Elevated uric acid and adenosine triphosphate concentrations in bronchoalveolar lavage fluid of eosinophilic pneumonia

Publication date: Available online 10 July 2017
Source:Allergology International
Author(s): Takehito Kobayashi, Kazuyuki Nakagome, Toru Noguchi, Kiyoko Kobayashi, Yutaka Ueda, Tomoyuki Soma, Kenji Ikebuchi, Hidetomo Nakamoto, Makoto Nagata
BackgroundRecent evidence has suggested that the innate immune response may play a role in the development of eosinophilic airway inflammation. We previously reported that uric acid (UA) and adenosine triphosphate (ATP), two important damage-associated molecular pattern molecules (DAMPs), activate eosinophil functions, suggesting that these molecules may be involved in the development of eosinophilic airway inflammation. The objective of this study was to measure the concentrations of DAMPs including UA and ATP in the bronchoalveolar lavage fluid (BALF) of patients with eosinophilic pneumonia (EP).MethodsBAL was performed in patients with EP including acute and chronic eosinophilic pneumonia, and in patients with hypersensitivity pneumonia, and sarcoidosis. UA, ATP, and cytokine concentrations in the BALF were then measured.ResultsThe UA concentration was increased in the BALF of EP patients. UA concentrations correlated with eosinophil numbers, and with eosinophil-derived neurotoxin and interleukin (IL)-5 concentrations. Furthermore, the ATP concentration was increased in the BALF of EP patients and ATP concentrations correlated with UA concentrations. Moreover, IL-33 was increased in EP patients and IL-33 concentrations correlated with UA and ATP concentrations.ConclusionsThe UA and ATP concentration was increased in the BALF of EP patients. UA concentrations correlated with eosinophil numbers, and with ATP and IL-33 concentrations. Our findings suggest that DAMPs such as UA and ATP play a role in the pathogenesis of EP.



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Ethambutol partitioning in tuberculous pulmonary lesions explains its clinical efficacy [PublishAheadOfPrint]

Clinical trials and practice have shown that ethambutol is an important component of the first line tuberculosis (TB) regime. This contrasts the drug's rather modest potency and lack of activity against non-growing persister mycobacteria. The standard plasma-based pharmacokinetic-pharmacodynamic profile of ethambutol suggests that the drug may be of limited clinical value. Here we hypothesized that this apparent contradiction may be explained by favorable penetration of the drug into TB lesions. First we utilized novel in vitro lesion pharmacokinetic assays and predicted good penetration of the drug into lesions. We then employed mass spectrometry imaging and laser capture microdissection coupled to liquid chromatography and tandem mass spectrometry (LCM/LCMS) to show that ethambutol indeed accumulates in diseased tissues and penetrates the major human-like lesion types represented in the rabbit model of TB disease with a lesion-to-plasma exposure ratio ranging from 9 to 12. In addition, ethambutol exhibits slow but sustained passive diffusion into caseum to reach concentrations markedly higher than measured in plasma at steady state. The results explain why ethambutol has retained its place in the first line regimen, validate our in vitro lesion penetration assays and demonstrate the critical importance of effective lesion penetration for anti-TB drugs. Our findings suggest that in vitro and in vivo lesion penetration evaluation should be included in TB drug discovery programs. Finally, this is the first time that LCM/LCMS is used to quantify a small molecule at high spatial resolution in infected tissues, a method that can easily be extended to other infectious diseases.

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Characterization of the complete nucleotide sequence of IncA/C2 plasmids carrying In809-like integrons from Enterobacteriaceae of wildlife origin [PublishAheadOfPrint]

A total of 18 Enterobacteriaceae (seventeen from gulls, and one from a clinical sample), carrying IncA/C plasmids with the IMP-encoding In809-like integrons, collected from Australia were studied. Seven plasmids being representatives of different origins, plasmid sizes, replicon combinations and resistance genes, were completely sequenced. Plasmid pEc158, identified in a clinical ST752 Escherichia coli isolate, showed extensive similarity to type 2 IncA/C₂ plasmids. pEc158 carried none of the bla_CMY-2-like region, ARI-B and ARI-A regions, while it contained a hybrid transposon structure. The six remaining plasmids, which were of wildlife origin, were highly similar to each other and probably were fusion derivatives of type 1 and type 2 A/C₂ plasmids. The latter plasmids contained an ARI-B region and hybrid transposon structures. In all plasmids, hybrid transposon structures containing In809-like integrons were inserted 3434 bp downstream the rhs2 start codon. In all cases, the one outermost 38 bp IR of the transposon was associated with the Tn1696 tnp module, while the other outermost 38 bp IR of the transposon was associated with either a Tn6317-like module or a Tn21 mer module. However, the internal structure of the transposon and the resistance genes were different in each plasmid. These findings indicated that, for the specific periods of time and settings, different IncA/C₂ plasmid types carrying In809-like elements circulated among isolates of wildlife and clinical origin. Additionally, they provided the basis for speculations regarding the reshuffling of IncA/C₂ plasmids with In809-like integrons and confirmed the rapid evolution of IncA/C₂ plasmid lineages.

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The sterilizing effect of ertapenem-clavulanate in a hollow fiber model of tuberculosis and implications on clinical dosing [PublishAheadOfPrint]

Carbapenems are now being explored for treatment of multi-drug resistant tuberculosis (MDR-TB), especially in conjunction with clavulanate. Clinical use is constrained by the need for multiple parenteral doses per day, and lack of knowledge of the optimal dose for sterilizing effect. Our objective was to identify the ertapenem exposure associated with optimal sterilizing effect and then design a once a day dose for clinical use. We utilized the hollow fiber system model of tuberculosis in a 28-day exposure-response study of 8 different ertapenem doses in combination with clavulanate. The systems were sampled at predetermined time-points to verify the concentration-time profile and identify the total bacterial burden. Inhibitory sigmoid E_max modeling was used to identify the relationship between total bacterial burden and the drug exposure, and identify optimal exposures. Contrary to the literature, ertapenem-clavulanate combination demonstrated good microbial kill and sterilizing effect. In a dose-fractionation hollow fiber study, efficacy was linked to percentage of the 24 hour dosing interval of ertapenem concentration persisting above MIC (%T_MIC). We performed a 10,000 MDR-TB patient computer-aided clinical trial simulations, based on Monte Carlo methods, to identify the doses and schedule that would achieve or exceed %T_MIC ≥40%. We identified an intravenous dose of 2 grams once per day as achieving the target in 96% of patients. An ertapenem susceptibility breakpoint MIC 2 mg/L was identified for that dose. An ertapenem dose of 2g once daily is the most suitable to be tested in a phase II study of sterilizing effect in MDR-TB patients.

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Evaluation of Combination Drug Therapy for Treatment of Antibiotic Resistant Inhalation Anthrax in a Murine Model [PublishAheadOfPrint]

Bacillus anthracis is considered a likely agent to be used as a bioweapon and use of a strain resistance to the first-line antimicrobial treatments is a concern. We determined treatment efficacy against a ciprofloxacin-resistant (C^r) strain of B. anthracis (C^r Ames) in a murine inhalational anthrax model. Ten groups of 46 BALB/c mice were exposed by inhalation to 7-35 LD₅₀ of B. anthracis C^r Ames spores. Commencing at 36 hours (h) post-exposure, groups were administered intraperitoneal doses of sterile water for injections (SWI) and ciprofloxacinalone (control groups), or ciprofloxacin combined with two antimicrobials including meropenem/linezolid, meropenem/clindamycin, meropenem/rifampin, meropenem/doxycycline, penicillin/linezolid, penicillin/doxycycline, rifampin/linezolid, or rifampin/clindamycin at appropriate dosing intervals(6 or 12 hours) for the respective antibiotics. Ten mice per group were treated for 14 days and observed until day 28. Remaining animals were euthanized every 6-12h and blood, lungs, and spleens collected for lethal factor (LF) and/or bacterial load determinations. All combination groups showed significant survival over the SWI and ciprofloxacin controls: meropenem/linezolid (p=0.004), meropenem/clindamycin (p=0.005), meropenem/rifampin (p=0.012), meropenem/doxycycline (p=0.032), penicillin/doxycycline (p=0.012), penicillin/linezolid (p=0.026), rifampin/linezolid (p=0.001), and rifampin/clindamycin (p=0.032). In controls, blood, lung, and spleen bacterial counts increased to terminal endpoints. In combination treatment groups, blood and spleen bacterial counts showed low/no colonies after 24 hours treatment. LF fell below detection limits for all combination groups, yet remained elevated in control groups. Combinations with linezolid had the greatest inhibitory effect on mean LF levels.

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Comparison of Omadacycline and Tigecycline Pharmacokinetics in the Plasma, Epithelial Lining Fluid, and Alveolar Cells in Healthy Adult Subjects [PublishAheadOfPrint]

The steady-state concentrations of omadacycline and tigecycline in plasma, epithelial lining fluid (ELF), and alveolar cells (AC) concentrations were obtained in 58 healthy adult subjects. Subjects were administered either omadacycline as 100 mg intravenously (IV) every 12 hours for two doses followed by 100 mg IV every 24 hours for three doses or tigecycline as an initial dose of 100 mg IV followed by 50 mg IV every 12 hours for six doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject following the start of the fifth dose of omadacycline at 0.5, 1, 2, 4, 8, 12, or 24 hours, and after the start of the seventh dose of tigecycline at 2, 4, 6, or 12 hours. The AUC_0-24 value (based on mean concentrations) in ELF and the ratio of ELF to total plasma omadacycline based on AUC_0-24 values were 17.23 mg·h/L and 1.47, respectively. The AUC_0-24 value in AC was 302.46 mg·h/L and the ratio of AC to total plasma omadacycline concentrations was 25.8. In comparison, AUC_0-12 values based on mean concentrations of tigecycline in ELF and AC were 3.16 and 38.50 mg·h/L, respectively. The ratio of ELF and AC to total plasma concentrations of tigecycline based on AUC_0-12 values were 1.71 and 20.8, respectively. The pharmacokinetic advantages of higher and sustained concentrations of omadacycline in plasma, ELF, and AC compared to tigecycline suggest that omadacycline is a promising antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

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Biofilms formed by isolates from recurrent vulvovaginal candidiasis patients are heterogeneous and insensitive to fluconazole [PublishAheadOfPrint]

Vulvovaginal candidiasis (VVC) is a global health problem affecting ~75% of women at least once in their lifetime. Here we examined the epidemiology of VVC from a patient cohort to identify the causative organisms associated with VVC. Biofilm forming capacity and antifungal sensitivity profiles were also assessed. We report a shifting prevalence of Candida species with heterogeneous biofilm forming capacity, both of which are associated with altered antifungal drug sensitivity.

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Comparison of Plasma and Intrapulmonary Concentrations of Nafithromycin (WCK 4873) in Healthy Adult Subjects [PublishAheadOfPrint]

Nafithromycin concentrations in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) of 37 healthy adult subjects were measured following repeated dosing of oral nafithromycin 800 mg once daily for three days. Noncompartmental pharmacokinetic (PK) parameters were determined from serial plasma samples collected over a 24-hour interval following the first and third oral doses. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) at 3, 6, 9, 12, 24 or 48 hours after the third dose of nafithromycin. Mean (± SD) plasma PK parameters after the first and third dose included C_max of 1.02 ± 0.31 and 1.39 ± 0.36 μg/mL, t_max of 3.97 ± 1.30 h and 3.69 ± 1.28 h, CL/F of 67.3 ± 21.3 L/h and 52.4 ± 18.5 L/h, and elimination t1/2 of 7.7 ± 1.1 and 9.1 ± 1.7 h. AUC_0-24 values of nafithromycin based on mean or median total plasma concentrations at BAL sampling times were 16.2 μg·h/mL. For ELF, the respective AUC_0-24 values based on mean and median concentrations were 224.1 and 176.3 μg·h/mL, whereas AUC_0-24 values for AM were 8538 and 5894 μg·hr/mL. Penetration ratios based on ELF and total plasma AUC_0-24 values based on mean and median concentrations were 13.8 and 10.9, whereas ratios of AM to total plasma concentrations were 527 and 364. The sustained ELF and AM concentrations for 48 hours after the third dose suggest that nafithromycin has the potential to be a useful agent for the treatment of lower respiratory tract infections.

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MDR1 and BCRP transporter-mediated drug-drug interaction between rilpivirine and abacavir; effect on intestinal absorption [PublishAheadOfPrint]

Rilpivirine (TMC278) is a highly potent second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters in vitro and assess its importance for pharmacokinetics in vivo.

Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2 or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP and Caco-2 cells demonstrated that rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport. In vivo experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir.

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Persistent Loss of HBV Markers in Serum without Cellular Immunity by Combination of PEG-IFN Plus ETV Therapy in Humanized Mice [PublishAheadOfPrint]

Nucleot(s)ide analogues and peg-interferon (PEG-IFN) treatment are the only approved therapies for chronic hepatitis B virus (HBV) infection. However, complete eradication of the virus, as indicated by persistent loss of hepatitis B surface antigen (HBsAg), is rare among treated patients. This is due to long-term persistence of the HBV genome in infected hepatocytes in the form of covalently closed circular DNA (cccDNA). In this study, we investigated whether administration of a large dose of a nucleoside analogue in combination with PEG-IFN can achieve long term loss of HBsAg in human hepatocyte chimeric mice. Mice were treated with a high dose of entecavir and/or PEG-IFN for six weeks. High dose combination therapy with both drugs resulted in persistently negative HBV DNA in serum. Although small amounts of HBV DNA and cccDNA (0.1 and 0.01 copy/cell, respectively) remained in the mouse livers, some of the mice remained persistently negative for serum HBV DNA 13 weeks after cessation of the therapy. Serum HBsAg and hepatitis B core-related antigen (HBcrAg) continued to decrease and eventually became negative 12 weeks after cessation of the therapy. Analysis of the HBV genome in treated mice showed accumulation of G to A hypermutation and CpG III island methylation. Persistent loss of serum HBV DNA and loss of HBV markers by high dose entecavir and PEG-IFN combination treatment in chimeric mice suggests that control of HBV can be achieved even in the absence of a cellular immune response.

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Role of daptomycin on wound healing in a MRSA burn infected animal model [PublishAheadOfPrint]

Prolonged hospitalization and antibiotic therapy are risk factors for the development of methicillin-resistant S. aureus (MRSA) infections in thermal burn patients. We used a rat model to study the in vivo efficacy of daptomycin in the treatment of burn wound infections by S. aureus and we evaluated the wound healing process through morphological and immunohistochemical analysis. A copper bar heated in boiling water was applied on paraspinal site of each rat resulting in two full thickness burns. A small gauze was placed over each burn and inoculated with 5x10⁷ cfu of S. aureus ATCC 43300. The study included two control not infected groups, with and without daptomycin treatment, a control infected group that did not receive any treatment and two infected groups treated, respectively, with intraperitoneal daptomycin and teicoplanin. The main outcome measures were quantitative culture, histological evaluation of tissue repair and immunohistochemical expression of wound healing markers: Epidermal Growth Factor Receptor (EGFR) and Fibroblast Growth Factor 2 (FGF-2). The highest inhibition of infection was achieved in the group that received daptomycin reducing the bacterial load from 10⁷ cfu/mL to about 10³ cfu/g (P<0.01). The groups treated with daptomycin showed better overall healing with epithelialization and significantly higher collagen scores than the other groups, also confirmed by immunohistochemical data.

In conclusion, our results support the hypothesis that daptomycin, is an important modulator of wound repair by, possibly, reducing hypertrophic burn scar formation.

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Metallo-{beta}-lactamases (DIM-1, NDM-1, VIM-2) and a 16S rRNA methyltransferase (RmtB4, RmtF2) producing Pseudomonas aeruginosa in Nepal [PublishAheadOfPrint]

A total of 11 multidrug-resistant Pseudomonas aeruginosa clinical isolates were obtained in Nepal. Four of these isolates harbored genes encoding one or more carbapenemases (DIM-1_, NDM-1 and/or VIM-2), and five harbored genes encoding a 16S rRNA methyltransferase (RmtB4 or RmtF2). A novel RmtF variant, RmtF2, had a substitution (K65E) compared with RmtF. To our knowledge, this is the first report describing carbapenemase- and 16S rRNA methyltransferase-co-producing P. aeruginosa clinical isolates in Nepal.

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Implications of antimicrobial combinations in complex wound biofilms containing fungi [PublishAheadOfPrint]

Diabetic foot ulcer treatment currently focuses on targeting bacterial biofilms, while dismissing fungi. To investigate this we used an in vitro biofilm model containing bacteria and fungi, reflective of the wound environment, to test the impact of antimicrobials. Here we showed that while mono-treatment approaches influenced biofilm composition it had no discernible effect on overall quantity. Only by combining bacterial and fungal specific antibiotics were we able to decrease the biofilm bioburden, irrespective of composition.

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Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis [PublishAheadOfPrint]

Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in immunocompromised patients. We hypothesized that simultaneous inhibition of biosynthesis of ergosterol in the fungal cell membrane and (1->3)-β-D-glucan in the cell wall, respectively, by the antifungal triazole isavuconazole and the echinocandin micafungin, may result in improved outcome in experimental IPA in persistently neutropenic rabbits. Treatment groups included isavuconazole (ISA) at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg/day, micafungin at 2 mg/kg/day (MFG2), or combinations of (ISA20+MFG2), (ISA40+MFG2), (ISA60+MFG2), and untreated rabbits (UC). Galactomannan index (GMI) and (1->3)-β-D-glucan levels were measured in serum. Residual fungal burden (CFU/g) was significantly reduced in ISA20-, ISA40-, ISA60-, ISA20+MFG2-, ISA40+MFG2-, and ISA60+MFG2-treated rabbits vs that of MFG2-treated or UC (p<0.01). Measures of organism-mediated pulmonary injury, lung weights and pulmonary infarct score, were lower in ISA40+MFG2-treated rabbits in comparison to those of ISA40 or MFG2 alone (p<0.01). Survival in ISA40+MFG2-treated rabbits was prolonged in comparison to those treated with ISA40 or MFG2 alone (p<0.01). These outcome variables correlated directly with a significant decline of GMI and serum (1->3)-β-D-glucan levels during therapy. GMI correlated with measures of organism-mediated pulmonary injury, lung weights (r=0.764; p<0.001) and pulmonary infarct score (r=0.911; p<0.001). In summary, rabbits receiving combination therapy with isavuconazole and micafungin demonstrated significant dose-dependent reduction of residual fungal burden, decreased pulmonary injury, prolonged survival, lower GMI and serum (1->3)-β-D-glucan levels in comparison to that of single agent isavuconazole or micafungin.

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Community composition determines activity of antibiotics against multispecies biofilms [PublishAheadOfPrint]

In young cystic fibrosis (CF) patients, Staphylococcus aureus is typically the most prevalent organism, while in adults, Pseudomonas aeruginosa is the major pathogen. More recently, it was observed that also Streptococcus anginosus plays an important role in exacerbations of respiratory symptoms. These species are often co-isolated from CF lungs, yet little is known about whether antibiotic killing of one species is influenced by the presence of others. In the present study, we compared the activity of various antibiotics against S. anginosus, S. aureus and P. aeruginosa when grown in monospecies biofilms, with the activity observed in a multispecies biofilm. Our results show that differences in antibiotic activity against species grown in mono- and multispecies biofilms are species- and antibiotic-dependent. Less S. anginosus cells are killed by antibiotics that interfere with cell wall synthesis (amoxicillin+sulbactam, cefepime, imipenem, meropenem, and vancomycin) in presence of S. aureus and P. aeruginosa, while for ciprofloxacin, levofloxacin, and tobramycin, no difference was observed. In addition, we observed that the cell-free supernatant of S. aureus, but not that of P. aeruginosa biofilms, also caused this decrease in killing. Overall, S. aureus was more affected by antibiotic treatment in a multispecies biofilm, while for P. aeruginosa, no differences were observed between growth in mono- or multispecies biofilms.

The results of the present study suggest that it is important to take the community composition into account when evaluating the effect of antimicrobial treatments against certain species in mixed biofilms.

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The adverse effects and choice of injectable agents in MDR-TB: amikacin or capreomycin [PublishAheadOfPrint]

Background: The prolonged use of injectable agents in an MDR-TB regimen is recommended by the WHO despite association with ototoxicity and nephrotoxicity.

Objective: We undertook this study to look at the relative adverse effects of capreomycin and amikacin.

Methods: We reviewed the case notes of 100 consecutive patients treated at 4 MDR-TB treatment centres in the UK.

Results: The median total duration of treatment with an injectable agent was 178 (IQR 109-192, n=73) days for those with MDR-TB, 179 (104-192, n=12) days for those with MDR-TB plus fluoroquinolone resistance and 558 (324-735, n=8) days for those with XDR-TB. Injectable use was longer for those started with capreomycin at 183 (IQR 123-197) days compared to 119 (IQR 83-177) days with amikacin (p=0.002). Excluding XDR-TB, 51 (51/85, 60%) patients were treated with an injectable for over 6 months and 12 (12/85, 14%) for over 8 months. 40 % of all patients discontinued the injectable due to hearing loss. 55% of patients experienced ototoxicity: 5 times (hazard ratio (HR) 5.2, CI 1.2-22.6, p=0.03) more likely in those started on amikacin compared to treatment with capreomycin only. Amikacin was associated with less hypokalemia than capreomycin (Odds ratios: 0.28 (0.11-0.72)), with 5 (5/37, 14%) patients stopping capreomycin due to recurrent electrolyte loss. There was no difference in the number experiencing a creatinine rise of > 1.5 times baseline.

Conclusion: Hearing loss is frequent in this cohort, though significantly lower in those starting capreomycin which should be given greater consideration as a first line agent.

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Successful pregnancy after mucinous cystic neoplasm with invasive carcinoma of the pancreas in a patient with polycystic ovarian syndrome: a case report

The incidence of invasive cancer within a mucinous cystic neoplasm of the pancreas varies between 6 and 36%. Polycystic ovarian syndrome is a disorder characterized by hyperandrogenism and anovulatory infertil...

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Is peanut causing food allergy in Cuba? Preliminary assessment of allergic sensitization and IgE specificity profile to peanut allergens in Cuban allergic patients

Peanut allergy is increasing at an alarming pace in developed countries. Peanut (Arachis hypogaea) is a common food in Cuba. Nevertheless, reported values of sensitization and symptom severity are usually low. As...

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Social Justice, Equality and Primary Care: (How) Can ‘Big Data’ Help?

Abstract

A growing body of research emphasises the role of 'social determinants of health' in generating inequalities in health outcomes. How, if at all, should primary care providers respond? In this paper, I want to shed light on this issue by focusing on the role that 'big data' might play in allowing primary care providers to respond to the social determinants that affect individual patients' health. The general idea has been proposed and endorsed by the Institute of Medicine, and the idea has been developed in more detail by Bazemore et al. (2016). In Bazemore et al.'s proposal, patients' addresses are used to generate information about the patients' neighbourhood; this information is then included in patients' health care records and made available to providers. This allows primary care providers to take this information into account when interacting with, and providing care to, patients. I explore three issues arising from this proposal. First, while questions of privacy have been central to discussions about big data, Bazemore et al.'s proposal also allows us to see that there might be costs to not making certain information available. Second, I consider some of the questions arising for primary care from the influence of social factors on health outcomes: given that we know these factors to be significant contributors to social inequalities in health, what precisely should be done about this in the primary care context? Finally, I address problems arising from the use of population level data when dealing with individuals.

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Advances in midface reconstruction: beyond the reconstructive ladder.

Purpose of review: This article reviews the anatomy and function of the midface, defect classifications and the breadth of common and novel reconstructive techniques including medical modeling, dental splints, and dental rehabilitation. Recent findings: Historically many classification systems for midface and maxillary defects exist but most defects are unique and an individualized approach is required. There has been an increased interest in using regional pedicled flaps with bone for reconstruction. Free flap reconstruction with the osteocutaneous radial forearm and fibula flap have been recently modified to increase the success of osseointegrated implants. Scapular free flap reconstruction has become increasingly popular because of the versatility, good bony contour match, and long pedicle length with the scapular tip flap. Dental splints are more cost effective than medical modeling and cutting guides but both techniques are complimentary in complex reconstruction. Summary: Midface reconstruction is a unique and challenging surgery demonstrated by the numerous classification systems and techniques available to reconstruct. Recent developments have further augmented these challenging reconstructions. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Prophylaxis of postoperative complications after craniotomy.

Purpose of review: This review reports an update of the evidence on practices applied for the prevention and management of the most common complications after craniotomy surgery. Recent findings: Latest guidelines support the combined thromboprophylaxis with the use of both mechanical and chemical modalities, preferably applied within 24 h after craniotomy. Nevertheless, a heightened risk of minor hemorrhagic events remains an issue of concern. Postoperative nausea and vomiting (PONV) and pain constitute the complications most commonly encountered during the first 24 h postcraniotomy. Recently, neurokinin type-1 receptor antagonists have been tested as adjuncts for PONV prophylaxis with encouraging results, whereas dexmedetomidine and gabapentinoids emerge as promising alternatives for postcraniotomy pain management. The available data for seizure prophylaxis following craniotomy lacks scientific quality; thus, this remains still a debatable issue. Significantly, a growing body of evidence supports the superiority of levetiracetam over the older antiepileptic drugs (AEDs), in terms of efficacy and safety. Summary: Optimum management of postoperative complications is incorporated as an integral part of the augmented quality of care in patients undergoing craniotomy surgery, aiming to improve outcomes. This review may serve as a benchmark for neuroanesthetists for heightened clinical awareness and prompt institution of well-documented practices. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Lipid emulsion in local anesthetic toxicity.

Purpose of review: Enthusiasm for regional anesthesia has been driven by multimodal benefits to patient outcomes. Despite widespread awareness and improved techniques (including the increasing use of ultrasound guidance for block placement), intravascular sequestration and the attendant risk of local anesthetic systemic toxicity (LAST) remains. Intravenous lipid emulsion (ILE) for the treatment of LAST has been endorsed by anesthetic regulatory societies on the basis of animal study and human case report data. The accumulated mass of reporting now permits objective interrogation of published literature. Recent findings: Although incompletely elucidated the mechanism of action for ILE in LAST seemingly involves beneficial effects on initial drug distribution (i.e., pharmacokinetic effects) and positive cardiotonic and vasoactive effects (i.e., pharmacokinetic effects) acting in concert. Recent systematic review by collaborating international toxicologic societies have provided reserved endorsement for ILE in bupivacaine-induced toxicity, weak support for ILE use in toxicity from other local anesthetics, and largely neutral recommendation for all other drug poisonings. Work since publication of these recommendations has concluded that there is a positive effect on survival for ILE when animal models of LAST are meta-analyzed and evidence of a positive pharmacokinetic effect for lipid in human models of LAST. Summary: Lipid emulsion remains first-line therapy (in conjunction with standard resuscitative measures) in LAST. Increasing conjecture as to the clinical efficacy of ILE in LAST, however, calls for high-quality human data to refine clinical recommendations. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Effects of Interleukin 17 on the cardiovascular system

Publication date: Available online 10 July 2017
Source:Autoimmunity Reviews
Author(s): Marie Robert, Pierre Miossec
Cardiovascular diseases remain the leading cause of death worldwide and account for most of the premature mortality observed in chronic inflammatory diseases. Common mechanisms underlie these two types of disorders, where the contribution of Interleukin (IL)-17A, the founding member of the IL-17 family, is highly suspected. While the local effects of IL-17A in inflammatory disorders have been well described, those on the cardiovascular system remain less studied. This review focuses on the effects of IL-17 on the cardiovascular system both on isolated cells and in vivo. IL-17A acts on vessel and cardiac cells, leading to inflammation, coagulation and thrombosis. In vivo and clinical studies have shown its involvement in the pathogenesis of cardiovascular diseases including atherosclerosis and myocardial infarction that occur prematurely in chronic inflammatory disorders. As new therapeutic approaches are targeting the IL-17 pathway, this review should help to better understand their positive and negative outcomes on the cardio-vascular system.



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Biologics in Myelodysplastic Syndrome-related Systemic Inflammatory and Autoimmune Diseases: French Multicenter Retrospective Study of 29 Patients

Publication date: Available online 10 July 2017
Source:Autoimmunity Reviews
Author(s): Arsene Mekinian, Guillaume Dervin, Nathanael Lapidus, Jean-Emmanuel Kahn, Louis Terriou, Eric Liozon, Eric Grignano, Jean-Charles Piette, Odile Beyne Rauzy, Vincent Grobost, Pascal Godmer, Jerome Gillard, Julien Rossignol, David Launay, Achille Aouba, Thierry Cardon, Laurence Bouillet, Jonathan Broner, Julien Vinit, Lionel Ades, Fabrice Carrat, Clementine Salvado, Eric Toussirot, Mathilde Versini, Nathalie Costedoat-Chalumeau, Jean Baptiste Fraison, Philippe Guilpain, Pierre Fenaux, Olivier Fain
BackgroundSystemic inflammatory and autoimmune diseases (SIADs) associated with myelodysplastic syndromes are often difficult to treat. Corticosteroids are efficient but only usually at high doses. The use of biologics needs to be specified.MethodsIn a French multicenter retrospective study, we analyzed the efficacy and safety of biologics (tumor necrosis factor-α [TNF-α] antagonists, tocilizumab, rituximab and anakinra) for SIADs associated with myelodysplastic syndromes (MDSs). Clinical, biological and overall treatment responses were evaluated. When several lines of treatment were used, data were analyzed before and at the end of each treatment line and were pooled to compare overall response among steroids, disease-modifying anti-rheumatic drugs (DMARDs) and biologics.ResultsWe included 29 patients (median age 67years [interquartile range 62–76], 83% males) with MDS-related SIADs treated with at least one biologic. The MDSs were predominantly refractory anemia with excess blasts 1 (38%) and refractory cytopenia with multilineage dysplasia (21%). The SIADs were mainly arthritis (n=6; 20%), relapsing polychondritis (n=8; 30%) and vasculitis (n=10; 34%). During a 3-year median follow-up (IQR 1.3–4.5), a total of 114 lines of treatments were used for all patients: steroids alone (22%), DMARDs (23%), TNF-α antagonists (14%), anakinra (10%), rituximab (10%), tocilizumab (7%) and azacytidine (9%). Considering all 114 lines, overall response (complete and partial was showed in 54% cases. Overall response was more frequent with steroids (78%) and rituximab (66%) than DMARDs (45%) and other biologics (33%) (p<0.05). Rituximab had better response in vasculitis and TNF-α antagonists in arthritis. During follow-up, 20 patients (71%) presented at least one severe infection.ConclusionThis nationwide study demonstrates the efficacy of steroids for SIAD-associated MDSs but a high frequency of steroid dependence. The response to biologics seems low, but rituximab and azacytidine seem promising.



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Otolaryngology exposure in a longitudinal integrated clerkship setting

Although 20–40% of primary care complaints are Otolaryngology-Head and Neck Surgery (OtoHNS) related, little emphasis is placed on OtoHNS instruction at the undergraduate medical education level. An OtoHNS cle...

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Bringing Your Baby Home From the Hospital

When it comes to bringing baby home from the hospital, what do you really NEED? Tune in right now to Belly to Baby as Abby chats with Libby and Dr Bryanne Colvin to review car seats, feeding, bathing and safe sleep. Type your comments below and we'll try to address them live!

The post Bringing Your Baby Home From the Hospital appeared first on ChildrensMD.

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Theranostik

Zusammenfassung

Hintergrund

Die erfolgreiche Behandlung von neuroendokrinen Tumoren nach dem Theranostik-Prinzip ist ein Durchbruch, der auch andere Tumorentitäten in den Fokus der molekularen Bildgebung und Therapie mit radiosiotopenmarkierten Liganden gerückt hat.

Ergebnisse

Der Nachweis von primären und metastasierten Prostatakarzinomen mit Gallium-68(⁶⁸Ga)-markiertem PSMA („prostate-specific membrane antigen") und die molekulare Radiotherapie mit Lutetium-177(¹⁷⁷Lu)-PSMA unter Verwendung sog. kleiner Moleküle in Form der PSMA-vermittelten Radioligandentherapie (PRLT) gilt als nächster Meilenstein der personalisierten nuklearmedizinischen Diagnostik und Therapie. Die ⁶⁸Ga-PSMA-PET-CT ermöglicht den spezifischen Nachweis von primären Prostatakarzinomen und die Detektion sehr kleiner Metastasen im Bereich von wenigen Millimetern mit bisher nicht gekannter Sensitivität und Spezifität. Die quantitativen PET-CT-Bilddatensätze dienen auch der gezielten Selektion von Patienten für die PRLT im Sinne der „precision medicine" und können ebenso für die Evaluation des Ansprechens auf die Therapie (molekulare Therapieantwort) herangezogen werden.

Schlussfolgerung

Die Ergebnisse der seit Frühjahr 2013 mit ¹⁷⁷Lu-PSMA behandelten Patienten in verschiedenen deutschen Zentren zeigen, dass die PRLT ein sehr großes Potenzial zur effektiven Therapie von Patienten mit metastasierten Prostatakarzinomen hat, die auf eine Hormon- und/oder Chemotherapie nicht mehr ansprechen. Weitere, möglichst prospektive und randomisierte Studien zur validen Ermittlung von Daten zum progressionsfreien und zum Gesamtüberleben müssen den Stellenwert der Radioligandentherapie mit ¹⁷⁷Lu-PSMA und den evtl. früheren Einsatz und die Abfolge im Rahmen verschiedener Therapiemodalitäten zukünftig noch genauer definieren, insbesondere im Vergleich (oder auch in Kombination) mit bereits etablierten Substanzen wie Enzalutamid, Abirateron oder Docetaxel. Weitere Verbesserungen sind durch die Anwendung von α‑Strahlern (z. B. Actinium-225- oder Bismuth-213-markierte PSMA-Liganden) sowie die Kombination mit Hormonsyntheseinhibitoren oder mit Radiosensitizern denkbar.

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Otolaryngology exposure in a longitudinal integrated clerkship setting

Abstract

Background

Although 20–40% of primary care complaints are Otolaryngology-Head and Neck Surgery (OtoHNS) related, little emphasis is placed on OtoHNS instruction at the undergraduate medical education level. An OtoHNS clerkship rotation is not required at most Canadian medical schools. Furthermore, at institutions offering an OtoHNS rotation, less than 20% of students are able to complete a placement. Given that a large percentage of medical students in Canada will pursue primary care as a career, there remains a gap in providing OtoHNS clinical training. During the longitudinal integrated clerkship at the Northern Ontario School of Medicine (NOSM), students are assigned to one of 14 sites, and not all have access to an otolaryngologist. This study looks to quantify the level of exposure students are receiving in OtoHNS at NOSM and to assess their comfort level with diagnosing and treating common otolaryngologic conditions.

Methods

A structured 13-item survey was administered to second, third and fourth year medical students at NOSM.

Results

A majority (67.9%) of medical students surveyed had not observed an otolaryngologist. Furthermore, most students (90.6%) reported receiving very little OtoHNS classroom based and clinical instruction during medical school.

Conclusions

A discrepancy exists between the quantity and breadth of OtoHNS training received in undergraduate medical education and the volume of OtoHNS encounters in primary care practice. Although geographic dissemination of students in the distributed learning model may be a challenge, strategies such as standardized objectives and supplemental electronic resources may serve to solidify clinical knowledge.

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The Convention of The Hague and the Constitutional Debates in the Estates of Flanders and Brabant, 1790-1794

Following the Brabant Revolution and the declaration of independence of the Southern Netherlands, Vienna made a series of constitutional assurances to the rebels while at the same time preparing to recover the region by force. In December 1790, these promises culminated in the Convention of The Hague, in which Emperor Leopold II – under allied pressure – pledged to restore the ancient constitutions of the Southern Netherlands, which led to constitutional debates among the rebellious provinces. This article examines why the imperial commitments did not placate the estates of the leading provinces, Flanders and Brabant. The Flemish Estates grasped the opportunity to draft their own constitutional charter; Brabant primarily pursued additional safeguards to protect its charter, the Joyous Entry. I argue that these debates chiefly reflect the language of ancient constitutionalism and in essence served conservative goals even as actual circumstances compelled the estates to integrate innovative concepts in their reasoning. Moreover, these debates are very telling for the constitutional sensitivities in the separate Southern Netherlandish regions. Embedded as they were in specific regional constitutional traditions, these debates produced different outcomes in Flanders and Brabant.

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Lexematics

Lexematics is a theory of word meaning in natural languages, conceived as a synthesis of lexical field theory and assumptions of structural-functional language theory.

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Search for dark matter at root s=13 TeV in final states containing an energetic photon and large missing transverse momentum with the ATLAS detector

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Scanlon, T; Scannicchio, DA; Scarcella, M; Scarfone, V; Schaarschmidt, J; Schacht, P; Schachtner, BM; Schaefer, D; Schaefer, L; Schaefer, R; Schaeffer, J; Schaepe, S; Schaetzel, S; Schaefer, U; Schaffer, AC; Schaile, D; Schamberger, RD; Scharf, V; Schegelsky, VA; Scheirich, D; Schernau, M; Schiavi, C; Schier, S; Schildgen, LK; Schillo, C; Schioppa, M; Schlenker, S; Schmidt-Sommerfeld, KR; Schmieden, K; Schmitt, C; Schmitt, S; Schmitz, S; Schnoor, U; Schoeffel, L; Schoening, A; Schoenrock, BD; Schopf, E; Schott, M; Schouwenberg, JFP; Schovancova, J; Schramm, S; Schuh, N; Schulte, A; Schultens, MJ; Schultz-Coulon, H-C; Schulz, H; Schumacher, M; Schumm, BA; Schune, P; Schwartzman, A; Schwarz, TA; Schweiger, H; Schwemling, P; Schwienhorst, R; Schwindling, J; Sciandra, A; Sciolla, G; Scuri, F; Scutti, F; Searcy, J; Seema, P; Seidel, SC; Seiden, A; Seixas, JM; Sekhniaidze, G; Sekhon, K; Sekula, SJ; Semprini-Cesari, N; Senkin, S; Serfon, C; Serin, L; Serkin, L; Sessa, M; Seuster, R; Severini, H; Sfiligoj, T; Sforza, F; Sfyrla, A; Shabalina, E; Shaikh, NW; Shana, LY; Shang, R; Shank, JT; Shapiro, M; Shatalov, PB; Shaw, K; Shaw, SM; Shcherbakova, A; Shehu, CY; Shen, Y; Sherafati, N; Sherwood, P; Shi, L; Shimizu, S; Shimmin, CO; Shimojima, M; Shipsey, IPJ; Shirabe, S; Shiyakova, M; Shlomi, J; Shmeleva, A; Saadi, DS; Shochet, MJ; Shojaii, S; Shope, DR; Shrestha, S; Shulga, E; Shupe, MA; Sicho, P; Sickles, AM; Sidebo, PE; Haddad, ES; Sidiropoulou, O; Sidoti, A; Siegert, F; Sijacki, D; Silva, J; Silverstein, SB; Simak, V; Simic, L; Simion, S; Simioni, E; Simmons, B; Simon, M; Sinervo, P; Sinev, NB; Sioli, M; Siragusa, G; Siral, I; Sivoklokov, SY; Sjolin, J; Skinner, MB; Skubic, P; Slater, M; Slavicek, T; Slawinska, M; Sliwa, K; Slovak, R; Smakhtin, V; Smart, BH; Smiesko, J; Smirnov, N; Smirnov, SY; Smirnov, Y; Smirnova, LN; Smirnova, O; Smith, JW; Smith, MNK; Smith, RW; Smizanska, M; Smolek, K; Snesarev, AA; Snyder, IM; Snyder, S; Sobie, R; Socher, F; Soffer, A; Soh, DA; Sokhrannyi, G; Sanchez, CAS; Solar, M; Soldatov, EY; Soldevila, U; Solodkov, AA; Soloshenko, A; Solovyanov, OV; Solovyev, V; Sommer, P; Son, H; Sopczak, A; Sosa, D; Sotiropoulou, CL; Soualah, R; Soukharev, AM; South, D; Sowden, BC; Spagnolo, S; Spalla, M; Spangenberg, M; Spano, F; Sperlich, D; Spettel, F; Spieker, TM; Spighi, R; Spigo, G; Spiller, LA; Spousta, M; St Denis, RD; Stabile, A; Stamen, R; Stamm, S; Stanecka, E; Stanek, RW; Stanescu, C; Stanitzki, MM; Stapf, BS; Stapnes, S; Starchenko, EA; Stark, GH; Stark, J; Stark, SH; Staroba, P; Starovoitova, P; Starz, S; Staszewski, R; Steinberg, P; Stelzer, B; Stelzer, HJ; Stelzer-Chilton, O; Stenzel, H; Stewart, GA; Stockton, MC; Stoebe, M; Stoicea, G; Stolte, P; Stonjek, S; Stradling, AR; Straessner, A; Stramaglia, ME; Strandberg, J; Strandberg, S; Strauss, M; Strizenecb, P; Stroehmer, R; Strom, DM; Stroynowski, R; Strubig, A; Stucci, SA; Stugu, B; Styles, NA; Su, D; Su, J; Suchek, S; Sugaya, Y; Suk, M; Sulin, VV; Sultan, DMS; Sultansoy, S; Sumida, T; Sun, S; Sun, X; Suruliz, K; Suster, CJE; Sutton, MR; Suzuki, S; Svatos, M; Swiatlowski, M; Swift, SP; Sykora, I; Sykora, T; Ta, D; Tackmann, K; Taenzer, J; Taffard, A; Tafirout, R; Taiblum, N; Takai, H; Takashima, R; Takasugi, EH; Takeshita, T; Takubo, Y; Talby, M; Talyshev, AA; Tanaka, J; Tanaka, M; Tanaka, R; Tanaka, S; Tanioka, R; Tannenwald, BB; Araya, ST; Tapprogge, S; Tarem, S; Tartarelli, GF; Tas, P; Tasevsky, M; Tashiro, T; Tassi, E; Tavares Delgado, A; Tayalati, Y; Taylor, AC; Taylor, GN; Taylor, PTE; Taylor, W; Teixeira-Dias, P; Temple, D; Ten Kate, H; Teng, PK; Teoh, JJ; Tepel, F; Terada, S; Terashi, K; Terron, J; Terzo, S; Testa, M; Teuscher, RJ; Theveneaux-Pelzer, T; Thomas, JP; Thomas-Wilsker, J; Thompson, PD; Thompson, AS; Thomsen, LA; Thomson, E; Tibbetts, MJ; Torres, RET; Tikhomirov, VO; Tikhonov, YA; Timoshenko, S; Tipton, P; Tisserant, S; Todome, K; Todorova-Nova, S; Tojo, J; Tokar, S; Tokushuku, K; Tolley, E; Tomlinson, L; Tomoto, M; Tompkins, L; Toms, K; Tong, B; Tornambe, P; Torrence, E; Torres, H; Pastor, ET; Toth, J; Touchard, F; Tovey, DR; Treado, CJ; Trefzger, T; Tresoldi, F; Tricoli, A; Trigger, IM; Trincaz-Duvoid, S; Tripiana, MF; Trischuk, W; Trocme, B; Trofymov, A; Troncon, C; Trottier-McDonald, M; Trovatelli, M; Truong, L; Trzebinski, M; Trzupek, A; Tsang, KW; Tseng, JC-L; Tsiareshka, PV; Tsipolitis, G; Tsirintanis, N; Tsiskaridze, S; Tsiskaridze, V; Tskhadadze, EG; Tsui, KM; Tsukerman, II; Tsulaia, V; Tsuno, S; Tsybychev, D; Tu, Y; Tudorache, A; Tudorache, V; Tulbure, TT; Tuna, AN; Tupputi, SA; Turchikhin, S; Turgeman, D; Cakir, IT; Turra, R; Tuts, PM; Ucchielli, G; Ueda, I; Ughetto, M; Ukegawa, F; Unal, G; Undrus, A; Unel, G; Ungaro, FC; Unno, Y; Unverdorben, C; Urban, J; Urquijo, P; Urrejola, P; Usai, G; Usui, J; Vacavant, L; Vacek, V; Vachon, B; Valderanis, C; Santurio, EV; Valentinetti, S; Valero, A; Valery, L; Valkar, S; Vallier, A; Valls Ferrer, JA; Van den Wollenberg, W; van der Graaf, H; Van Gemmeren, P; van Nieuwkoop, J; van Vulpen, I; van Woerden, MC; Vanadia, M; Vandelli, W; Vaniachine, A; Vankov, P; Vardanyan, G; Vari, R; Varnes, EW; Varni, C; Varol, T; Varouchas, D; Vartapetian, A; Varvell, KE; Vasquez, JG; Vasquez, GA; Vazeille, F; Schroeder, TV; Veatch, J; Veeraraghavan, V; Veloce, LM; Veloso, F; Veneziano, S; Ventura, A; Venturi, M; Venturi, N; Venturini, A; Vercesi, V; Verducci, M; Verkerke, W; Vermeulen, AT; Vermeulen, JC; Vetterli, MC; Viaux Maira, N; Viazlo, O; Vichou, I; Vickey, T; Boeriu, OEV; Viehhauser, GHA; Viel, S; Vigani, L; Villa, M; Perez, MV; Vilucchi, E; Vincter, MG; Vinogradov, VB; Vishwakarma, A; Vittori, C; Vivarelli, I; Vlachos, S; Vlasak, M; Vogel, M; Vokac, P; Volpi, G; von der Schmitt, H; von Toerne, E; Vorobel, V; Vorobev, K; Vos, M; Voss, R; Vossebeld, JH; Vranjes, N; Milosavljevic, MV; Vrba, V; Vreeswijk, M; Vuillermet, R; Vukotic, I; Wagner, P; Wagner, W; Wagner-Kuhr, J; Wahlberg, H; Wahrmund, S; Wakabayashi, J; Walder, J; Walker, R; Walkowiak, W; Wallangen, V; Wang, C; Wang, C; Wang, F; Wang, H; Wang, H; Wang, J; Wang, J; Wang, Q; Wang, R; Wang, SM; Wang, T; Wang, W; Wang, W; Wang, Z; Wanotayaroj, C; Warburton, A; Ward, CP; Wardrope, DR; Washbrook, A; Watkins, PM; Watson, AT; Watson, MF; Watts, G; Watts, S; Waugh, BM; Webb, AF; Webb, S; Weber, MS; Weber, SW; Watson, MF; Watts, G; Watts, S; Waugh, BM; Webb, AF; Webb, S; Weber, MS; Weber, SW; Weber, SA; Webster, JS; Weidberg, AR; Weinert, B; Weingarten, J; Weirich, M; Weiser, C; Weits, H; Wells, PS; Wenaus, T; Wengler, T; Wenig, S; Wermes, N; Werner, MD; Werner, P; Wessels, M; Whalen, K; Whallon, NL; Wharton, AM; White, AS; White, A; White, MJ; White, R; Whiteson, D; Whitmore, BW; Wickens, FJ; Wiedenmann, W; Wielers, M; Wiglesworth, C; Wiik-Fuchs, LAM; Wildauer, A; Wilk, F; Wilkens, HG; Williams, HH; Williams, S; Willis, C; Willocq, S; Wilson, JA; Wingerter-Seez, I; Winkels, E; Winklmeier, F; Winston, OJ; Winter, BT; Wittgen, M; Wobisch, M; Wolf, TMH; Wolff, R; Wolter, MW; Wolters, H; Wong, VWS; Worm, SD; Wosiek, BK; Wotschack, J; Wozniak, KW; Wu, M; Wu, SL; Wu, X; Wu, Y; Wyatt, TR; Wynne, BM; Xella, S; Xi, Z; Xia, L; Xu, D; Xu, L; Yabsley, B; Yacoob, S; Yamaguchi, D; Yamaguchi, Y; Yamamoto, A; Yamamoto, S; Yamanaka, T; Yamatani, M; Yamauchi, K; Yamazaki, Y; Yan, Z; Yang, H; Yang, H; Yang, Y; Yang, Z; Yao, W-M; Yap, YC; Yasu, Y; Yatsenko, E; Wong, KHY; Ye, J; Ye, S; Yeletskikh, I; Yigitbasi, E; Yildirim, E; Yorita, K; Yoshihara, K; Young, C; Young, CJS; Yu, J; Yu, J; Yuen, SPY; Yusuff, I; Zabinski, B; Zacharis, G; Zaidan, R; Zaitsev, AM; Zakharchuk, N; Zalieckas, J; Zaman, A; Zambito, S; Zanzi, D; Zeitnitz, C; Zemla, A; Zeng, JC; Zeng, Q; Zenin, O; Zenis, T; Zerwas, D; Zhang, D; Zhang, F; Zhang, G; Zhang, H; Zhang, J; Zhang, L; Zhang, L; Zhang, M; Zhang, P; Zhang, R; Zhang, R; Zhang, X; Zhang, Y; Zhang, Z; Zhao, X; Zhao, Y; Zhao, Z; Zhemchugov, A; Zhou, B; Zhou, C; Zhou, L; Zhou, M; Zhou, M; Zhou, N; Zhu, CG; Zhu, H; Zhu, J; Zhu, Y; Zhuang, X; Zhukov, K; Zibell, A; Zieminska, D; Zimine, NI; Zimmermann, C; Zimmermann, S; Zinonos, Z; Zinser, M; Ziolkowski, M; Zivkovic, L; Zobernig, G; Zoccoli, A; Zou, R; zur Nedden, M; Zwalinski, L; - view fewer (2017) Search for dark matter at root s=13 TeV in final states containing an energetic photon and large missing transverse momentum with the ATLAS detector. The European Physical Journal C , 77 (6) , Article 393. 10.1140/epjc/s10052-017-4965-8 . Green open access

http://ift.tt/2sX1MJB

Effects of economic downturns on child mortality: a global economic analysis, 1981-2010

Maruthappu, M; Watson, RA; Watkins, J; Zeltner, T; Raine, R; Atun, R; (2017) Effects of economic downturns on child mortality: a global economic analysis, 1981-2010. BMJ Global Health , 2 (2) , Article e000157. 10.1136/bmjgh-2016-000157 . Green open access

http://ift.tt/2sWn1LA

Approaching the socialist factory and its workforce: considerations from fieldwork in (former) Yugoslavia

Archer, R; Musić, G; (2017) Approaching the socialist factory and its workforce: considerations from fieldwork in (former) Yugoslavia. Labor History , 58 (1) pp. 44-66. 10.1080/0023656X.2017.1244331 . Green open access

http://ift.tt/2tGij1T

The Greek world and medical tradition healers and healing on the eve of the Greek revival (1700-1821)

Papadopoulaos, C; (2009) The Greek world and medical tradition healers and healing on the eve of the Greek revival (1700-1821). Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2tG5JiV

The experience of friendship and bullying in children with an autism spectrum disorder

Rowley, E; (2008) The experience of friendship and bullying in children with an autism spectrum disorder. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2tGfHRl

All-optical endoscopic probe for high resolution 3D photoacoustic tomography

Ansari, R; Zhang, E; Desjardins, AE; Beard, PC; (2017) All-optical endoscopic probe for high resolution 3D photoacoustic tomography. In: Photons Plus Ultrasound: Imaging and Sensing 2017. Society of Photo-Optical Instrumentation Engineers (SPIE): San Francisco, California, United States. Green open access

http://ift.tt/2tGllmC

Segmenting subregions of the human hippocampus on structural magnetic resonance image scans: An illustrated tutorial

Dalton, MA; Zeidman, P; Barry, DN; Williams, E; Maguire, EA; (2017) Segmenting subregions of the human hippocampus on structural magnetic resonance image scans: An illustrated tutorial. Brain and Neuroscience Advances , 1 10.1177/2398212817701448 . (In press). Green open access

http://ift.tt/2sWZ2w0

The evolution of the early tetrapod middle ear and associated structures

Robinson, J; (2006) The evolution of the early tetrapod middle ear and associated structures. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2sWt9Ui

Immediate Constituent Analysis (IC analysis)

Immediate Constituent Analysis is a structural method for analysing the hierarchical relations among the constituents of complex linguistic constructions, proceeding consecutively from the higher to the next lower level until no further breakdown into smaller units is possible.

http://ift.tt/2tGliHs

Discovering activity patterns in office environment using a network of low-resolution visual sensors

Understanding activity patterns in office environments is important in order to increase workers' comfort and productivity. This paper proposes an automated system for discovering activity patterns of multiple persons in a work environment using a network of cheap low-resolution visual sensors (900 pixels). Firstly, the users' locations are obtained from a robust people tracker based on recursive maximum likelihood principles. Secondly, based on the users' mobility tracks, the high density positions are found using a bivariate kernel density estimation. Then, the hotspots are detected using a confidence region estimation. Thirdly, we analyze the individual's tracks to find the starting and ending hotspots. The starting and ending hotspots form an observation sequence, where the user's presence and absence are detected using three powerful Probabilistic Graphical Models (PGMs). We describe two approaches to identify the user's status: a single model approach and a two-model mining approach. We evaluate both approaches on video sequences captured in a real work environment, where the persons' daily routines are recorded over 5 months. We show how the second approach achieves a better performance than the first approach. Routines dominating the entire group's activities are identified with a methodology based on the Latent Dirichlet Allocation topic model. We also detect routines which are characteristic of persons. More specifically, we perform various analysis to determine regions with high variations, which may correspond to specific events.

http://ift.tt/2sWXhic

Double articulation

http://ift.tt/2tGbixO

isomorphism

Isomorphism: Initially referring to the structuralist, in particular glossematic, hypothesis that the expression and meaning of linguistic signs show structural parallelisms, the term isomorphism is used in current linguistic theory to designate the one-to-one correspondence between expression and meaning.

http://ift.tt/2sX3drn

Ravana empereur universel? Point de vue sémantique et problèmes de référence chez le jaïn Prabhacandra

http://ift.tt/2tFSA9F

Taking Care of Vulnerable Populations as Global Health – Case Reports on Refugees and Migrants

By Nathan Douthit

According to the United Nations High Commissioner for Refugees, a refugee is someone who," owing to a well-founded fear of being persecuted for reasons of race, religion, nationality, membership of a particular social group, or political opinion, is outside the country of his nationality, and is unable to or, owing to such fear, is unwilling to avail himself of the protection of that country ." ¹ Globally, the World Health Organization estimates there are 65 million forcibly displaced persons, 86% of whom are in developing countries .²  Implicit in the care of refugees are complex healthcare challenges including language barriers, unfamiliarity with the theory and practice of primary health care, common exposure to violence, torture and warfare, the high prevalence of PTSD, anxiety and depression and anti-immigrant sentiment in their new host country. Access to primary care is an essential facet of refugee care. Low socio-economic status and social isolation complicates the management of chronic non-communicable disease.

 

In the case report  "A Rohingya refugee's journey in Australia and the barriers to accessing healthcare," Jiwrajka et al discuss some of these issues.³ The case describes the peculiar challenge of the Rohingya people

 

"[o]ver 200000 Rohingya refugees are currently resettled in Bangladesh, a country with already limited health-care for its own citizens as well as a non-signatory country to any of the United Nations Refugee or Stateless Conventions. As a result, refugees are not guaranteed access to basic human rights, including healthcare."

 

Even with a robust translation service freely available in Australia, this patient states the interpreter spoke an "unfamiliar dialect." She did not understand her prescriptions as a result.  The patient did not feel that her doctors cared about her concerns of infertility, instead she states that "the doctors were more interested in her diabetes." The low socio-economic status of this patient is linked to her health – the authors write:

 

"[T]here is a disproportionate burden of diabetes among minority groups, migrants and the socioeconomically vulnerable. [Socioeconomic status] and social stratification are intrinsically linked to health, in turn creating a social gradient of health. As a result, adverse health outcomes within vulnerable populations, including refugees, transgress beyond the individual to affect whole communities."

 

Due to a variety of factors, most notably the conflict in Syria, the world is in the midst of the largest migration of people since World War II. BMJ Case Reports invites authors to publish cases regarding the health of these vulnerable patients as well as the dilemmas created by migration on national health systems. Global health case reports can emphasize:

-Barriers to access of care due to linguistic, social and cultural differences

-Problems created by lack of cultural competence in healthcare systems

-Discrimination and effects on healthcare for refugees and migrants

-Uncontrolled chronic conditions due to migration or delays in access to healthcare

-Other factors that exacerbate the vulnerability of migrant populations

Manuscripts may be submitted by students, physicians, nurses or other medical professionals to BMJ Case Reports. For more information, review the blog on how to write a global health case report.

Read more about refugee health at BMJCR:

–Paired suicide in a young refugee couple on the Thai-Myanmar border

–A Syrian man with abdominal pain

–Ethiopian-Israeli community

References:

1. UNHCR. Global Strategy for Public Health: A UNHCR Strategy 2014-2018. United Nations High Commission for Refugees, Geneva. 2014.
2. WHO. Refugee and migrant health [internet]. World Health Organization 2017 [cited July 6 2017] Available at: http://ift.tt/2uIs27X
3. A Rohingya refugee's journey in Australia and the barriers to accessing healthcare. Manasi Jiwrajka, Ahmad Mahmoud, Maneeta Uppal. BMJ Case Reports 2017: published online 9 May 2017, doi:10.1136/bcr-2017-219674.

Selected References on Refugee and Migrant Health from other sources:

-Hunter P. The refugee crisis challenges national health care systems. EMBO reports. 2016 Apr 1;17(4):492-5.

-Onnell C. Healthcare for Syrian refugees. BMJ. 2015 Aug 8:13.

-Jackson JC, Haider M, Owens CW et al. Healthcare Recommendations For Recently Arrived Refugees: Observations from EthnoMed. Harvard Public Health Review. 2016 April;7

 

 

 

http://ift.tt/2u9WTxa

Applying Quality Indicators For Administrative Databases To Evaluate End-Of-Life Care For Cancer Patients In Belgium

http://ift.tt/2tGfRIy

On-Site Ecstasy Pill-Testing Services May Reduce User Risks at Concerts and Raves

Johns Hopkins scientists report that data collected over five years by volunteers who tested pills free of charge at music festivals and raves across the United States suggest that at least some recreational users of illegal drugs may choose not to take them if tests show the pills are adulterated or fake.

http://ift.tt/2u4KKIW

“Tumor immunology meets oncology (TIMO) XII”, April 28th–30th 2016, Halle/Saale, Germany

http://ift.tt/2tFIfKI

POLYIMIDE-ALD-POLYIMIDE LAYERS AS HERMETIC ENCAPSULANT FOR IMPLANTS

Several requirements exist for medical devices for long term implantation. Firstly, the foreign body reaction and/or inflammation occurring upon implantation should remain mild and short in time. Moreover, the device needs to be biocompatible during the total implantation duration, hence not causing reactions which decrease the patient's health. Finally, the device needs to work properly and safe during the total period of implantation, not suffering from corrosion or chemical degradation. To meet these requirements, diffusion of body fluids into the package should be avoided as well as diffusion of toxic device materials into the body, hence a hermetic packaging method is an absolute necessity. Here, a flexible hermetic packaging is presented using alternating polyimide and atomic layer deposited (ALD) metal oxides. Good adhesion between the inorganic ALD layers and the polyimide is required to avoid the creation of lateral diffusion pads. To obtain this, surface modifications of both polyimide and ALD layers are optimized, as presented in this paper. The hermeticity is evaluated in terms of water vapor transmission rate measurements of the film stack.

http://ift.tt/2tFyo7T

Effects of the surroundings and conformerisation of n-dodecane molecules on evaporation/condensation processes.

Gun'ko, VM; Nasiri, R; Sazhin, SS; (2015) Effects of the surroundings and conformerisation of n-dodecane molecules on evaporation/condensation processes. J Chem Phys , 142 (3) 034502. 10.1063/1.4905496 . Green open access

http://ift.tt/2sWxw1t

The evolution of a craft: The use of metal threads in the decoration of late and post Byzantine ecclesiastical textiles

Karatzani, A; (2007) The evolution of a craft: The use of metal threads in the decoration of late and post Byzantine ecclesiastical textiles. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2tFpmaN

Core outcome measures for interventions to prevent or slow the progress of dementia for people living with mild to moderate dementia: Systematic review and consensus recommendations

Webster, L; Groskreutz, D; Grinbergs-Saull, A; Howard, R; O'Brien, JT; Mountain, G; Banerjee, S; Webster, L; Groskreutz, D; Grinbergs-Saull, A; Howard, R; O'Brien, JT; Mountain, G; Banerjee, S; Woods, B; Perneczky, R; Lafortune, L; Roberts, C; McCleery, J; Pickett, J; Bunn, F; Challis, D; Charlesworth, G; Featherstone, K; Fox, C; Goodman, C; Jones, R; Lamb, S; Moniz-Cook, E; Schneider, J; Shepperd, S; Surr, C; Thompson-Coon, J; Ballard, C; Brayne, C; Burns, A; Clare, L; Garrard, P; Kehoe, P; Passmore, P; Holmes, C; Maidment, I; Robinson, L; Livingston, G; - view fewer (2017) Core outcome measures for interventions to prevent or slow the progress of dementia for people living with mild to moderate dementia: Systematic review and consensus recommendations. PLoS One , 12 (6) , Article e0179521. 10.1371/journal.pone.0179521 . Green open access

http://ift.tt/2sWyhaJ

The implications of direct participation for organisational commitment, job satisfaction and affective psychological well-being: a longitudinal analysis

Gallie, D; Zhou, Y; Felstead, A; Green, F; Henseke, G; (2017) The implications of direct participation for organisational commitment, job satisfaction and affective psychological well-being: a longitudinal analysis. Industrial Relations Journal , 48 (2) pp. 174-191. 10.1111/irj.12174 . Green open access

http://ift.tt/2tFoQd1

Experiences of end of life amongst family carers of people with advanced dementia: longitudinal cohort study with mixed methods

Moore, KJ; Davis, S; Gola, A; Harrington, J; Kupeli, N; Vickerstaff, V; King, M; Moore, KJ; Davis, S; Gola, A; Harrington, J; Kupeli, N; Vickerstaff, V; King, M; Leavey, G; Nazareth, I; Jones, L; Sampson, EL; - view fewer (2017) Experiences of end of life amongst family carers of people with advanced dementia: longitudinal cohort study with mixed methods. BMC Geriatrics , 17 (1) , Article 135. 10.1186/s12877-017-0523-3 . Green open access

http://ift.tt/2sWnzRL

The Virtues of National Ethics Committees

Montgomery, J; (2017) The Virtues of National Ethics Committees. Hastings Center Report , 47 (Supp 1) S24-S27. 10.1002/hast.715 . Green open access

http://ift.tt/2tFOvlY

The evaluation of hypoxia in human bladder cancer using intrinsic and extrinsic markers

Sibtain, A; (2006) The evaluation of hypoxia in human bladder cancer using intrinsic and extrinsic markers. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2sWpXI9

The effects of sleep deprivation on brain fMRI activation during motion detection and tracking

Robinson, G; (2008) The effects of sleep deprivation on brain fMRI activation during motion detection and tracking. Doctoral thesis, UCL (University College London). Green open access

http://ift.tt/2tFRfzB

Hereditary leiomyomatosis and renal cell cancer syndrome: A novel mutation in the FH gene

http://ift.tt/2sH2Q08

Infectious urticaria complicated with intestinal edema

http://ift.tt/2tZuycg

Grundlage der Behandlung ekzematöser Erkrankungen im HNO-Bereich

Zusammenfassung

Zellvermittelte Immunantworten sind Typ-IV-Reaktionen nach Coombs und Gell und werden v. a. durch T‑Lymphozyten getragen. Die auslösenden Allergene sind in aller Regel sog. Haptene, also Stoffe, die erst durch Bindung an Proteinträgersubstanzen zu Vollantigenen werden. Allergische Spättypreaktionen imponieren im HNO-Bereich überwiegend als Kontaktekzeme, oft als Gesichtsdermatitis, Ohrmuschel- und Gehörgangsekzem und periorale Ekzeme. Anamnese und Morphologie eines Ekzems sind diagnostisch wegweisend. Die Verifizierung erfolgt mittels Epikutantest nach den Leitlinien der AWMF (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften). Hierbei werden die häufigsten Kontaktallergene im „Standardblock" getestet, den man anamnesebezogen auf ein individualisiertes Allergenspektrum reduzieren kann. In der Therapie ist die wichtigste Maßnahme die Allergenkarenz, die auch prophylaktisch eingesetzt werden sollte. Darüber hinaus wird das Kontaktekzem antiinflammatorisch ausschleichend mit einem topischen Kortikosteroid behandelt. Je nach Alter, Lokalisation und Schweregrad des Kontaktekzems ist hier ein neueres Klasse-II- oder -III-Präparat zu wählen. Pflegepräparate helfen dabei, Kortikosteroide einzusparen und sind nach der akuten Phase zusätzlich indiziert. Eine wichtige Differenzialdiagnose des Kontaktekzems ist die atopische Dermatitis. Während das Kontaktekzem durch Meiden der auslösenden Noxe eine Abheilung erfährt, zeigt die genetisch determinierte atopische Dermatitis einen chronisch-rezidivierenden Verlauf. Zusätzlich zu den topischen Kortikosteroiden sind auch Calcineurin-Inhibitoren zur Therapie des atopischen Ekzems zugelassen. Bei allen Ekzemerkrankungen ist die regelmäßige Pflege eine notwendige Maßnahme, die v. a. zur Barrierereparatur beiträgt.

http://ift.tt/2u4Im4Z

Phasen, Störungen und Förderung der Wundheilung

Zusammenfassung

Durch Verletzung der Haut setzt die Wundheilung ein, welche durch Interaktion verschiedener Zellen und Ausschüttung diverser pro- und antiinflammatorischer Mediatoren in 3 aufeinanderfolgenden, teils überlappenden Phasen zur primären oder sekundären Defektheilung führt. Verschiedene lokale und systemische Faktoren können das fein aufeinander abgestimmte Gleichgewicht zwischen Auf- und Abbau stören und die einzelnen Phasen verzögern oder gar zum Stillstand bringen, sodass eine chronische Wunde oder eine fehlerhafte Heilung resultiert. Hier gilt es, die verschiedenen zur Verfügung stehenden chirurgischen und nichtchirurgischen Maßnahmen einzusetzen, um eine gestörte Wundheilung in die physiologische Abheilung zu überführen und die Integrität der Schutzschicht wiederherzustellen, damit der Organismus vor äußerlichen Schädigungen bewahrt wird.

http://ift.tt/2v2R80l

Histiocytic and dendritic cell neoplasms: what have we learnt by studying 67 cases

Abstract

Tumors derived from histiocytic and dendritic cells encompass a large and heterogeneous group of neoplastic and reactive conditions, and their diagnosis is challenging both for pathologists and clinicians. Diagnosis is based on morphological and phenotypical findings, but hybrid features are not uncommon. Furthermore, recent studies uncovered the molecular mechanisms driving some of these tumors, improving diagnostic adequacy, and providing the basis for effective therapeutic breakthroughs.

Sixty-seven cases were submitted to the accessory cell and histiocytic neoplasms session at the European Association of Haematopathology/Society for Hematopathology workshop 2016 held in Basel, Switzerland. The cases included histiocytic sarcomas (HS), Langerhans cell tumors (LCT), Erdheim-Chester disease, interdigitating dendritic cell sarcomas (IDCS), indeterminate dendritic cell tumors (IND-DCT), follicular dendritic cell sarcomas, and blastic plasmacytoid dendritic cell neoplasms. Rosai-Dorfman disease and, more rare, conditions such as ALK-positive histiocytosis were also submitted. These cases illustrated classical and unexpected features at morphological, phenotypical, and molecular levels, providing a valuable compendium for pathologists confronting with these tumors.

The paper summarizes the most notable features of every single group of diseases, with comments about the most challenging issues, in the attempt to provide practical indications for their recognition.

http://ift.tt/2sWoZf1

Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer

Abstract

This study sought to evaluate whether myeloid-derived suppressor cells (MDSC) could be affected by chemotherapy and correlate with pathologic complete response (pCR) in breast cancer patients receiving neo-adjuvant chemotherapy. Peripheral blood levels of granulocytic (G-MDSC) and monocytic (M-MDSC) MDSC were measured by flow cytometry prior to cycle 1 and 2 of doxorubicin and cyclophosphamide and 1st and last administration of paclitaxel or paclitaxel/anti-HER2 therapy. Of 24 patients, 11, 6 and 7 patients were triple negative, HER2+ and hormone receptor+, respectively. 45.8% had pCR. Mean M-MDSC% were <1. Mean G-MDSC% and 95% confidence intervals were 0.88 (0.23–1.54), 5.07 (2.45–7.69), 9.32 (4.02–14.61) and 1.97 (0.53–3.41) at draws 1–4. The increase in G-MDSC by draw 3 was significant (p < 0.0001) in all breast cancer types. G-MDSC levels at the last draw were numerically lower in patients with pCR (1.15; 95% CI 0.14–2.16) versus patients with no pCR (2.71; 95% CI 0–5.47). There was no significant rise in G-MDSC from draw 1 to 3 in African American patients, and at draw 3 G-MDSC levels were significantly lower in African Americans versus Caucasians (p < 0.05). It was concluded that G-MDSC% increased during doxorubicin and cyclophosphamide therapy, but did not significantly differ between patients based on pathologic complete response.

http://ift.tt/2sGJgRB

First Report on Fetal Cerebral Polyglucosan Bodies in Mucopolysaccharidosis Type VII

We report on the detection of discordant inclusions in the brain of a 25-week female fetus with a very rare lysosomal storage disease, namely, Sly disease (mucopolysaccharidosis (MPS) type VII), presenting with nonimmune hydrops fetalis. Besides vacuolated neurons, we found abundant deposition of polyglucosan bodies (PGBs) in the developing brain of this fetus in whom MPS-VII was corroborated by lysosomal beta-glucuronidase-deficiency detected in fetal blood and fetal skin-fibroblasts and by the presence of a heterozygous pathogenic variant in the GUSB gene in the mother. Fetal/neonatal metabolic disorders with PGB-deposition are extremely rare (particularly in relation to CNS involvement) and include almost exclusively subtypes of glycogenosis (types IV and VII). The accumulation of PGBs (particularly in the fetal brain) has so far not been depicted in Sly disease. This is the first report on such "aberrant" association. Besides, the detection of these CNS inclusions at such an early developmental stage is remarkably unique.

http://ift.tt/2u3EJML

Discourses on Well-Being

In the current South African socio-political framework children have been afforded the highest priority within government, via affirmation of their rights. Not only have the rights and needs of children been entrenched in the development strategies of the government, but children themselves have been guaranteed socio-economic rights and protection from abuse, exploitation, and neglect. Subsequently, knowledge and information on the well-being of children have become important pursuits. It has also become increasingly important to obtain an understanding of what children regard as essential to their well-being. The current study explores children's subjective perceptions of well-being, with a specific focus on elucidating the discourses that children use to assign meaning to well-being. A qualitative study was conducted using a series of focus group discussions with 56 children between the ages of 13 and 15 from rural and urban geographical locations. A discourse analysis reveals a complex interplay between the social environment and the children's sense of well-being. Three key thematic domains were identified, namely, personal safety, infrastructural deficiencies, and psycho-social functioning. Central discourses to emerge from these thematic domains were closely interrelated and mutually influencing and focussed on, personal safety, the social environment and a stable self as 'non-negotiables' of well-being, helplessness and vulnerability, desensitisation, marginalisation, (non)acknowledgement and (dis)respect. A notable finding emerging from the study was the extent to which the participants' discursive constructions of well-being were ideologically configured. The findings raise important considerations for educational and intervention programmes and policies aimed at children and youth.

http://ift.tt/2u3uAzp