Bayesian Optimization of Environmentally Sustainable Graphene Inks Produced by Wet Jet Milling.

Liquid phase exfoliation (LPE) of graphene is a potentially scalable method to produce conductive graphene inks for printed electronic applications. Among LPE methods, wet jet milling (WJM) is an emerging approach that uses high-speed, turbulent flow to exfoliate graphene nanoplatelets from graphite in a continuous flow manner. Unlike prior WJM work based on toxic, high-boiling-point solvents such as n-methyl-2-pyrollidone (NMP), this study uses the environmentally friendly solvent ethanol and the polymer stabilizer ethyl cellulose (EC). Bayesian optimization and iterative batch sampling are employed to guide the exploration of the experimental phase space (namely, concentrations of graphite and EC in ethanol) in order to identify the Pareto frontier that simultaneously optimizes three performance criteria (graphene yield, conversion rate, and film conductivity). This data-driven strategy identifies vastly different optimal WJM conditions compared to literature precedent, including an optimal loading of 15 wt% graphite in ethanol compared to 1 wt% graphite in NMP. These WJM conditions provide superlative graphene production rates of 3.2 g hr-1 with the resulting graphene nanoplatelets being suitable for screen-printed micro-supercapacitors. Finally, life cycle assessment reveals that ethanol-based WJM graphene exfoliation presents distinct environmental sustainability advantages for greenhouse gas emissions, fossil fuel consumption, and toxicity.

Incidence and remission rates of self-reported hidradenitis suppurativa - A prospective cohort study conducted in Danish blood donors.

BACKGROUND: A large discrepancy between physician-diagnosed and self-reported Hidradenitis suppurativa (HS) exists. Knowledge regarding incidence and remission rates of self-reported HS is missing, but may help bridge the gap in understanding between these two phenotypes. OBJECTIVES: To determine the incidence and remission rates of self-reported HS, and to what degree these are affected by sex, smoking and BMI. METHODS: A prospective cohort of 23 930 Danish blood donors. Information on self-reported HS, symptom-localisation, sex, age, BMI and smoking status was collected at baseline and study termination. Self-reported HS fulfilled clinical obligatory diagnostic criteria. Cox proportional hazards regression analyses were conducted for both incidence and remission rates providing a hazard ratio (HR) of risk for each variable in the regression. RESULTS: Incidence rate of self-reported HS was 10.8/1000 person-years (95% confidence interval (CI): 9.9-11.7), decreasing as a function of numbers of areas affected. Female BMI points above 25 (HR = 1.11, 95% CI: 1.09-1.13), male BMI points above 25 (HR = 1.07, 95% CI: 1.04-1.11), active smoking (HR = 1.72, 95% CI: 1.15-2.57), male sex (HR = 0.55, 95% CI: 0.45-0.67) and years of age above 25 (HR = 0.97, 95% CI: 0.96-0.97) were all statistically associated with the development of self-reported HS. Remission rate of self-reported HS was 256.7/1000 person-years (95% CI: 223.9-292.6), decreasing as a function of numbers of affected areas. Symptoms in ≥3 areas (HR = 0.54, 95% CI: 0.34-0.85), active smoking (HR = 0.49, 95% CI: 0.32-0.76) and female weight loss (every percentage drop in BMI: HR = 1.07, 95% CI: 1.05-1.11) all significantly affected the remission rate. CONCLUSIONS: Both incidence and remission rates of self-reported HS are high, indicating that many with self-reported HS are unlikely to be diagnosed, as they to a higher degree experience mild transient HS symptoms.

Milk osteopontin retains integrin-binding activity after in vitro gastrointestinal transit.

Osteopontin (OPN) is a multifunctional protein highly expressed in milk, where it is hypothesized to be involved in immunological signaling via the conserved Arg-Gly-Asp (RGD) integrin-binding sequence. Intervention studies have indicated beneficial effects of orally administered OPN in animal and human infants, but the mechanisms underlying these effects are not well described. To induce physiological effects, OPN must resist gastrointestinal transit in a bioactive form. In this study, we subjected bovine milk OPN to in vitro gastrointestinal transit, and characterized the generated fragments using monoclonal antibody and mass spectrometric analyses. We found that the fragment Trp27-Phe151 containing the integrin-binding RGD sequence resisted in vitro gastric digestion. This resistance was dependent on glycosylation of threonine residues near the integrin-binding sequence in both human and bovine milk OPN. Furthermore, the fragment Trp27-Phe151 retained the ability to interact with integrins in an RGD-dependent process. These results suggest a mechanism for how ingested milk OPN can induce physiological effects via integrin signaling in the intestine.

Changes in circulating inflammatory markers following febrile non-haemolytic transfusion reactions to leucoreduced red cells.

It would be desirable to be able to distinguish fever as a result of febrile non-haemolytic transfusion reactions (FNHTR) from other febrile conditions. To further characterize the inflammatory feature of FNHTR, we measured a large panel of inflammatory markers in pre- and posttransfusion plasma samples from patients with and without FNHTR following the transfusion of leucoreduced red blood cells. As FNHTR patients only displayed a significant increase in IL-6, we conclude that changes in plasma cytokine levels during FNHTR are unlikely to be used diagnostically. An incidental finding of a distinct cytokine pattern in pretransfusion samples from FNHTR patients warrants further investigations, as it might be used to characterize the nature of FNHTR and to predict the risk of these adverse events.

Intensive care doctors' preferences for arterial oxygen tension levels in mechanically ventilated patients.

BACKGROUND: Oxygen is liberally administered in intensive care units (ICUs). Nevertheless, ICU doctors' preferences for supplementing oxygen are inadequately described. The aim was to identify ICU doctors' preferences for arterial oxygenation levels in mechanically ventilated adult ICU patients. METHODS: In April to August 2016, an online multiple-choice 17-part-questionnaire was distributed to 1080 ICU doctors in seven Northern European countries. Repeated reminder e-mails were sent. The study ended in October 2016. RESULTS: The response rate was 63%. When evaluating oxygenation 52% of respondents rated arterial oxygen tension (PaO2 ) the most important parameter; 24% a combination of PaO2 and arterial oxygen saturation (SaO2 ); and 23% preferred SaO2 . Increasing, decreasing or not changing a default fraction of inspired oxygen of 0.50 showed preferences for a PaO2 around 8 kPa in patients with chronic obstructive pulmonary disease, a PaO2 around 10 kPa in patients with healthy lungs, acute respiratory distress syndrome or sepsis, and a PaO2 around 12 kPa in patients with cardiac or cerebral ischaemia. Eighty per cent would accept a PaO2 of 8 kPa or lower and 77% would accept a PaO2 of 12 kPa or higher in a clinical trial of oxygenation targets. CONCLUSION: Intensive care unit doctors preferred PaO2 to SaO2 in monitoring oxygen treatment when peripheral oxygen saturation was not included in the question. The identification of PaO2 as the preferred target and the thorough clarification of preferences are important when ascertaining optimal oxygenation targets. In particular when designing future clinical trials of higher vs lower oxygenation targets in ICU patients.

Low-grade inflammation is associated with lower haemoglobin levels in healthy individuals: results from the Danish blood donor study.

BACKGROUND AND OBJECTIVES: Chronic inflammation can lead to anaemia of chronic disease due to the sequestration of iron caused by inflammatory cytokines and the protein hepcidin. However, the effect of low-grade inflammation (LGI) on haemoglobin among healthy individuals is not known. This study examines the effect of LGI on haemoglobin among Danish blood donors. MATERIALS AND METHODS: We performed multivariable linear regression to assess the effect of LGI (i.e. high-sensitivity C-reactive protein above 3 mg/l but below 10 mg/l) on haemoglobin in 17 322 Danish blood donors. We also performed multivariable logistic regression to evaluate the effect of LGI on the risk of having low haemoglobin (below the 10th percentile among men and women, respectively). We adjusted for donation activity, age, sex, low ferritin, oral contraceptives and menopause. All analyses were stratified by current smoking status. RESULTS: LGI was associated with lower haemoglobin (0·08 mm lower [0·12 g/dl], 95% confidence interval (CI): -0·11-0·05) and increased risk of low haemoglobin (OR = 1·22, 95% CI: 1·05-1·43) in non-smokers. Conversely, LGI was associated with higher haemoglobin in smokers (0·12 mm [0·19 g/dl], 95% CI: 0·06-0·18). CONCLUSION: In this first study of LGI and haemoglobin in healthy individuals, there was a negative association between LGI and haemoglobin in non-smokers. The association was positive in smokers, probably because smoking leads to both increased inflammation and increased haemoglobin through CO exposure.

Osteopontin is highly susceptible to cleavage in bovine milk and the proteolytic fragments bind the αVß3-integrin receptor.

Site-specific and partial proteolysis of milk proteins can both alter and increase their biological activity. The milk protein osteopontin (OPN) is a highly phosphorylated integrin-binding molecule present in most tissues and body fluids. Osteopontin is a biological substrate for matrix metalloproteinases, thrombin, plasmin, and cathepsin D. These proteases cleave OPN at several positions near the integrin-binding sequence Arg-Gly-Asp(138). This cleavage can either increase or reduce the ability of OPN to bind integrins and illustrates that small differences in the cleavage pattern can have a substantial effect on the functionality of OPN. Bovine milk OPN (bOPN) exists in both intact full-length and cleaved forms, and in this study, 6 N-terminal bOPN fragments originating from proteolytic cleavage were purified and characterized by mass spectrometry. These fragments were generated by cleavage at the Lys(145)-Ser(146), Arg(147)-Ser(148), Lys(149)-Lys(150), Phe(151)-Arg(152), Arg(152)-Arg(153), and Arg(153)-Ser(154) peptide bonds. The principal protease in milk, plasmin, appeared to cleave 3 of these sites. However, the major cleavage site was observed to be at the Phe(151)-Arg(152) bond, which does not match the specificity of plasmin. The bOPN fragments were shown to interact with the integrin receptor αVß3 as efficiently as the well-characterized and highly active OPN fragment Ile(1)-Arg(152), generated by thrombin cleavage of human milk OPN. These data show that OPN in milk is highly susceptible to proteolytic cleavage in the region containing the integrin-binding motifs, and the generated fragments are highly capable of binding cells via the αVß3-integrin.

Human leukocyte antigen system associations in Malassezia-related skin diseases.

BACKGROUND: The human leukocyte antigen system (HLA) is divided into two classes involved in antigen presentation: class I presenting intracellular antigens and class II presenting extracellular antigens. While susceptibility to infections is correlated with the HLA system, data on associations between HLA genotypes and Malassezia-related skin diseases (MRSD) are lacking. Thus, the objective of this study was to investigate associations between HLA alleles and MRSD. MATERIALS AND METHODS: Participants in The Danish Blood Donor Study (2010-2018) provided questionnaire data on life style, anthropometric measures, and registry data on filled prescriptions. Genotyping was done using Illumina Infinium Global Screening Array, and HLA alleles were imputed using the HIBAG algorithm. Cases and controls were defined using filled prescriptions on topical ketoconazole 2% as a proxy of MRSD. Logistic regressions assessed associations between HLA alleles and MRSD adjusted for confounders and Bonferroni corrected for multiple tests. RESULTS: A total of 9455 participants were considered MRSD cases and 24,144 participants as controls. We identified four risk alleles B*57:01, OR 1.19 (95% CI: 1.09-1.31), C*01:02, OR 1.19 (95% CI: 1.08-1.32), C*06:02, OR 1.14 (95% CI: 1.08-1.22), and DRB1*01:01, OR 1.10 (95% CI: 1.04-1.17), and two protective alleles, DQB1*02:01, OR 0.89 (95% CI: 0.85-0.94), and DRB1*03:01, OR 0.89 (95% CI: 0.85-0.94). CONCLUSION: Five novel associations between HLA alleles and MRSD were identified in our cohort, and one previous association was confirmed. Future studies should assess the correlation between Malassezia antigens and antigen-binding properties of the associated HLA alleles.

Proteolytic activation of proteose peptone component 3 by release of a C-terminal peptide with antibacterial properties.

The milk protein proteose peptone component 3 (PP3, also known as lactophorin) is a small phosphoglycoprotein, which is exclusively expressed in the lactating mammary gland. A 23-residue synthetic peptide (lactophoricin, Lpcin S), corresponding to the C-terminal amphipathic α-helix of PP3, has previously been shown to permeabilize membranes and display antibacterial activity. Lactophorin readily undergoes proteolytic cleavage in milk and during dairy processing, and it has been suggested that PP3-derived peptides are part of milk's endogenous defense system against bacteria. Here, we report that a 26-residue C-terminal peptide (Lpcin P) can be generated by trypsin proteolysis of PP3 and that structural and functional studies of Lpcin P indicate that the peptide has antibacterial properties. The Lpcin P showed α-helical structure in both anionic and organic solvents, and the amount of α-helical structure was increased in the presence of lipid vesicles. Oriented circular dichroism showed that Lpcin P oriented parallel to the membrane surface. However, the peptide permeabilized calcein-containing vesicles efficiently. Lpcin P displayed antibacterial activity against Streptococcus thermophilus, but not against Staphylococcus aureus and Escherichia coli. The PP3 full-length protein did not display the same properties, which could indicate that PP3 functions as a precursor protein that upon proteolysis, releases a bioactive antibacterial peptide.

Expression cloning of a human granulocyte colony-stimulating factor receptor: a structural mosaic of hematopoietin receptor, immunoglobulin, and fibronectin domains.

We report the isolation from a placental library, of two cDNAs that can encode high affinity receptors for granulocyte colony-stimulating factor (G-CSF) when expressed in COS-7 cells. The cDNAs are predicted to encode integral membrane proteins of 759 and 812 amino acids in length. The predicted extracellular and membrane spanning sequences of the two clones are identical, as are the first 96 amino acids of their respective cytoplasmic regions. Different COOH termini of 34 or 87 residues are predicted for the two cDNAs, due apparently to alternate splicing. The receptor with the longer cytoplasmic domain is the closest human homologue of the murine G-CSF receptor recently described by Fukunaga et al. (Fukunaga, R., E. Ishizaka-Ikeda, Y. Seto, and S. Nagata. 1990. Cell. 61:341). A hybridization probe derived from the placental G-CSF receptor cDNA detects a approximately 3-kb transcript in RNAs isolated from placenta and a number of lymphoid and myeloid cells. The extracellular region of the G-CSF receptors is composed of four distinct types of structural domains, previously recognized in other cell surface proteins. In addition to the two domains of the HP receptor family-defining region (Patthy, L. 1990. Cell. 61:13) it incorporates one NH2-terminal Ig-like domain, and three additional repeats of fibronectin type III-like domains. The presence of both an NH2-terminal Ig-like domain and multiple membrane-proximal FN3-like domains suggests that the G-CSF receptor may be derived from an ancestral NCAM-like molecule and that the G-CSF receptor may function in some adhesion or recognition events at the cell surface in addition to the binding of G-CSF.

Considerable variation in the concentration of osteopontin in human milk, bovine milk, and infant formulas.

Osteopontin (OPN) is a multifunctional bioactive protein that is implicated in numerous biological processes such as bone remodeling, inhibition of ectopic calcification, and cellular adhesion and migration, as well as several immune functions. Osteopontin has cytokine-like properties and is a key factor in the initiation of T helper 1 immune responses. Osteopontin is present in most tissues and body fluids, with the highest concentrations being found in milk. In the present study, ELISA for human and bovine milk OPN were developed and OPN concentration in human breast milk, bovine milk, and infant formulas was measured and compared. The OPN concentration in human milk was measured to approximately 138 mg/L, which corresponds to 2.1% (wt/wt) of the total protein in human breast milk. This is considerably higher than the corresponding OPN concentrations in bovine milk (approximately 18 mg/L) and infant formulas (approximately 9 mg/L). Moreover, bovine milk OPN is shown to induce the expression of the T helper 1 cytokine IL-12 in cultured human lamina propria mononuclear cells isolated from intestinal biopsies. Finally, the OPN concentration in plasma samples from umbilical cords, 3-mo-old infants, and pregnant and nonpregnant adults was measured. The OPN level in plasma from 3-mo-old infants and umbilical cords was found to be 7 to 10 times higher than in adults. Thus, the high levels of OPN in milk and infant plasma suggest that OPN is important to infants and that ingested milk OPN is likely to induce cytokine production in neonate intestinal immune cells.

Challenging the six-hour recommendation for reprocessing sterilizable medical equipment.

BACKGROUND: At present, reprocessing of sterilizable medical equipment is recommended to be initiated within 6 h after completion of surgery, to ensure that the quality of the instruments does not deteriorate. A literature search showed a lack of evidence for consequences that may occur if medical personnel deviate from the standard 6 h sterilization protocol. AIM: To evaluate the 6 h recommendation for reprocessing sterilizable medical equipment by determining whether residual protein increased proportional to holding time before reprocessing was initiated, and likewise whether an increase in corrosion was present on surgical scissors proportional to holding time. METHODS: Residual protein was identified on surgical instruments contaminated with human blood after different holding times and before washes using the o-phthaldialdehyde (OPA) method. Corrosion was identified on surgical scissors contaminated with human blood after different holding times and after reprocessing using light stereomicroscopy and scanning electron microscopy. FINDINGS: Protein residues ranged between 14.0 and 51.9 µg and thus below the accepted threshold of 100 µg per instrument surface. Corrosion corresponding to 0.05% of the surface was identified on 22 of 30 scissors. Pitting corrosion was seen on four of 30 scissors. CONCLUSION: No association was identified between residual protein and holding time, nor between incidence of corrosion and holding time. The study thereby challenges the relevance of upholding the recommendation of a maximum wait of 6 h prior to reprocessing. The findings will potentially have an impact on the organization of reprocessing of surgical instruments in Denmark and internationally.

Long-term mental wellbeing of adolescents and young adults diagnosed with venous thromboembolism: results from a multistage mixed methods study.

Essentials Long-term mental wellbeing of adolescents and young adults with venous thromboembolism is unclear. This multistage mixed methods study was based on Danish nationwide registry data and interviews. Mental wellbeing is negatively impacted in the long-term and uncertainty of recurrence is pivotal. The perceived health threat is more important than disease severity for long-term mental wellbeing. SUMMARY: Background Critical and chronic illness in youth can lead to impaired mental wellbeing. Venous thromboembolism (VTE) is a potentially traumatic and life-threatening condition. Nonetheless, the long-term mental wellbeing of adolescents and young adults (AYAS) with VTE is unclear. Objectives To investigate the long-term mental wellbeing of AYAS (aged 13-33 years) diagnosed with VTE. Methods We performed a multistage mixed method study based on data from the Danish nationwide health registries, and semistructured interviews with 12 AYAS diagnosed with VTE. An integrated mixed methods interpretation of the findings was conducted through narrative weaving and joint displays. Results The integrated mixed methods interpretation showed that the mental wellbeing of AYAS with VTE had a chronic perspective, with a persistently higher risk of psychotropic drug purchase among AYAS with a first-time diagnosis of VTE than among sex-matched and age-matched population controls and AYAS with a first-time diagnosis of insulin-dependent diabetes mellitus. Impaired mental wellbeing was largely connected to a fear of recurrence and concomitant uncertainty. Therefore, it was important for the long-term mental wellbeing to navigate uncertainty. The perceived health threat played a more profound role in long-term mental wellbeing than disease severity, as the potential life threat was the pivot which pointed back to the initial VTE and forward to the perception of future health threat and the potential risk of dying of a recurrent event. Conclusion Our findings show that the long-term mental wellbeing of AYAS diagnosed with VTE is negatively affected, and highlights these patients' need for adequate support.

Gamma-ray imaging with a Si/CsI(Tl) Compton detector.

We present results from Compton imaging of gamma-ray sources using an instrument constructed from thin silicon scattering detectors and CsI(Tl) absorbing detectors. We have successfully imaged single and double point sources for several common radioactive isotopes ((137)Cs, (60)Co, (22)Na, (54)Mn). The measured angular resolution is 11.6( composite function) FWHM at 662keV. In parallel with the hardware effort, a GEANT4-based simulation code was developed. Comparisons between real and simulated data are discussed.

Component alignment and clinical outcome following total knee arthroplasty: a randomised controlled trial comparing an intramedullary alignment system with patient-specific instrumentation.

AIMS: We conducted a randomised controlled trial to assess the accuracy of positioning and alignment of the components in total knee arthroplasty (TKA), comparing those undertaken using standard intramedullary cutting jigs and those with patient-specific instruments (PSI). PATIENTS AND METHODS: There were 64 TKAs in the standard group and 69 in the PSI group. The post-operative hip-knee-ankle (HKA) angle and positioning was investigated using CT scans. Deviation of > 3° from the planned position was regarded as an outlier. The operating time, Oxford Knee Scores (OKS) and Short Form-12 (SF-12) scores were recorded. RESULTS: There were 14 HKA-angle outliers (22%) in the standard group and nine (13%) in the PSI group (p = 0.251). The mean HKA-angle was 0.5° varus in the standard group and 0.2° varus in the PSI group (p = 0.492). The accuracy of alignment in the coronal and axial planes and the proportion of outliers was not different in the two groups. The femoral component was more flexed (p = 0.035) and there were significantly more tibial slope outliers (29% versus 13%) in the PSI group (p = 0.032). Operating time and the median three-month OKS were similar (p = 0.218 and p = 0.472, respectively). Physical and mental SF-12 scores were not significantly different at three months (p = 0.418 and p = 0.267, respectively) or at one year post-operatively (p = 0.114 and p = 0.569). The median one-year Oxford knee score was two points higher in the PSI group (p = 0.049). CONCLUSION: Compared with standard intramedullary jigs, the use of PSI did not significantly reduce the number of outliers or the mean operating time, nor did it clinically improve the accuracy of alignment or the median Oxford Knee Scores. Our data do not support the routine use of PSI when undertaking TKA. Cite this article: Bone Joint J 2016;98-B:1043-9.

Digital questionnaire platform in the Danish Blood Donor Study.

OBJECTIVES: The Danish Blood Donor Study (DBDS) is a prospective, population-based study and biobank. Since 2010, 100,000 Danish blood donors have been included in the study. Prior to July 2015 all participating donors had to complete a paper-based questionnaire. Here we describe the establishment of a digital tablet-based questionnaire platform implemented in blood bank sites across Denmark. METHODS: The digital questionnaire was developed using the open source survey software tool LimeSurvey. The participants accesses the questionnaire online with a standard SSL encrypted HTTP connection using their personal civil registration numbers. The questionnaire is placed at a front-end web server and a collection server retrieves the completed questionnaires. Data from blood samples, register data, genetic data and verification of signed informed consent are then transferred to and merged with the questionnaire data in the DBDS database. RESULTS: The digital platform enables personalized questionnaires, presenting only questions relevant to the specific donor by hiding unneeded follow-up questions on screening question results. New versions of questionnaires are immediately available at all blood collection facilities when new projects are initiated. CONCLUSION: The digital platform is a faster, cost-effective and more flexible solution to collect valid data from participating donors compared to paper-based questionnaires. The overall system can be used around the world by the use of Internet connection, but the level of security depends on the sensitivity of the data to be collected.

Characterization of a bovine mammary gland PP3 cDNA reveals homology with mouse and rat adhesion molecule GlyCAM-1.

A full length PP3 (Proteose-Peptone component 3) cDNA of 679 bp was isolated from a bovine mammary gland cDNA library. The cDNA encodes a signal peptide of 18 amino acids followed by the mature PP3 sequence of 135 amino acids. This polypeptide showed homology with mouse and rat GlyCAM-1 (Glycosylation dependent Cell Adhesion Molecule 1) a protein which has been shown to act as a ligand for lymphocytes. The similarity was most profound between the signal peptides and three short regions of the mature polypeptides. Additionally structural conservation was predicted by computer analysis in the shape of a C-terminal amphipathic helix. PP3 was found to be expressed in mammary gland but not in peripheral lymph nodes, Peyer's pathes, lung, spleen, heart, and muscle.

SorCS3 does not require propeptide cleavage to bind nerve growth factor.

The functional properties of the Vps10p-domain receptor SorCS3 are undescribed. Here, we examine its processing and sorting in cellular transfectants, and analyze the binding of potential ligands to the purified receptor. We show that SorCS3 is synthesized as a proprotein and converted to its mature form by N-terminal propeptide cleavage in distal Golgi compartments. The propeptide is not a requirement for normal processing of the receptor and does not prevent ligands from binding to the SorCS3 precursor form. Expression of wt and chimeric receptors further suggests that SorCS3 predominates on the plasma membrane, exhibits slow internalization and does not engage in intracellular trafficking. SorCS3 emerges as a new neurotrophin binding Vps10p-domain receptor functionally distinct from its relatives Sortilin and SorLA.