection performance of admixed Melaleuca alternifolia and Citrus paradisi Macf. oil extracts (MACP) on high carbon steel (HCS) and 3310 low-grade alloy steel (AS33) were studied in 0.5 M HCl solution. Potentiodynamic polarization technique, weight loss analysis, open circuit potential measurement, optical microscopy, X-ray diffractometry, and ATR–FTIR spectroscopy were employed to assess their effectiveness. Results from weight loss analysis and potentiodynamic polarization showed MACP performed very poorly at low concentrations (0.5% and 1% MACP concentration for HCS, and 0.5–2% MACP concentration for AS33). However, at higher concentrations, effective protection of the alloys was obtained with peak performance values of 92.45% and 86.32% for HCS, and 73.25% and 78.01% for AS33 from weight loss and polarization techniques. The protection performance of MACP increased with an increase in its concentration with cathodic-type inhibition effect on HCS and mixed-type on AS33. MACP induced passivation characteristics on the anodic portion of the polarization plot compared to the extended cathodic slope. X-ray diffractometry revealed the presence of Fe2O3 as the dominant phase compound on HCS and AS33 after corrosion in HCl. FeS2, Fe(ZnS2), SiO2, and ZnCO3 were the dominant compounds on HCS and AS33 after corrosion in the presence of MACP indicating the formation of complex pseudo-corrosion-resistant precipitates on both alloys. ATR–FTIR spectroscopy identified the active groups (alkyl halides, aromatics, primary, secondary amines, aliphatic amines, alcohols, carboxylic acids, nitro compounds, etc.) and bonds responsible for corrosion inhibition of the alloys. Optical images of the corroded HCS indicate severe general corrosion compared to localized corrosion on the AS33 surface. These images significantly differed from MACP inhibited HCS and AS33 surfaces where corrosion oxidation was suppressed

Impact of deep learning-determined smoking status on mortality of cancer patients: never too late to quit

BackgroundPersistent smoking after cancer diagnosis is associated with increased overall mortality (OM) and cancer mortality (CM). According to the 2020 Surgeon General's report, smoking cessation may reduce CM but supporting evidence is not wide. Use of deep learning-based modeling that enables universal natural language processing of medical narratives to acquire population-based real-life smoking data may help overcome the challenge. We assessed the effect of smoking status and within-1-year smoking cessation on CM by an in-house adapted freely available language processing algorithm.Materials and methodsThis cross-sectional real-world study included 29 823 patients diagnosed with cancer in 2009-2018 in Southwest Finland. The medical narrative, International Classification of Diseases-10th edition codes, histology, cancer treatment records, and death certificates were combined. Over 162 000 sentences describing tobacco smoking behavior were analyzed with ULMFiT and BERT algorithms.ResultsThe language model classified the smoking status of 23 031 patients. Recent quitters had reduced CM [hazard ratio (HR) 0.80 (0.74-0.87)] and OM [HR 0.78 (0.72-0.84)] compared to persistent smokers. Compared to never smokers, persistent smokers had increased CM in head and neck, gastro-esophageal, pancreatic, lung, prostate, and breast cancer and Hodgkin's lymphoma, irrespective of age, comorbidities, performance status, or presence of metastatic disease. Increased CM was also observed in smokers with colorectal cancer, men with melanoma or bladder cancer, and lymphoid and myeloid leukemia, but no longer independently of the abovementioned covariates. Specificity and sensitivity were 96%/96%, 98%/68%, and 88%/99% for never, former, and current smokers, respectively, being essentially the same with both models.ConclusionsDeep learning can be used to classify large amounts of smoking data from the medical narrative with good accuracy. The results highlight the detrimental effects of persistent smoking in oncologic patients and emphasize that smoking cessation should always be an essential element of patient counseling.</p

Tumor infiltrating B-cells are increased in prostate cancer tissue

BACKGROUND: The presence of increased B-cell tumor infiltrating lymphocytes (TILs) was seen in mouse prostate cancer (PCa) but has not been fully documented in human PCa. We, therefore, investigated the density of infiltrating B cells within human PCa utilizing a quantitative computational method. METHODS: Archived radical prostatectomy specimens from 53 patients with known clinical outcome and D’Amico risk category were obtained and immunohistochemically (IHC) stained for the B cell marker, CD20. Slides were reviewed by a genitourinary pathologist who manually delineated the tumoral regions of PCa. Slides were digitally scanned and a computer algorithm quantified the area of CD20 stained B-cells as a measure of B cell density within the outlined regions of prostate cancer (intra-tumoral region), versus extra-tumoral prostate tissue. Correlations were analyzed between B-cell density and demographic and clinical variables, including D’Amico risk groups and disease recurrence. RESULTS: For the entire cohort, the mean intra-tumoral B cell density was higher (3.22 SE = 0.29) than in the extra-tumoral region of each prostatectomy section (2.24, SE = 0.19) (paired t test; P < 0.001). When analyzed according to D’Amico risk group, the intra-tumoral B cell infiltration in low risk (0.0377 vs. 0.0246; p = 0.151) and intermediate risk (0.0260 vs. 0.0214; p = 0.579) patient prostatectomy specimens did not show significantly more B-cells within the PCa tumor. However, patient specimens from the high-risk group (0.0301 vs. 0.0197; p < 0.001) and from those who eventually had PCa recurrence or progression (0.0343 vs. 0.0246; p = 0.019) did show significantly more intra-tumoral CD20+ B-cell staining. Extent of B-cell infiltration in the prostatectomy specimens did not correlate with any other clinical parameters. CONCLUSIONS: Our study shows that higher B-cell infiltration was present within the intra-tumoral PCa regions compared to the extra-tumoral benign prostate tissue regions in prostatectomy sections. For this study we developed a new method to measure B-cells using computer-assisted digitized image analysis. Accurate, consistent quantitation of B-cells in prostatectomy specimens is essential for future clinical trials evaluating the effect of B cell ablating antibodies. The interaction of B-cells and PCa may serve as the basis for new therapeutic targets

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Prolyl 4-hydroxylase:genomic cloning of the human and mouse α(II) subunit, tissue distribution of type I and II isoenzymes, and cloning and characterization of a novel prolyl 4-hydroxylase from Caenorhabditis elegans

Abstract The collagens are a family of extracellular matrix proteins with a widespread tissue distribution. Collagen biosynthesis requires the hydroxylation of a number of proline residues by prolyl 4-hydroxylase. This posttranslational modification is essential for the synthesis of all collagens, as 4-hydroxyproline deficient collagens cannot form stable triple helices at body temperature. The genes for the human and mouse prolyl 4-hydroxylase α(II) subunits were cloned and characterized in this study. The human and mouse genes are 34.6 and 30.3 kb in size, respectively, consisting of 16 exons and 15 introns. The intron sizes vary from 48-49 bp to over 8 kb in both genes. The 5' flanking regions contain no TATA box, but there are several motifs that may act as transcription factor binding sites. A novel mutually exclusively spliced exon 12a was identified in both genes. Both variants of the α(II) subunit were found to be expressed in a variety of tissues and both formed a fully active recombinant tetramer with the β subunit when expressed in insect cells. Tissue distribution of the type I and type II prolyl 4-hydroxylase isoenzymes was studied in developing, mature, and malignant cells and tissues by immunofluorescence and Western blotting. The results indicate that the type I isoenzyme is the main form in many cell types. Skeletal myocytes and smooth muscle cells appeared to have the type I isoenzyme as their only prolyl 4-hydroxylase form, whereas the type II isoenzyme was clearly the main form in chondrocytes. A strong signal for the type II enzyme was detected in cultured umbilical and capillary endothelial cells, whereas the type I isoenzyme could not be detected in these cells by immunostaining or Western blotting. Similar studies on primary chondro- and osteosarcomas and benign bone tumours indicated that the type I isoenzyme is the predominant form in both types of bone sarcoma, whereas the type II isoenzyme was more abundantly expressed in benign tumours. In chondrosarcomas, the type II isoenzyme was expressed in the nonmalignant chondrocytes, whereas their malignant counterparts switched their expression pattern to that of the type I isoenzyme. Two isoforms of the catalytic prolyl 4-hydroxylase α subunit, PHY-1 and PHY-2, have previously been characterized from Caenorhabditis elegans. This study reports the cloning and characterization of a third C. elegans α subunit isoform, PHY-3, which is much shorter than the previously characterized vertebrate and C. elegans α subunits. Nematodes homozygous for a phy-3 deletion were phenotypically wild type and fertile, but the 4-hydroxyproline content of their early embryos was reduced by about 90%. The expression of PHY-3 was found to be restricted to spermatheca of late larvae and adult nematode, indicating that PHY-3 is likely to be involved in the synthesis of collagens of the early embryo egg shells