bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Release of Lipoteichoic and Teichoic Acids from
Streptococcus pneumoniae
as a Result of Exposure to β-Lactam Antibiotics, Rifamycins, Trovafloxacin, and Quinupristin-Dalfopristin
Authors: Stuertz K. , Schmidt H. , Eiffert H. , Schwartz P. , Mäder M. , Nau R.
Published: April 2020

The release of lipoteichoic acid (LTA) and teichoic acid (TA) from a
Streptococcus pneumoniae
type 3 strain during exposure to ceftriaxone, meropenem, rifampin, rifabutin, quinupristin-dalfopristin, and trovafloxacin in tryptic soy broth was monitored by a newly developed enzyme-linked immunosorbent assay. At a concentration of 10 μg/ml, a rapid and intense release of LTA and TA occurred during exposure to ceftriaxone (3,248 ± 1,688 ng/ml at 3 h and 3,827 ± 2,133 ng/ml at 12 h) and meropenem (2,464 ± 1,081 ng/ml at 3 h and 2,900 ± 1,364 ng/ml at 12 h). Three hours after exposure to rifampin, rifabutin, quinupristin-dalfopristin, and trovafloxacin, mean LTA and TA concentrations of less than 460 ng/ml were observed (for each group,
P
< 0.01 versus the concentrations after exposure to ceftriaxone). After 12 h of treatment, the LTA and TA concentrations were 463 ± 126 ng/ml after exposure to rifampin, 669 ± 303 ng/ml after exposure to rifabutin, and 1,236 ± 772 ng/ml after exposure to quinupristin-dalfopristin (for each group,
P
< 0.05 versus the concentrations after exposure to ceftriaxone) and 1,745 ± 1,185 ng/ml after exposure to trovafloxacin (
P
= 0.12 versus the concentration after exposure to ceftriaxone). At 10 μg/ml, bactericidal antibacterial agents that do not primarily affect cell wall synthesis reduced the amount of LTA and TA released during their cidal action against
S. pneumoniae
in comparison with the amount released after exposure to β-lactams. Larger quantities of LTA and TA were released after treatment with low concentrations (1× the MIC and 1× the minimum bactericidal concentration) than after no treatment for all antibacterial agents except the rifamycins. This does not support the concept of using a low first antibiotic dose to prevent the release of proinflammatory cell wall components.
β-Lactamase Inhibitors Are Substrates for the Multidrug Efflux Pumps of
Pseudomonas aeruginosa
Authors: Li Xian-Zhi , Zhang Li , Srikumar Ramakrishnan , Poole Keith
Published: April 2020

The MexAB-OprM multidrug efflux system exports a number of antimicrobial compounds, including β-lactams. In an attempt to define more fully the range of antimicrobial compounds exported by this system, and, in particular, to determine whether β-lactamase inhibitors were also accommodated by the MexAB-OprM pump, the influence of pump status (its presence or absence) on the intrinsic antibacterial activities of these compounds and on their abilities to enhance β-lactam susceptibility in intact cells was assessed. MIC determinations clearly demonstrated that all three compounds tested, clavulanate, cloxacillin, and BRL42715, were accommodated by the pump. Moreover, by using β-lactams which were readily hydrolyzed by the
Pseudomonas aeruginosa
class C chromosomal β-lactamase, it was demonstrated that elimination of the
mexAB-oprM
-encoded efflux system greatly enhanced the abilities of cloxacillin and BRL42715 (but not clavulanate) to increase β-lactam susceptibility. With β-lactams which were poorly hydrolyzed, however, the inhibitors failed to enhance β-lactam susceptibility in MexAB-OprM
+
strains, although BRL42715 did enhance β-lactam susceptibility in MexAB-OprM
−
strains, suggesting that even with poorly hydrolyzed β-lactams this inhibitor was effective when it was not subjected to efflux. MexEF-OprN-overexpressing strains, but not MexCD-OprJ-overexpressing strains, also facilitated resistance to β-lactamase inhibitors, indicating that these compounds are also substrates for the MexEF-OprN pump. These data indicate that an ability to inactivate MexAB-OprM (and like efflux systems in other bacteria) will markedly enhance the efficacies of β-lactam–β-lactamase inhibitor combinations in treating bacterial infections.
Repeated-Dose Pharmacokinetics of an Oral Solution of Itraconazole in Infants and Children
Authors: de Repentigny Louis , Ratelle Johanne , Leclerc Jean-Marie , Cornu Guy , Sokal Étienne M. , Jacqmin Philippe , de Beule Karel
Published: April 2020

The safety, tolerability, and pharmacokinetics of an oral solution of itraconazole and its active metabolite hydroxyitraconazole were investigated in an open multicenter study of 26 infants and children aged 6 months to 12 years with documented mucosal fungal infections or at risk for the development of invasive fungal disease. The most frequent underlying illness was acute lymphoblastic leukemia, except in the patients aged 6 months to 2 years, of whom six were liver transplant recipients. The patients were treated with itraconazole at a dosage of 5 mg/kg of body weight once daily for 2 weeks. Blood samples were taken after the first dose, during treatment, and up to 8 days after the last itraconazole dose. On day 1, the mean peak concentrations in plasma after the first and last doses (
C
max
) and areas under the concentration-time curve from 0 to 24 h (AUC
0–24
) for itraconazole and hydroxyitraconazole were lower in the children aged 6 months to 2 years than in children aged 2 to 12 years but were comparable on day 14. The mean AUC
0–24
-based accumulation factors of itraconazole and hydroxyitraconazole from day 1 to 14 ranged from 3.3 to 8.6 and 2.3 to 11.4, respectively. After 14 days of treatment,
C
max
, AUC
0–24
, and the half-life, respectively, were (mean ± standard deviation) 571 ± 416 ng/ml, 6,930 ± 5,830 ng · h/ml, and 47 ± 55 h in the children aged 6 months to 2 years; 534 ± 431 ng/ml, 7,330 ± 5,420 ng · h/ml, and 30.6 ± 25.3 h in the children aged 2 to 5 years; and 631 ± 358 ng/ml, 8,770 ± 5,050 ng · h/ml, and 28.3 ± 9.6 h in the children aged 5 to 12 years. There was a tendency to have more frequent low minimum concentrations of the drugs in plasma for both itraconazole and hydroxyitraconazole for the children aged 6 months to 2 years. The oral bioavailability of the solubilizer hydroxypropyl-β-cyclodextrin was less than 1% in the majority of the patients. In conclusion, an itraconazole oral solution given at 5 mg/kg/day provides potentially therapeutic concentrations in plasma, which are, however, substantially lower than those attained in adult cancer patients, and is well tolerated and safe in infants and children.
Pharmacokinetics and Inflammatory Fluid Penetration of Clinafloxacin
Authors: Wise R. , Jones S. , Das I. , Andrews J. M.
Published: April 2020

A single 200-mg dose of clinafloxacin was given orally to each of nine healthy male volunteers, and the concentrations of the drug were measured in plasma, cantharidin-induced inflammatory fluid, and urine over the following 24 h (48 h in the case of urine). The mean maximum concentration in plasma was 1.34 μg/ml at a mean time of 1.8 h postdose. The mean maximum concentration in the inflammatory fluid was 1.3 μg/ml at 3.8 h postdose. The mean elimination half-life of clinafloxacin in plasma was 5.65 h. The overall penetration into the inflammatory fluid was 93.1%, as assessed by determining the ratio of area under the concentration-time curves. Recovery of clinafloxacin in urine was 58.8% by 24 h and 71.8% by 48 h postdose.
Rationale for and Efficacy of Prolonged-Interval Treatment Using Liposome-Encapsulated Amikacin in Experimental
Mycobacterium avium
Infection
Authors: Leitzke S. , Bucke W. , Borner K. , Müller R. , Hahn H. , Ehlers S.
Published: April 2020

The potential of liposome-encapsulated antibiotics for prolonging drug application intervals was investigated by using a murine model of chronic lethal
Mycobacterium avium
infection. Liposomal encapsulation of amikacin, but not of ciprofloxacin, resulted in high and sustained drug levels in infected tissues, exceeding the minimal inhibitory concentration for
M. avium
for at least 28 days. As a consequence, once-weekly and even once-monthly treatments with liposomal amikacin significantly reduced bacterial replication in infected tissues and extended the survival time of infected mice.
Qualitative Variation among Commercial Immunoassays for Detection of Measles-Specific IgG
Authors: Latner Donald R. , Sowers Sun B. , Anthony Kiana , Colley Heather , Badeau Christine , Coates Jessica , Wong Phili , Fakile Yetunde , Interiano Cristina , Pannell Kevin B. , Leung-Pineda Van , Patel Manisha M. , Rota Paul A. , Limbago Brandi M. , Hickman Carole J.
Published: April 2020

Measurement of measles virus-specific IgG is used to assess presumptive evidence of immunity among immunocompetent individuals with uncertain immune or vaccination status. False-negative test results may lead to unnecessary quarantine and exclusion from activities such as employment, education, and travel or result in unnecessary revaccination. In contrast, false-positive results may fail to identify susceptible individuals and promote spread of disease by those who are exposed and unprotected. To better understand the performance characteristics of tests to detect measles IgG, we compared five widely used, commercially available measles IgG test platforms using a set of 223 well-characterized serum samples.
The C-Terminal Domain of the Sudan Ebolavirus L Protein Is Essential for RNA Binding and Methylation
Authors: Valle Coralie , Martin Baptiste , Debart Françoise , Vasseur Jean-Jacques , Imbert Isabelle , Canard Bruno , Coutard Bruno , Decroly Etienne
Published: April 2020

Ebola virus infects human and nonhuman primates, causing severe infections that are often fatal. The epidemics, in West and Central Africa, emphasize the urgent need to develop antiviral therapies. The Ebola virus large protein (L), which is the central protein for viral RNA replication/transcription, harbors a methyltransferase domain followed by a C-terminal domain of unknown function. We show that the C-terminal domain regulates the L protein methyltransferase activities and consequently participates in viral replication and escape of the host innate immunity.
Supplemental Material: The Chief Joseph dike swarm of the Columbia River flood basalts, and the legacy data set of William H. Taubeneck
Authors: Morriss M.C.
Published: April 2020

Supplemental Plates. Plate S1: Large-scale map of entire extent of Chief Joseph dike swarm. Also incorporates dikes of Ice Harbor, Steens, and Monument swarms. Plate S1 represents the most complete record of dikes related to Columbia River Basalt Group (CRBG) event known. Plate S2: Simplified map of CRBG-related dikes across the inland Pacific Northwest. Dikes are colored by their orientation and dike line density is also shown. Plate S3: Simplified map of CRBG-related dikes across the inland Pacific Northwest.
Supplemental Material: The Chief Joseph dike swarm of the Columbia River flood basalts, and the legacy data set of William H. Taubeneck
Authors: Morriss M.C. , al. et
Published: April 2020

dike swarm, Large igneous province, Columbia River Basalts, Eastern Oregon, Wallowa Mountains
Bilateral morphometric analysis of corneal sub-basal nerve plexus in patients undergoing unilateral cataract surgery: a preliminary in vivo confocal microscopy study
Authors: Giannaccare Giuseppe , Bernabei Federico , Pellegrini Marco , Guaraldi Fabio , Turchi Federica , Torrazza Carlo , Senni Carlotta , Scotto Riccardo , Sindaco Daniele , Di Cello Luca , Versura Piera , Scorcia Vincenzo , Traverso Carlo E , Vagge Aldo
Published: April 2020

Aims

To evaluate bilateral morphometric changes of corneal sub-basal nerve plexus (CSNP) occurring after unilateral cataract surgery by in vivo confocal microscopy (IVCM) images analysed with automated software.

Methods

IVCM was performed before (V0) and 1 month after surgery (V1) in both operated eyes (OEs) and unoperated eyes (UEs) of 30 patients. Thirty age and sex-matched subjects acted as controls. Corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD), corneal nerve fibre length (CNFL), corneal nerve total branch density (CTBD), corneal nerve fibre area (CNFA), corneal nerve fibre width, corneal nerve fractal dimension (CNFrD) and dendritic cells density were calculated.

Results

Mean CNFD, CNBD, CNFL, CTBD, CNFA and CNFrD significantly decreased at V1 versus V0 in both eyes (respectively, 15.35±7.00 vs 21.21±6.56 n/mm2 in OEs and 20.11±6.69 vs 23.20±7.26 in UEs; 13.57±12.16 vs 26.79±16.91 n/mm2 in OEs and 24.28±14.88 vs 29.76±15.25 in UEs; 9.67±3.44 mm/mm2 vs 13.49±3.42 in OEs and 12.53±3.60 vs 14.02±3.82 in UEs; 22.81±18.77 vs 42.25±24.64 n/mm2 in OEs and 38.06±20.52 vs 43.93±22.27 in UEs; 0.0040±0.0021 vs 0.0058±0.0020 mm2/mm2 in OEs and 0.0049±0.0016 vs 0.0057±0.0019 in UEs; 1.418±0.058 vs 1.470±0.037 in OEs and 1.466±0.040 vs 1.477±0.036 in UEs; always p<0.049).

Conclusion

Patients undergoing cataract surgery exhibit bilateral alterations of CSNP. This finding could have broad implications in the setting of sequential cataract surgery.
Vision loss in anterior uveitis
Authors: Al-Ani Haya H , Sims Joanne L , Tomkins-Netzer Oren , Lightman Susan , Niederer Rachael L
Published: April 2020

Aims

To evaluate the long-term risk of permanent vision loss in subjects with anterior uveitis.

Methods

Retrospective study of subjects attending uveitis clinic at Auckland District Health Board and Moorfields Eye Hospital between 2008 and 2018. Main outcome measures were: best corrected visual acuity (BCVA); moderate vision loss (MVL ≤20/50); and severe vision loss (SVL ≤20/200).

Results

2526 eyes of 1814 subjects were included with a mean follow-up of 6.8 years (17 235.4 eye-years of follow-up). MVL occurred in 240 eyes (9.5%) during the follow-up period, of which 97 (3.8%) had permanent MVL due to uveitis. The incidence of permanent MVL due to uveitis was 0.006 per eye-year with a cumulative risk at 10 years of 6.6% (5.2%–8.4%). The most common cause of permanent MVL due to uveitis was uveitic glaucoma (31.3%), followed by cystoid macular oedema (27.1%) and corneal scar (21.9%). SVL occurred in 80 eyes (3.2%) during the follow-up period, of which 39 (1.5%) had permanent SVL due to uveitis. The incidence of permanent SVL due to uveitis was 0.002 per eye-year with a cumulative risk at 10 years of 2.6% (1.8%–3.7%). Multivariate analysis showed older age at presentation, chronic anterior uveitis (CAU), infectious aetiology and poor presenting BCVA were all risk factors for permanent MVL due to uveitis.

Conclusions

Although vision loss is an uncommon complication in anterior uveitis, the risk is greatest in those with CAU, infectious aetiology and poor presenting BCVA. Uveitic glaucoma is the most common cause of vision loss.
Relationship of obesity to adipose tissue insulin resistance
Authors: Jiang Jiajia , Cai Xueli , Pan Yuesong , Du Xiaoyan , Zhu Huiping , Yang Xinghua , Zheng Deqiang , Gaisano Herbert , Wei Tiemin , He Yan
Published: April 2020

Aims

This study aimed to examine the association of different anatomical forms of obesity with adipose tissue insulin resistance and to assess the diagnostic value and contribution of obesity to adipose tissue insulin resistance.

Methods

This cross-sectional study included a total of 499 subjects aged 50 years or over. Multivariate regression analysis was conducted to clarify the association of different forms of obesity with adipose tissue insulin resistance (calculated as fasting insulin level×fasting free fatty acids level). Receiver operating characteristic cure analyses were used to assess the diagnostic value of each anthropometric indicator for adipose tissue insulin resistance. Attributable risk per cent and population attributable risk per cent were calculated to assess the contribution of obesity to adipose tissue insulin resistance.

Results

After adjustment for potential confounders, we showed that anthropometric indicators were all positively associated with adipose tissue insulin resistance. In males, waist circumference (WC) was the strongest associated factor (OR, 3.43 (95% CI 2.03 to 5.82)) and indicator (area under the curve (AUC): 0.79) of adipose tissue insulin resistance among those indicators. Here, abdominal obesity (WC≥90 cm) accounted for 64.9% of adipose tissue insulin resistance in the abdominal obese males. Accordingly, body mass index (BMI) was the strongest associated factor (OR,3.08 (95% CI 2.04 to 4.66)) and indicator (AUC: 0.78) of adipose tissue insulin resistance in females. Here, general obesity of BMI≥25 kg/m2accounted for 66.2% of the adipose tissue insulin resistance in the general obese females. We further demonstrated that adipose tissue insulin resistance was associated or trended to be associated with the metabolic diseases of cardiovascular disease, type 2 diabetes and fatty liver in subjects with normal BMI and WC.

Conclusions

Maintaining WC in males and BMI in females to a normal range could be an important strategy to significantly reduce the occurrence of adipose tissue insulin resistance and the subsequent metabolic diseases.
Risk of chronic kidney disease defined by decreased estimated glomerular filtration rate in individuals with different prediabetic phenotypes: results from a prospective cohort study in China
Authors: Li Wei , Wang Anping , Jiang Jiajia , Liu Guangxu , Wang Meiping , Li Dongxue , Wen Jing , Mu Yiming , Du Xiaoyan , Gaisano Herbert , Dou Jingtao , He Yan
Published: April 2020

Objective

We aimed to investigate the effects of prediabetes and its phenotypes of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and elevated glycated hemoglobin A1c (EHbA1c) on chronic kidney disease (CKD) occurrence, and define the cut-off point of each glycemic index that significantly increases the risk of CKD.

Research design and methods

In this prospective cohort study, 6446 non-diabetic subjects aged 40 years and over were followed over a period of 3 years to track the new onset of CKD. Cox regression was used to assess the association of prediabetes and its phenotypes with CKD. Receiver operating characteristic curves were used to define the cut-off point of each glycemic index that significantly increases the occurrence of CKD. Population attributable risk percent was calculated to estimate the contribution of prediabetes to CKD.

Results

Compared to subjects with normal glucose tolerance, patients with prediabetes significantly increased the risk of development of CKD (HR=2.33 (1.19–4.55)). Specifically, this increased risk of CKD development was observed in patients with IFG, IGT and EHbA1c. The cut-off points shown to significantly increase the risk of CKD are fasting plasma glucose of 5.63 mmol/L, 2-hour plasma glucose of 6.80 mmol/L and HbA1cof 5.6%. The contribution of prediabetes to CKD occurrence in the study population was 60.6%.

Conclusions

This result suggests that the stricter criteria might be needed to define normal plasma glucose level in China that would not be predisposed to diabetic complications, particularly CKD.
Estimating the incidence of abortion: a comparison of five approaches in Ghana
Authors: Keogh Sarah C , Otupiri Easmon , Chiu Doris W , Polis Chelsea B , Hussain Rubina , Bell Suzanne O , Nakua Emmanuel K , Larsen-Reindorf Roderick
Published: April 2020

Introduction

Induced abortion estimates are critical for reproductive health programming. In countries like Ghana where abortion is somewhat legally restricted and highly stigmatised, official records are incomplete and different approaches are needed to measure abortion incidence. We conducted a study in Ghana to test five methodologies for estimating incidence: direct reporting, the list experiment, the confidante method, the Abortion Incidence Complications Method (AICM) and a modified AICM.

Methods

The direct reporting, list experiment and confidante method were implemented through a nationally representative community-based survey (CBS) of 4722 women. The AICM used data from a nationally representative health facilities survey (HFS) and a knowledgeable informant survey. The modified AICM combined CBS and HFS data. For each approach, we calculated abortion incidence nationally and for Ghana’s three ecological zones and conducted checks to determine the most internally valid approaches.

Results

National incidence estimates ranged from 27 per 1000 (AICM) to 61 (confidante method). The Northern zone displayed lower rates than the other two zones for all approaches. Validity and reliability checks found that the list experiment was invalid. The approaches that stood up to the internal validity checks and were most reliable were the direct reporting, confidante method and modified AICM. These approaches provide lower and upper bound estimates for the abortion rate, and the mean of the estimates from the three approaches yields a final abortion rate of 44 per 1000 and an unintended pregnancy rate of 103 per 1000.

Conclusions

Comparing five approaches to estimating abortion enabled cross-validation of findings and highlighted strengths, pitfalls and requirements of each approach that can inform abortion estimation in other settings.
Retrospective chart review of minor tibial fractures in preschoolers: immobilisation and complications
Authors: Ferrier Charlotte A , Schembri Rachel , Hopper Sandy M
Published: April 2020

Objective

To compare the treatment practices (immobilisation vs non-immobilisation) of toddler fractures and other minor tibial fractures (both proven and suspected) in preschoolers, aged 9 months–4 years, and examine rates of ED re-presentations and complications.

Methods

Retrospective chart review of presentations of minor tibial fractures, both proven (radiologically confirmed) or suspected (negative X-ray but clinical evidence of bony injury), in children aged 9 months–4 years presenting to a single tertiary level paediatric ED from May 2016 to April 2018. Data collected included treatment practices, subsequent unscheduled re-presentations (including reasons) and complications (defined as problems relating to the injury that required further active care).

Results

A search of medical records yielded 240 cases: 102 had proven fractures (spiral, buckle or Salter-Harris II) and 138 were diagnosed with a suspected fracture. 73.5% of proven fractures were immobilised, predominantly with backslabs. 79% of suspected fractures were treated with expectant observation without immobilisation. Patients treated with immobilisation were more likely to re-present to ED compared with non-immobilised patients (18/104, 17.3% vs 9/136, 6.6% RR 2.62, 95% CI 1.23 to 5.58). 21 complications were seen in 19/104 (18.3%) immobilised patients. There were eight skin complications (complication rate of 7.7%) and 11 cast issues (complication rate of 10.6%). Two (1.5%) of the 136 patients had complications related to pain or limp. Pain was uncommonly found, although follow-up was not universal.

Conclusion

In our centre, proven minor tibial fractures were more likely to receive a backslab, whereas for suspected fractures, expectant observation without immobilisation was performed. Although there is potential bias in the identification of complications with immobilisation, the study suggests that non-immobilisation approach should be investigated.
Johne's disease in dairy herds 2. Effective control using the National Johne's Management Plan
Authors: Orpin Pete , Sibley Dick , Bond Karen
Published: April 2020

Background

The major focus of the National Johne's Management Plan is to secure engagement, enthusiasm and compliance with robust Johne's disease control. The primary method of control depends largely on husbandry to block direct and indirect transmission from infectious animals to animals and environments where susceptible youngstock are reared.

Aim of the article

This article, the second in a two‐part series, describes how to control Johne's disease (JD) effectively using the National Johne's Management Plan (NJMP). The first article in this series, which was published in the January/February issue of In Practice (Orpin and others 2020), provided information on JD and the NJMP, giving an understanding of the disease in terms of the importance and economics of its control in dairy herds, and its transmission routes.
Ultrastructural mechanisms of macrophage-induced demyelination in Guillain-Barré syndrome
Authors: Koike Haruki , Fukami Yuki , Nishi Ryoji , Kawagashira Yuichi , Iijima Masahiro , Katsuno Masahisa , Sobue Gen
Published: April 2020

Objective

To describe the pathological features of Guillain-Barré syndrome focusing on macrophage-associated myelin lesions.

Methods

Longitudinal sections of sural nerve biopsy specimens from 11 patients with acute inflammatory demyelinating polyneuropathy (AIDP) exhibiting macrophage-associated demyelinating lesions were examined using electron microscopy. A total of 1205 nodes of Ranvier were examined to determine the relationship of the macrophage-associated demyelinating lesions with the nodal regions. Additionally, immunohistochemical and immunofluorescent studies were performed to elucidate the sites of complement deposition.

Results

Overall, 252 macrophage-associated myelin lesions were identified in longitudinal sections. Of these, 40 lesions exhibited complete demyelination with no association with the lamellar structures of myelin. In 183 lesions, macrophage cytoplasm was located at internodes without association with the nodes of Ranvier or paranodes. In particular, these internodal lesions were more frequent in one patient (152 lesions). In the remaining 29 lesions, the involvement of nodal regions was obvious. Lesions involving nodal regions were more frequently observed than those involving internodes in four patients. Invasion of the macrophage cytoplasmic processes into the space between the paranodal myelin terminal loops and the axolemma from the nodes of Ranvier was observed in three of these patients. Immunostaining suggested complement deposition corresponding to putative initial macrophage-associated demyelinating lesions.

Conclusions

The initial macrophage-associated demyelinating lesions appeared to be located at internodes and at nodal regions. The sites at which the macrophages initiated phagocytosis of myelin might be associated with the location of complement deposition in certain patients with AIDP.
Primer on an ethics of AI-based decision support systems in the clinic
Authors: Braun Matthias , Hummel Patrik , Beck Susanne , Dabrock Peter
Published: April 2020

Making good decisions in extremely complex and difficult processes and situations has always been both a key task as well as a challenge in the clinic and has led to a large amount of clinical, legal and ethical routines, protocols and reflections in order to guarantee fair, participatory and up-to-date pathways for clinical decision-making. Nevertheless, the complexity of processes and physical phenomena, time as well as economic constraints and not least further endeavours as well as achievements in medicine and healthcare continuously raise the need to evaluate and to improve clinical decision-making. This article scrutinises if and how clinical decision-making processes are challenged by the rise of so-called artificial intelligence-driven decision support systems (AI-DSS). In a first step, this article analyses how the rise of AI-DSS will affect and transform the modes of interaction between different agents in the clinic. In a second step, we point out how these changing modes of interaction also imply shifts in the conditions of trustworthiness, epistemic challenges regarding transparency, the underlying normative concepts of agency and its embedding into concrete contexts of deployment and, finally, the consequences for (possible) ascriptions of responsibility. Third, we draw first conclusions for further steps regarding a ‘meaningful human control’ of clinical AI-DSS.
Genetic diversity of HIV in seminal plasma remains higher than in blood after short-term antiretroviral therapy
Authors: López Zúñiga Miguel Ángel , Chueca Natalia , de Salazar Adolfo , Fernández Caballero José Angel , Gutierrez Valencia Alicia , Vinuesa García David , Omar Mohamed Balgahata Mohamed , Hidalgo Tenorio Carmen , Lopez-Ruz Miguel Angel , Garcia Federico
Published: April 2020

Objective

To provide insight on viral kinetics and genetic diversity of HIV in seminal plasma at baseline and 1 month after initiating antiretroviral therapy (ART).

Patients and methods

Blood and seminal samples from patients with newly diagnosed HIV were obtained before ART initiation (T0) and 1 month after ART initiation (T1). HIVenvgenetic diversity was studied using deep sequencing Nextera and V3 chemistry in a MiSeq Illumina platform. The number of viral quasispecies (5% cut-off) and Shannon Index were used to analyse diversity.

Results

Forty-seven ART-naive patients were recruited between September 2016 and November 2018. At enrolment, the number of quasispecies in blood (median 4 (IQR 2–5)) was lower than in the seminal compartment (median 6, (IQR 4–8)) (p<0.01); the Shannon Index was also higher (p<0.001) in the seminal compartment than in blood (1.77 vs 0.64). At T1, for the 13 patients with detectable HIV in both blood/seminal plasma, viral diversity remained higher (p=0.139) in seminal plasma (median 2 (IQR 1–4.5)) than in blood (median 1 (IQR 1–1.5)) Integrase inhibitors (INI)-based regimens achieved higher levels of undetectability and led more frequently to lower variability (p<0.001) than protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI).

Conclusion

We provide here further evidence of a larger genetic diversity in seminal plasma, both at diagnosis and short term after ART initiation. Our results strengthen previous findings on HIV diversity in seminal plasma. In addition, INIs decrease variability more rapidly than PI and NNRTI in both blood and seminal plasma.
Chronic obstructive pulmonary disease and lung cancer incidence in never smokers: a cohort study
Authors: Park Hye Yun , Kang Danbee , Shin Sun Hye , Yoo Kwang-Ha , Rhee Chin Kook , Suh Gee Young , Kim Hojoong , Shim Young Mog , Guallar Eliseo , Cho Juhee , Kwon O Jung
Published: April 2020

There has been limited evidence for the association between chronic obstructive pulmonary disease (COPD) and the incidence of lung cancer among never smokers. We aimed to estimate the risk of lung cancer incidence in never smokers with COPD, and to compare it with the risk associated with smoking. This cohort study involved 338 548 subjects, 40 to 84 years of age with no history of lung cancer at baseline, enrolled in the National Health Insurance Service National Sample Cohort. During 2 355 005 person-years of follow-up (median follow-up 7.0 years), 1834 participants developed lung cancer. Compared with never smokers without COPD, the fully-adjusted hazard ratios (95% CI) for lung cancer in never smokers with COPD, ever smokers without COPD, and ever smokers with COPD were 2.67 (2.09 to 3.40), 1.97 (1.75 to 2.21), and 6.19 (5.04 to 7.61), respectively. In this large national cohort study, COPD was also a strong independent risk factor for lung cancer incidence in never smokers, implying that COPD patients are at high risk of lung cancer, irrespective of smoking status.
Computed tomographic findings in a case of feline insulinoma
Authors: Shorten Eimear , Swallow Adam , McCallum Katie Elizabeth , Holzhausen Cornelia , Hughes Katherine , Genain Marie‐Aude
Published: April 2020

Insulinomas are functional insulin‐secreting tumours of the beta cells of the pancreatic islets which are rare in cats. Clinical signs are a result of hypoglycaemia and include seizures, collapse, weakness, ataxia, disorientation, mental dullness and visual disturbances. An 11‐year‐old male neutered domestic shorthair cat was presented with a history of having a single abnormal neurological episode. Persistent hypoglycaemia, hyperinsulinaemia and the presence of a well‐defined pancreatic nodule on abdominal ultrasound resulted in a suspected diagnosis of insulinoma. Multiphasic CT angiography revealed a well‐defined, homogeneous pancreatic mass which was isoattenuating to pancreatic parenchyma on precontrast images, had marked contrast enhancement in the arterial phase and moderate enhancement in the venous phase. CT angiography was a useful imaging modality for evaluating this case of histologically confirmed malignant insulinoma and its associated metastases.
Chronic coenurosis in sheep: spontaneous remission of clinical signs and role of CT and MRI in the diagnosis and follow‐up
Authors: Tena Laura , De Miguel Ricardo , Castells Enrique , Escudero Amaia , Lacasta Delia
Published: April 2020

Coenurosis is a fatal disease caused by the larval stage of Taenia multiceps that leads to enormous economic losses in sheep production. Five ewes affected by chronic coenurosis were studied by CT and one of them by MRI. CT allowed detection, localisation and characterisation of the parasitic cyst in all evaluated animals. MRI evinced the white and grey matter damage in the areas adjacent to the coenurus. One of the affected animals recovered spontaneously, showing a shrunken and collapsed parasitic cyst surrounded by partially mineralised tissue in the CT and MRI images. These findings were confirmed at postmortem examination. In conclusion, CT and MRI are valuable non‐invasive techniques that allow early diagnosis, characterisation and follow‐up of ovine CNS diseases. To the authors’ knowledge, this is the first report of a spontaneous clinical remission of chronic coenurosis in small ruminants.
Study of the interactions of the axion with mesons and photons using a chiral effective Lagrangian model
Authors: Landini Giacomo , Meggiolaro Enrico
Published: April 2020

We investigate the most interesting decay processes involving axions, photons and the lightest pseudoscalar mesons, making use of a chiral effective Lagrangian model with $$L=3$$L=3 light quark flavors, which also includes the flavor-singlet pseudoscalar meson and implements the U(1) axial anomaly of the fundamental theory. In particular, we compute the electromagnetic coupling of the axion to photons and we compare our result with the prediction of the Chiral Effective Lagrangian with $$L=2$$L=2 light quark flavors. Moreover, we study the decay channels $$\eta /\eta '\rightarrow \pi \pi a$$η/η′→ππa and we estimate the corresponding decay widths, using the existing bounds on the $$U(1)_{PQ}$$U(1)PQ breaking scale.
Visual detection of LSB-encoded natural image steganography
Authors: Watters Paul , Martin Frances , Stripf H. Steffen
Published: April 2020

Many steganographic systems embed hidden messages inside the least significant bit layers of colour natural images. The presence of these messages can be difficult to detect by using statistical steganalysis. However, visual steganalysis by humans may be more successful in natural image discrimination. This study examined whether humans could detect least-significant bit steganography in 15 color natural images from the VisTex database using a controlled same/different task (
N
= 58) and a
yes/no
task (
N
= 61). While
d
′ > 1 was observed for color layers 4--8, layers 1--3 had
d
′ < 1 in both experiments. Thus, layers 1--3 appear to be highly resistant to visual steganalysis.
Unmanned systems and Ada
Authors: Cicalese Cynthia , Sherrill Joel , Sward Ricky E. , Weatherly Richard
Published: April 2020

This tutorial provides an introduction to the growing field of Unmanned Systems and the role that Ada plays in solving the challenges presented when designing, building, and operating Unmanned Systems. The tutorial begins with an introduction to the fundamentals of ground, air, and maritime Unmanned Systems and the specific challenges of these systems. The authors will demonstrate how they are using Ada over RTEMS in developing Large Unmanned Ground Vehicles. RTEMS is an open source, real-time operating system that provides a high performance environment for embedded applications on a range of processors and embedded hardware. The attendee will gain hands-on experience in developing an Ada application over RTEMS using an environment that provides a complete GNAT Ada installation with all sources and scripts as well as the prebuilt toolset and simulators. The attendee will gain from this tutorial an understanding of Unmanned Systems and a practical application of how Ada can be used in the development of these systems.
"Automatic Prototype Generating" restated with re-ADA
Authors: Liang Sheldon X. , Reibling Lyle , Sambasivam Samuel
Published: April 2020

Structured System Analysis and Design (SSAD) is still considered one of the most straightforward systems approaches, despite both supporting arguments and criticisms. One philosophy in software engineering is to "document everything". However, the waterfall model within SSAD discourages frequent changing of requirements, which is a significant problem to designers. Compared with SSAD, Component-Based Software Engineering (CBSE) with its modular structured solution allows individual components to be replaced easily at design time or run time if the requirements of the initial component (expressed via the interface) are met by the replacement component.

After years of experience in developing and architecting reliable architectures for software-intensive distributed systems, the authors present a PAISE (Perspective-bridged Architecture with Interoperability, Substitutability, and Extensibility) model with the aim of automating systems perspective transitioning through a document-driven approach within SSAD. The authors stress important abilities of architecting application systems such as
interoperability
,
substitutability
, and
extensibility
in support of component-based software engineering. PAISE starts with a conceptual system that is rapidly prototyped for requirements, follows with a technical system that addresses the interior structure of the system, and results in an operational system for business process.

In combination with re-ADA (an architectural description language as well as its runtime foundation), PAISE/re-ADA can not only promote a document-driven approach with SSAD, but also automate system perspective transitioning with CBSE.
Distributed container
Authors: Dinh Tong , Barkataki Shan
Published: April 2020

We describe a design patterns for achieving fast data transfer in a distributed system with a high reliability requirement. Also described are techniques for utilizing the Ada-95 serialization facilities in implementing the design patterns.
Multi-stage replay with crosscut
Authors: Chow Jim , Lucchetti Dominic , Garfinkel Tal , Lefebvre Geoffrey , Gardner Ryan , Mason Joshua , Small Sam , Chen Peter M.
Published: April 2020

Deterministic record-replay has many useful applications, ranging from fault tolerance and forensics to reproducing and diagnosing bugs. When choosing a record-replay solution, the system administrator must choose a priori how comprehensively to record the execution and at what abstraction level to record it. Unfortunately, these choices may not match well with how the recording is eventually used. A recording may contain too little information to support the end use of replay, or it may contain more sensitive information than is allowed to be shown to the end user of replay. Similarly, fixing the abstraction level at the time of recording often leads to a semantic mismatch with the end use of replay.

This paper describes how to remedy these problems by adding customizable replay stages to create special-purpose logs for the end users of replay. Our system, called Crosscut, allows replay logs to be "sliced" along time and abstraction boundaries. Using this approach, users can create slices that include only the processes, applications, or components of interest, excluding parts that handle sensitive data. Users can also retarget the abstraction level of the replay log to higher-level platforms, such as Perl or Valgrind. Execution can then be augmented with additional analysis code at replay time, without disturbing the replayed components in the slice. Crosscut thus uses replay itself to transform logs into a more efficient, secure, and usable form for replay-based applications.

Our current Crosscut prototype builds on VMware Workstation's record-replay capabilities, and supports a variety of different replay environments. We show how Crosscut can create slices of only the parts of the computation of interest and thereby avoid leaking sensitive information, and we show how to retarget the abstraction level of the log to enable more convenient use during replay debugging.
Neon
Authors: Zhang Qing , McCullough John , Ma Justin , Schear Nabil , Vrable Michael , Vahdat Amin , Snoeren Alex C. , Voelker Geoffrey M. , Savage Stefan
Published: April 2020

Modern organizations face increasingly complex information management requirements. A combination of commercial needs, legal liability and regulatory imperatives has created a patchwork of mandated policies. Among these, personally identifying customer records must be carefully access-controlled, sensitive files must be encrypted on mobile computers to guard against physical theft, and intellectual property must be protected from both exposure and "poisoning." However, enforcing such policies can be quite difficult in practice since users routinely share data over networks and derive new files from these inputs--incidentally laundering any policy restrictions. In this paper, we describe a virtual machine monitor system called Neon that transparently labels derived data using byte-level "tints" and tracks these labels end to end across commodity applications, operating systems and networks. Our goal with Neon is to explore the viability and utility of transparent information flow tracking within conventional networked systems when used in the manner in which they were intended. We demonstrate that this mechanism allows the enforcement of a variety of data management policies, including data-dependent confinement, mandatory I/O encryption, and intellectual property management.
AASH
Authors: Kazempour Vahid , Kamali Ali , Fedorova Alexandra
Published: April 2020

Asymmetric multicore processors (AMP) consist of cores exposing the same instruction-set architecture (ISA) but varying in size, frequency, power consumption and performance. AMPs were shown to be more power efficient than conventional symmetric multicore processors, and it is therefore likely that future multicore systems will include cores of different types. AMPs derive their efficiency from core specialization: instruction streams can be assigned to run on the cores best suited to their demands for architectural resources. System efficiency is improved as a result. To perform effective matching of threads to cores, the thread scheduler must be asymmetry-aware; and while asymmetry-aware schedulers for operating systems are a well studied topic, asymmetry-awareness in hypervisors has not been addressed. A hypervisor must be asymmetry-aware to enable proper functioning of asymmetry-aware guest operating systems; otherwise they will be ineffective in virtual environments. Furthermore, a hypervisor must ensure that asymmetric cores are shared among multiple guests in a fair fashion or in accordance with their priorities.

This work for the first time implements simple changes to the hypervisor scheduler, required to make it asymmetry-aware, and evaluates the benefits and overheads of these asymmetry-aware mechanisms. Our evaluation was performed using an open source hypervisor Xen on a real multicore system where asymmetry was emulated via CPU frequency scaling. We compared the asymmetry-aware hypervisor to default Xen. Our results indicate that asymmetry support can be implemented with low overheads, and resulting performance improvements can be significant, reaching up to 36% in our experiments. Most performance improvements are derived from the fact that an asymmetry-aware hypervisor ensures that the fast cores do not go idle before slow cores and from the fact that it maps virtual cores to physical cores for asymmetry-aware guests according to the guest's expectations. Other benefits from asymmetry awareness are fairer sharing of computing resources among VMs and more stable execution times.
Evaluation of a just-in-time compiler retrofitted for PHP
Authors: Tatsubori Michiaki , Tozawa Akihiko , Suzumura Toyotaro , Trent Scott , Onodera Tamiya
Published: April 2020

Programmers who develop Web applications often use dynamic scripting languages such as Perl, PHP, Python, and Ruby. For general purpose scripting language usage, interpreter-based implementations are efficient and popular but the server-side usage for Web application development implies an opportunity to significantly enhance Web server throughput. This paper summarizes a study of the optimization of PHP script processing. We developed a PHP processor, P9, by adapting an existing production-quality just-in-time (JIT) compiler for a Java virtual machine, for which optimization technologies have been well-established, especially for server-side application. This paper describes and contrasts microbenchmarks and SPECweb2005 benchmark results for a well-tuned configuration of a traditional PHP interpreter and our JIT compiler-based implementation, P9. Experimental results with the microbenchmarks show 2.5-9.5x advantage with P9, and the SPECweb2005 measurements show about 20-30% improvements. These results show that the acceleration of dynamic scripting language processing does matter in a realistic Web application server environment. CPU usage profiling shows our simple JIT compiler introduction reduces the PHP core runtime overhead from 45% to 13% for a SPECweb2005 scenario, implying that further improvements of dynamic compilers would provide little additional return unless other major overheads such as heavy memory copy between the language runtime and Web server frontend are reduced.
Novel online profiling for virtual machines
Authors: Namjoshi Manjiri A. , Kulkarni Prasad A.
Published: April 2020

Application
profiling
is a popular technique to improve program performance based on its behavior.
Offline
profiling, although beneficial for several applications, fails in cases where prior program runs may not be feasible, or if changes in input cause the profile to not match the behavior of the actual program run. Managed languages, like Java and C\#, provide a unique opportunity to overcome the drawbacks of offline profiling by generating the profile information online during the current program run. Indeed, online profiling is extensively used in current VMs, especially during selective compilation to improve program
startup
performance, as well as during other feedback-directed optimizations.

In this paper we illustrate the drawbacks of the current
reactive
mechanism of online profiling during selective compilation. Current VM profiling mechanisms are slow -- thereby delaying associated transformations, and estimate future behavior based on the program's immediate past -- leading to potential misspeculation that limit the benefits of compilation. We show that these drawbacks produce an average performance loss of over 14.5% on our set of benchmark programs, over an
ideal offline
approach that accurately compiles the hot methods early. We then propose and evaluate the potential of a novel strategy to achieve similar performance benefits with an online profiling approach. Our new online profiling strategy uses early determination of loop iteration bounds to predict future method hotness. We explore and present promising results on the potential, feasibility, and other issues involved for the successful implementation of this approach.