bluuebunny/crossref_metadata_2025 huggingface dataset:
Semiparametric estimation of structural failure time models in continuous-time processes
Authors: Yang S , Pieper K , Cools F
Published: September 2019

Structural failure time models are causal models for estimating the effect of time-varying treatments on a survival outcome. G-estimation and artificial censoring have been proposed for estimating the model parameters in the presence of time-dependent confounding and administrative censoring. However, most existing methods require manually pre-processing data into regularly spaced data, which may invalidate the subsequent causal analysis. Moreover, the computation and inference are challenging due to the nonsmoothness of artificial censoring. We propose a class of continuous-time structural failure time models that respects the continuous-time nature of the underlying data processes. Under a martingale condition of no unmeasured confounding, we show that the model parameters are identifiable from a potentially infinite number of estimating equations. Using the semiparametric efficiency theory, we derive the first semiparametric doubly robust estimators, which are consistent if the model for the treatment process or the failure time model, but not necessarily both, is correctly specified. Moreover, we propose using inverse probability of censoring weighting to deal with dependent censoring. In contrast to artificial censoring, our weighting strategy does not introduce nonsmoothness in estimation and ensures that resampling methods can be used for inference.
Comparison of Repeated Doses of Ivermectin Versus Ivermectin Plus Albendazole for the Treatment of Onchocerciasis: A Randomized, Open-label, Clinical Trial
Authors: Batsa Debrah Linda , Klarmann-Schulz Ute , Osei-Mensah Jubin , Dubben Bettina , Fischer Kerstin , Mubarik Yusif , Ayisi-Boateng Nana Kwame , Ricchiuto Arcangelo , Fimmers Rolf , Konadu Peter , Nadal Jennifer , Gruetzmacher Barbara , Weil Gary , Kazura James W , King Christopher L , Debrah Alexander Y , Hoerauf Achim
Published: September 2019

Background

Improved treatment for onchocerciasis is needed to accelerate onchocerciasis elimination in Africa. Aiming to better exploit registered drugs, this study was undertaken to determine whether annual or semiannual treatment with ivermectin (IVM; 200 µg/kg) plus albendazole (ALB; 800 mg single dose) is superior to IVM alone.

Methods

This trial was performed in Ghana and included 272 participants with microfilariae (MF), who were randomly assigned to 4 treatment arms: (1) IVM annually at 0, 12, and 24 months; (2) IVM semiannually at 0, 6, 12, 18, and 24 months; (3) IVM+ALB annually; or (4) IVM+ALB semiannually. Microfiladermia was determined pretreatment and at 6, 18, and 36 months. The primary outcome was the proportion of fertile and viable female worms in onchocercomata excised at 36 months.

Results

Posttreatment nodule histology showed that 15/135 (11.1%), 22/155 (14.2%), 35/154 (22.7%), and 20/125 (16.0%) living female worms had normal embryogenesis in the IVM annual, IVM semiannual, IVM+ALB annual, and IVM+ALB semiannual groups, respectively (P = .1229). Proportions of dead worms also did not differ between the 4 groups (P = .9198). Proportions of patients without MF at 36 months (1 year after the last treatment) were 35/56 (63%) after annual IVM, 42/59 (71%) after semiannual IVM, 39/64 (61%) after annual IVM+ALB, and 43/53 (81%) after semiannual IVM+ALB.

Conclusions

The combination treatment of IVM plus ALB was no better than IVM alone for sterilizing, killing adult worms, or achieving sustained MF clearance. However, semiannual treatment was superior to annual treatment for achieving sustained clearance of Onchocerca volvulus MF from the skin (P = .024).

Clinical Trials Registration

ISRCTN50035143
Imatinib in Refractory Crohn Disease: A Series of 6 Cases
Authors: Boctor Anna , Hugot Jean-Pierre , Leblanc Thierry , Martinez-Vinson Christine , Allez Matthieu , Bellaïche Marc
Published: September 2019

Biologics have revolutionized Crohn disease (CD) treatment. Nevertheless, absence or loss of response is frequent and alternative therapeutic options may be necessary. Imatinib is a tyrosine kinase inhibitor that is used in chronic myeloid leukemia. A positive impact on CD in 2 patients with chronic myeloid leukemia treated with imatinib led us to propose the drug in 4 additional patients with refractory CD. Four out of these 6 patients reached clinical and endoscopic remission at a median time of 3 months. Remission was maintained for 9 months to 7 years. Imatinib may thus be considered as new therapeutic options for refractory CD.

We report 6 CD patients treated with imatinib. Two of them because of a leukemia and 4 because of a disease refractory to all medical options. Four patients experienced full and sometimes prolonged remission of their digestive disease.
Revival of Krebs–Ringer balanced salt solution for the investigation of polymorphonuclear leukocytes andPseudomonas aeruginosabiofilm interaction
Authors: Bjarnsholt Thomas , Jensen Peter Østrup , Alhede Maria
Published: September 2019

To study the interaction between aggregating bacteria and polymorphonuclear leukocytes (PMNs) in vitro, the chosen medium must favor both the isolated PMNs and the bacteria. To investigate the best-suited medium for the in vitro survival of isolated unactivated human PMNs, we compared three different mammalian cell media: Krebs–Ringer balanced salt solution (BSS), Hanks’ BSS (HBSS) and Roswell Park Memorial Institute (RPMI) 1640. The death of PMNs was estimated by the release of lactate dehydrogenase activity. Furthermore, two types of serum, human (HS) and fetal bovine (FBS), were compared at different concentrations (0%, 2%, 5%, 10%) and at three different time points (2, 4, 20 h). We show that Krebs–Ringer BSS prolonged the survival of PMNs compared to HBSS and RPMI 1640 and that the addition of 10% FBS significantly enhanced the long-term survival (20 h) compared to HS. Furthermore, we observed aggregation of Pseudomonas aeruginosa when grown in the presence of either a mixture of histones, histone H3, arginine or lysine. In this study, we show that the use of Krebs–Ringer BSS is highly relevant for the study of the interaction of bacteria and PMNs in relation to novel treatment strategies of biofilm infections due to the reproduction of bacterial aggregation as seen in chronic bacterial infections.
Deep electrical resistivity tomography for the prospection of low- to medium-enthalpy geothermal resources
Authors: Carrier A , Fischanger F , Gance J , Cocchiararo G , Morelli G , Lupi M
Published: September 2019

The growth of the geothermal industry sector requires innovative methods to reduce exploration costs whilst minimizing uncertainty during subsurface exploration. Until now geoelectrical prospection had to trade between logistically complex cabled technologies reaching a few hundreds meters deep versus shallow-reaching prospecting methods commonly used in hydro-geophysical studies. We present a recent technology for geoelectrical prospection, and show how geoelectrical methods may allow the investigation of medium-enthalpy geothermal resources until about 1 km depth. The use of the new acquisition system, which is made of a distributed set of independent electrical potential recorders, enabled us to tackle logistics and noise data issues typical of urbanized areas. We acquired a 4.5-km-long 2-D geoelectrical survey in an industrial area to investigate the subsurface structure of a sedimentary sequence that was the target of a ∼700 m geothermal exploration well (Geo-01, Satigny) in the Greater Geneva Basin, Western Switzerland. To show the reliability of this new method we compared the acquired resistivity data against reflection seismic and gravimetric data and well logs. The processed resistivity model is consistent with the interpretation of the active-seismic data and density variations computed from the inversion of the residual Bouguer anomaly. The combination of the resistivity and gravity models suggest the presence of a low resistivity and low density body crossing Mesozoic geological units up to Palaeogene–Neogene units that can be used for medium-enthalpy geothermal exploitation. Our work points out how new geoelectrical methods may be used to identify thermal groundwater at depth. This new cost-efficient technology may become an effective and reliable exploration method for the imaging of shallow geothermal resources.
The relationships between quality management systems, safety culture and leadership and patient outcomes in Australian Emergency Departments
Authors: Clay-Williams Robyn , Taylor Natalie , Ting Hsuen P , Winata Teresa , Arnolda Gaston , Austin Elizabeth , Braithwaite Jeffrey
Published: September 2019

Objective

We aimed to examine whether Emergency Department (ED) quality strategies, safety culture and leadership were associated with patient-level outcomes, after controlling for other organization-level factors, in 32 large Australian hospitals.

Design

Quantitative observational study, using linear and multi-level modelling to identify relationships between quality management systems at organization level; quality strategies at ED level for acute myocardial infarction (AMI), hip fracture and stroke; clinician safety culture and leadership and patient-level outcomes of waiting time and length of stay.

Setting

Thirty-two large Australian public hospitals.

Participants

Audit of quality management processes at organization and ED levels, senior quality manager at each of the 32 participating hospitals, 394 ED clinicians (doctors, nurses and allied health professionals).

Main Outcome Measure(s)

Within the multi-level model, associations were assessed between organization-level quality measures and ED quality strategies; organization-level quality measures and ED quality strategies and ward-level clinician measures of teamwork climate (TC), safety climate (SC) and leadership for AMI, hip fracture and stroke treatment conditions; and organization-level quality measures and ED quality strategies and ward-level clinician measures of TC, SC and leadership, and ED waiting time and length of stay (performance).

Results

We found seven statistically significant associations between organization-level quality systems and ED-level quality strategies; four statistically significant associations between quality systems and strategies and ED safety culture and leadership; and nine statistically significant associations between quality systems and strategies and ED safety culture and leadership, and ED waiting time and length of stay.

Conclusions

Organization-level quality structures influence ED-level quality strategies, clinician safety culture and leadership and, ultimately, waiting time and length of stay for patients. By focusing only on time-based measures of ED performance we risk punishing EDs that perform well on patient safety measures. We need to better understand the trade-offs between implementing safety culture and quality strategies and improving patient flow in the ED, and to place more emphasis on other ED performance measures in addition to time.
The clinician safety culture and leadership questionnaire: refinement and validation in Australian public hospitals
Authors: Clay-Williams Robyn , Taylor Natalie , Ting Hsuen P , Winata Teresa , Arnolda Gaston , Braithwaite Jeffrey
Published: September 2019

Objective

This study aimed to refine and validate a tool to measure safety culture and leadership in Australian hospitals.

Design

The clinician safety culture and leadership questionnaire was constructed by combining and refining the following two previously validated scales: Safety Attitudes Questionnaire and the Leadership Effectiveness Survey. Statistical processes were used to explore the factor structure, reliability, validity and descriptive statistics of the new instrument.

Setting

Thirty-two large Australian public hospitals.

Participants

1382 clinicians (doctors, nurses and allied health professionals).

Main Outcome Measure(s)

Descriptive statistics, structure and validity of clinician safety culture and leadership scale.

Results

We received 1334 valid responses from participants. The distribution of ratings was left-skewed, with a small ceiling effect, meaning that scores were clustered toward the high end of the scale. Using confirmatory factor analysis, we confirmed the structure of the three scales as a combined measure of safety culture and leadership. The data were divided into equal calibration and validation datasets. For the calibration dataset, the Chi-square: df ratio was 4.4, the root mean square error of approximation RMSEA (a measure of spread of the data) was 0.071, the standardized root mean square residual SRMR (an absolute measure of the fit of the data) was 0.058 and the Confirmatory Fit Index (CFI) (another test confirming the fit of the data) was 0.82; while none of the indices suggested good fit, all but CFI fell within acceptable thresholds. All factors demonstrated adequate internal consistency and construct reliability, as desired. All three domains achieved discriminant validity through cross-loadings, meaning that the three domains were determined to be independent constructs. Results for the validation dataset were effectively identical to those found in the calibration dataset.

Conclusions

While the model may benefit from additional refinement, we have validated the tool for measuring clinician safety culture and leadership in our Australian sample. The DUQuA safety culture and leadership scale can be used by Australian hospitals to assess clinician safety culture and leadership, and is readily modifiable for other health systems depending on their needs.
Do quality management systems influence clinical safety culture and leadership? A study in 32 Australian hospitals
Authors: Clay-Williams Robyn , Taylor Natalie , Ting Hsuen P , Arnolda Gaston , Winata Teresa , Braithwaite Jeffrey
Published: September 2019

Objective

This study aimed to explore the associations between the organization-level quality arrangements, improvement and implementation and department-level safety culture and leadership measures across 32 large Australian hospitals.

Design

Quantitative observational study, using linear and multi-level modelling to identify relationships between quality management systems and clinician safety culture and leadership.

Setting

Thirty-two large Australian public hospitals.

Participants

Quality audit at organization level, senior quality manager at each participating hospital, 1382 clinicians (doctors, nurses and allied health professionals).

Main outcome measures

Associations between organization-level quality measures and department-level clinician measures of teamwork climate, safety climate and leadership for acute myocardial infarction (AMI), hip fracture and stroke treatment conditions.

Results

We received 1332 valid responses from participants. The quality management systems index (QMSI, a questionnaire-based measure of the hospitals’ quality management structures) was ‘positively’ associated with all three department-level scales in the stroke department, with safety culture and leadership in the emergency department, but with none of the three scales in the AMI and hip fracture departments. The quality management compliance index (QMCI, an external audit-based measure of the quality improvement activities) was ‘negatively’ associated with teamwork climate and safety climate in AMI departments, after controlling for QMSI, but not in other departments. There was no association between QMCI and leadership in any department, after controlling for QMSI, and there was no association between the clinical quality implementation index (CQII, an external audit-based measure of the level of implementation of quality activities) and any of the three department-level scales in any of the four departments, after controlling for both QMSI and QMCI.

Conclusions

The influence of organization-level quality management systems on clinician safety culture and leadership varied depending on the hospital department, suggesting that whilst there was some consistency on patient safety attitudes and behaviours throughout the organizations, there were also other factors at play.
Pandrug-resistant Gram-negative bacteria: a systematic review of current epidemiology, prognosis and treatment options
Authors: Karakonstantis Stamatis , Kritsotakis Evangelos I , Gikas Achilleas
Published: September 2019

Background

The literature on the epidemiology, mortality and treatment of pandrug-resistant (PDR) Gram-negative bacteria (GNB) is scarce, scattered and controversial.

Objectives

To consolidate the relevant literature and identify treatment options for PDR GNB infections.

Methods

A systematic search in MEDLINE, Scopus and clinical trial registries was conducted. Studies reporting PDR clinical isolates were eligible for review if susceptibility testing for all major antimicrobials had been performed. Characteristics and findings of retrieved studies were qualitatively synthesized.

Results

Of 81 studies reviewed, 47 (58%) were published in the last 5 years. The reports reflected a worldwide dissemination of PDR GNB in 25 countries in 5 continents. Of 526 PDR isolates reported, Pseudomonas aeruginosa (n=175), Acinetobacter baumannii (n=172) and Klebsiella pneumoniae (n=125) were most common. PDR GNB were typically isolated in ICUs, but several studies demonstrated wider outbreak potential, including dissemination to long-term care facilities and international spread. All-cause mortality was high (range 20%–71%), but appeared to be substantially reduced in studies reporting treatment regimens active in vitro. No controlled trial has been performed to date, but several case reports and series noted successful use of various regimens, predominantly synergistic combinations, and in selected patients increased exposure regimens and newer antibiotics.

Conclusions

PDR GNB are increasingly being reported worldwide and are associated with high mortality. Several treatment regimens have been successfully used, of which synergistic combinations appear to be most promising and often the only available option. More pharmacokinetic/pharmacodynamic and outcome studies are needed to guide the use of synergistic combinations.
Leiomyosarcoma arising from the right ovarian vein
Authors: Suzuki Kazuomi , Taniguchi Kiyoaki , Ito Shunichi , Serizawa Akiko , Yamamoto Masakazu
Published: September 2019

Leiomyosarcomas (LMS) of the ovarian vein are extremely rare and have a poor prognosis. Only 10 cases have been reported since 1977. The patient is a 69-year-old woman presented with right abdominal pain. Computed tomography showed a regularly shaped tumor, 80 mm in diameter in the retroperitoneum, adjacent to the descending part of the duodenum. Intraoperatively, the right ovarian vein was found to run through the tumor and was, therefore, resected together with the tumor. Pathological examination revealed a LMS of the right ovarian vein. Nine months postoperatively, multiple lung metastases were detected and chemotherapy was initiated. Delayed diagnosis is associated with high mortality. It is important that the diagnosis of LMS should be made preoperatively when you have already diagnosed a tumor to better direct the surgical approach. Multimodal therapy may improve prognosis.
Love is in the air: ethylene and sex determination in Cucurbita pepo
Authors: Schilling Susanne , McCabe Paul F , Melzer Rainer
Published: September 2019

This article comments on:

García A, Aguado E, Martínez C, Loska D, Beltrán S, Valenzuela JL, Garrido D, Jamilena M. 2019. The ethylene receptors CpETR1A and CpETR2B cooperate in the control of sex determination in Cucurbita pepo. Journal of Experimental Botany 70, 154–167.
More connected, more active: galaxy clusters and groups at z ∼ 1 and the connection between their quiescent galaxy fractions and large-scale environments
Authors: Lee Seong-Kook , Im Myungshin , Hyun Minhee , Park Bomi , Kim Jae-Woo , Kim Dohyeong , Kim Yongjung
Published: September 2019

High-redshift galaxy clusters, unlike local counterparts, show diverse star formation activities. However, it is still unclear what keeps some of the high-redshift clusters active in star formation. To address this issue, we performed a multiobject spectroscopic observation of 226 high-redshift (0.8 < z < 1.3) galaxies in galaxy cluster candidates and the areas surrounding them. Our spectroscopic observation reveals six to eight clusters/groups at z ∼ 0.9 and z ∼ 1.3. The redshift measurements demonstrate the reliability of our photometric redshift measurements, which in turn gives credibility for using photometric redshift members for the analysis of large-scale structures (LSSs). Our investigation of the large-scale environment (∼10 Mpc) surrounding each galaxy cluster reveals LSSs – structures up to ∼10 Mpc scale – around many of, but not all, the confirmed overdensities and the cluster candidates. We investigate the correlation between quiescent galaxy fraction of galaxy overdensities and their surrounding LSSs, with a larger sample of ∼20 overdensities including photometrically selected overdensities at 0.6 < z < 0.9. Interestingly, galaxy overdensities embedded within these extended LSSs show a lower fraction of quiescent galaxies ($\sim 20{{\ \rm per\ cent}}$) than isolated ones at similar redshifts (with a quiescent galaxy fraction of $\sim 50 {{\ \rm per\ cent}}$). Furthermore, we find a possible indication that clusters/groups with a high quiescent galaxy fraction are more centrally concentrated. Based on these results, we suggest that LSSs are the main reservoirs of gas and star-forming galaxies to keep galaxy clusters fresh and extended in size at z ∼ 1.
Mergers, starbursts, and quenching in the simba simulation
Authors: Rodríguez Montero Francisco , Davé Romeel , Wild Vivienne , Anglés-Alcázar Daniel , Narayanan Desika
Published: September 2019

We use the simba cosmological galaxy formation simulation to investigate the relationship between major mergers ($\lesssim$4:1), starbursts, and galaxy quenching. Mergers are identified via sudden jumps in stellar mass M* well above that expected from in situ star formation, while quenching is defined as going from specific star formation rate (sSFR) $\gt t_{\rm H}^{-1}$ to $\lt 0.2t_{\rm H}^{-1}$, where tH is the Hubble time. At z ≈ 0–3, mergers show ∼2–3× higher SFR than a mass-matched sample of star-forming galaxies, but globally represent $\lesssim 1{{\ \rm per\ cent}}$ of the cosmic SF budget. At low masses, the increase in SFR in mergers is mostly attributed to an increase in the H2 content, but for $M_*\gtrsim 10^{10.5} \,\mathrm{ M}_{\odot }$ mergers also show an elevated star formation efficiency suggesting denser gas within merging galaxies. The merger rate for star-forming galaxies shows a rapid increase with redshift, ∝(1 + z)3.5, but the quenching rate evolves much more slowly, ∝(1 + z)0.9; there are insufficient mergers to explain the quenching rate at $z\lesssim 1.5$. simba first quenches galaxies at $z\gtrsim 3$, with a number density in good agreement with observations. The quenching time-scales τq are strongly bimodal, with ‘slow’ quenchings (τq ∼ 0.1tH) dominating overall, but ‘fast’ quenchings (τq ∼ 0.01tH) dominating in M* ∼ 1010–1010.5 M$\odot$ galaxies, likely induced by simba’s jet-mode black hole feedback. The delay time distribution between mergers and quenching events suggests no physical connection to either fast or slow quenching. Hence, simba predicts that major mergers induce starbursts, but are unrelated to quenching in either fast or slow mode.
Supernovae and their host galaxies – VI. Normal Type Ia and 91bg-like supernovae in ellipticals
Authors: Barkhudaryan L V , Hakobyan A A , Karapetyan A G , Mamon G A , Kunth D , Adibekyan V , Turatto M
Published: September 2019

We present an analysis of the galactocentric distributions of the ‘normal’ and peculiar ‘91bg-like’ subclasses of 109 supernovae (SNe) Ia, and study the global parameters of their elliptical hosts. The galactocentric distributions of the SN subclasses are consistent with each other and with the radial light distribution of host stellar populations, when excluding bias against central SNe. Among the global parameters, only the distributions of u − r colours and ages are inconsistent significantly between the ellipticals of different SN Ia subclasses: the normal SN hosts are on average bluer/younger than those of 91bg-like SNe. In the colour–mass diagram, the tail of colour distribution of normal SN hosts stretches into the Green Valley – transitional state of galaxy evolution, while the same tail of 91bg-like SN hosts barely reaches that region. Therefore, the bluer/younger ellipticals might have more residual star formation that gives rise to younger ‘prompt’ progenitors, resulting in normal SNe Ia with shorter delay times. The redder and older ellipticals that already exhausted their gas for star formation may produce significantly less normal SNe with shorter delay times, outnumbered by ‘delayed’ 91bg-like events. The host ages (lower age limit of the delay times) of 91bg-like SNe does not extend down to the stellar ages that produce significant u-band fluxes – the 91bg-like events have no prompt progenitors. Our results favour SN Ia progenitor models such as He-ignited violent mergers that have the potential to explain the observed SN/host properties.
Detailed study of the Milky Way globular cluster Laevens 3
Authors: Longeard Nicolas , Martin Nicolas , Ibata Rodrigo A , Collins Michelle L M , Laevens Benjamin P M , Bell Eric , Mackey Dougal
Published: September 2019

We present a photometric and spectroscopic study of the Milky Way satellite Laevens 3. Using MegaCam/Canada–France–Hawaii Telescope $g$ and $i$ photometry and Keck II/DEIMOS multi-object spectroscopy, we refine the structural and stellar properties of the system. The Laevens 3 colour–magnitude diagram shows that it is quite metal-poor, old ($13.0 \pm 1.0$ Gyr), and at a distance of $61.4 \pm 1.0$ kpc, partly based on two RR Lyrae stars. The system is faint ($M_V = -2.8^{+0.2}_{-0.3}$ mag) and compact ($r_h = 11.4 \pm 1.0$ pc). From the spectroscopy, we constrain the systemic metallicity (${\rm [Fe/H]}_\mathrm{spectro} = -1.8 \pm 0.1$ dex) but the metallicity and velocity dispersions are both unresolved. Using Gaia DR2, we infer a mean proper motion of $(\mu _\alpha ^*,\mu _\delta)=(0.51 \pm 0.28,-0.83 \pm 0.27)$ mas yr−1, which, combined with the system’s radial velocity ($\langle v_r\rangle = -70.2 \pm 0.5 {\rm \, km \,\, s^{-1}}$), translates into a halo orbit with a pericenter and apocenter of $40.7 ^{+5.6}_{-14.7}$ and $85.6^{+17.2}_{-5.9}$ kpc, respectively. Overall, Laevens 3 shares the typical properties of the Milky Way’s outer halo globular clusters. Furthermore, we find that this system shows signs of mass segregation that strengthens our conclusion that Laevens 3 is a globular cluster.
Effects of magnetic fields on the location of the evaporation valley for low-mass exoplanets
Authors: Owen James E , Adams Fred C
Published: September 2019

The observed distribution of radii for exoplanets shows a bimodal form that can be explained by mass-loss from planetary atmospheres due to high-energy radiation emitted by their host stars. The location of the minimum of this radius distribution depends on the mass–radius relation, which in turn depends on the composition of planetary cores. Current studies suggest that super-Earth and mini-Neptune planets have iron-rich and hence largely Earth-like composition cores. This paper explores how non-zero planetary magnetic fields can decrease the expected mass-loss rates from these planets. These lower mass-loss rates, in turn, affect the location of the minimum of the radius distribution and the inferred chemical composition of the planetary cores.
Resting-State SEEG May Help Localize Epileptogenic Brain Regions
Authors: Goodale Sarah E , González Hernán F J , Johnson Graham W , Gupta Kanupriya , Rodriguez William J , Shults Robert , Rogers Baxter P , Rolston John D , Dawant Benoit M , Morgan Victoria L , Englot Dario J
Published: September 2019

BACKGROUND

Stereotactic electroencephalography (SEEG) is a minimally invasive neurosurgical method to localize epileptogenic brain regions in epilepsy but requires days in the hospital with interventions to trigger several seizures.

OBJECTIVE

To make initial progress in the development of network analysis methods to identify epileptogenic brain regions using brief, resting-state SEEG data segments, without requiring seizure recordings.

METHODS

In a cohort of 15 adult focal epilepsy patients undergoing SEEG, we evaluated functional connectivity (alpha-band imaginary coherence) across sampled regions using brief (2 min) resting-state data segments. Bootstrapped logistic regression was used to generate a model to predict epileptogenicity of individual regions.

RESULTS

Compared to nonepileptogenic structures, we found increased functional connectivity within epileptogenic regions (P < .05) and between epileptogenic areas and other structures (P < .01, paired t-tests, corrected). Epileptogenic areas also demonstrated higher clustering coefficient (P < .01) and betweenness centrality (P < .01), and greater decay of functional connectivity with distance (P < .05, paired t-tests, corrected). Our functional connectivity model to predict epileptogenicity of individual regions demonstrated an area under the curve of 0.78 and accuracy of 80.4%.

CONCLUSION

Our study represents a preliminary step towards defining resting-state SEEG functional connectivity patterns to help localize epileptogenic brain regions ahead of neurosurgical treatment without requiring seizure recordings.
Vaccination, Risks, and Freedom: The Seat Belt Analogy
Authors: Giubilini Alberto , Savulescu Julian
Published: September 2019

We argue that, from the point of view public health ethics, vaccination is significantly analogous to seat belt use in motor vehicles and that coercive vaccination policies are ethically justified for the same reasons why coercive seat belt laws are ethically justified. We start by taking seriously the small risk of vaccines’ side effects and the fact that such risks might need to be coercively imposed on individuals. If millions of individuals are vaccinated, even a very small risk of serious side effects implies that, statistically, at some point side effects will occur. Imposing such risks raises issues about individual freedom to decide what risks to take on oneself or on one’s children and about attribution of responsibility in case of adverse side effects. Seat belt requirements raise many of the same ethical issues as vaccination requirements, and seat belt laws initially encountered some opposition from the public that is very similar to some of the current opposition to vaccine mandates. The analogy suggests that the risks of vaccines do not constitute strong enough reasons against coercive vaccination policies and that the same reasons that justify compulsory seat belt use—a measure now widely accepted and endorsed—also justify coercive vaccination policies.
Desire and Satisfaction
Authors: Shaw Ashley
Published: September 2019

Desire satisfaction has not received detailed philosophical examination. Yet intuitive judgments about the satisfaction of desires have been used as data points guiding theories of desire, desire content, and the semantics of ‘desire’. This paper examines desire satisfaction and the standard propositional view of desire. Firstly, I argue that there are several distinct concepts of satisfaction. Secondly, I argue that separating them defuses a difficulty for the standard view in accommodating desires that Derek Parfit described as ‘implicitly conditional on their own persistence’, a problem posed by Shieva Kleinschmidt, Kris McDaniel, and Ben Bradley. The solution undercuts a key motivation for rejecting the standard view in favour of more radical accounts proposed in the literature.
Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization
Authors: Paul Friedman Katie , Gagne Matthew , Loo Lit-Hsin , Karamertzanis Panagiotis , Netzeva Tatiana , Sobanski Tomasz , Franzosa Jill A , Richard Ann M , Lougee Ryan R , Gissi Andrea , Lee Jia-Ying Joey , Angrish Michelle , Dorne Jean Lou , Foster Stiven , Raffaele Kathleen , Bahadori Tina , Gwinn Maureen R , Lambert Jason , Whelan Maurice , Rasenberg Mike , Barton-Maclaren Tara , Thomas Russell S
Published: September 2019

Use of high-throughput, in vitro bioactivity data in setting a point-of-departure (POD) has the potential to accelerate the pace of human health safety evaluation by informing screening-level assessments. The primary objective of this work was to compare PODs based on high-throughput predictions of bioactivity, exposure predictions, and traditional hazard information for 448 chemicals. PODs derived from new approach methodologies (NAMs) were obtained for this comparison using the 50th (PODNAM, 50) and the 95th (PODNAM, 95) percentile credible interval estimates for the steady-state plasma concentration used in in vitro to in vivo extrapolation of administered equivalent doses. Of the 448 substances, 89% had a PODNAM, 95 that was less than the traditional POD (PODtraditional) value. For the 48 substances for which PODtraditional < PODNAM, 95, the PODNAM and PODtraditional were typically within a factor of 10 of each other, and there was an enrichment of chemical structural features associated with organophosphate and carbamate insecticides. When PODtraditional < PODNAM, 95, it did not appear to result from an enrichment of PODtraditional based on a particular study type (eg, developmental, reproductive, and chronic studies). Bioactivity:exposure ratios, useful for identification of substances with potential priority, demonstrated that high-throughput exposure predictions were greater than the PODNAM, 95 for 11 substances. When compared with threshold of toxicological concern (TTC) values, the PODNAM, 95 was greater than the corresponding TTC value 90% of the time. This work demonstrates the feasibility, and continuing challenges, of using in vitro bioactivity as a protective estimate of POD in screening-level assessments via a case study.
Ambient and supplemental magnetic fields promote myogenesis via a TRPC1‐mitochondrial axis: evidence of a magnetic mitohormetic mechanism
Authors: Yap Jasmine Lye Yee , Tai Yee Kit , Fröhlich Jürg , Fong Charlene Hui Hua , Yin Jocelyn Naixin , Foo Zi Ling , Ramanan Sharanya , Beyer Christian , Toh Shi Jie , Casarosa Marco , Bharathy Narendra , Kala Monica Palanichamy , Egli Marcel , Taneja Reshma , Lee Chuen Neng , Franco‐Obregón Alfredo
Published: September 2019

We show that both supplemental and ambient magnetic fields modulate myogenesis. A lone 10 min exposure of myoblasts to 1.5 mT amplitude supplemental pulsed magnetic fields (PEMFs) accentuated in vitro myogenesis by stimulating transient receptor potential (TRP)‐C1‐mediated calcium entry and downstream nuclear factor of activated T cells (NFAT)‐transcriptional and P300/CBP‐associated factor (PCAF)‐epigenetic cascades, whereas depriving myoblasts of ambient magnetic fields slowed myogenesis, reduced TRPC1 expression, and silenced NFAT‐transcriptional and PCAF‐epigenetic cascades. The expression levels of peroxisome proliferatoractivated receptor g coactivator 1α, the master regulator of mitochondriogenesis, was also enhanced by brief PEMF exposure. Accordingly, mitochondriogenesis and respiratory capacity were both enhanced with PEMF exposure, paralleling TRPC1 expression and pharmacological sensitivity. Clustered regularly interspaced short palindromic repeats‐Cas9 knockdown of TRPC1 precluded proliferative and mitochondrial responses to supplemental PEMFs, whereas small interfering RNA gene silencing of TRPM7 did not, coinciding with data that magnetoreception did not coincide with the expression or function of other TRP channels. The aminoglycoside antibiotics antagonized and down‐regulated TRPC1 expression and, when applied concomitantly with PEMF exposure, attenuated PEMF‐stimulated calcium entry, mitochondrial respiration, proliferation, differentiation, and epigenetic directive in myoblasts, elucidating why the developmental potential of magnetic fields may have previously escaped detection. Mitochondrial‐based survival adaptations were also activated upon PEMF stimulation. Magnetism thus deploys an authentic myogenic directive that relies on an interplay between mitochondria and TRPC1 to reach fruition.—Yap, J. L. Y., Tai, Y. K., Fröhlich, J., Fong, C. H. H., Yin, J. N., Foo, Z. L., Ramanan, S., Beyer, C., Toh, S. J., Casarosa, M., Bharathy, N., Kala, M. P., Egli, M., Taneja, R., Lee, C. N., Franco‐Obregón, A. Ambient and supplemental magnetic fields promote myogenesis via a TRPC1‐mitochondrial axis: evidence of a magnetic mitohormetic mechanism. FASEB J. 33, 12853–12872 (2019). www.fasebj.org
Comparison of Male and Female Resident Milestone Assessments During Emergency Medicine Residency Training: A National Study
Authors: Santen Sally A. , Yamazaki Kenji , Holmboe Eric S. , Yarris Lalena M. , Hamstra Stanley J.
Published: September 2019

Purpose

A previous study found that milestone ratings at the end of training were higher for male than for female residents in emergency medicine (EM). However, that study was restricted to a sample of 8 EM residency programs and used individual faculty ratings from milestone reporting forms that were designed for use by the program’s Clinical Competency Committee (CCC). The objective of this study was to investigate whether similar results would be found when examining the entire national cohort of EM milestone ratings reported by programs after CCC consensus review.

Method

This study examined longitudinal milestone ratings for all EM residents (n = 1,363; 125 programs) reported to the Accreditation Council for Graduate Medical Education every 6 months from 2014 to 2017. A multilevel linear regression model was used to estimate differences in slope for all subcompetencies, and predicted marginal means between genders were compared at time of graduation.

Results

There were small but statistically significant differences between males’ and females’ increase in ratings from initial rating to graduation on 6 of the 22 subcompetencies. Marginal mean comparisons at time of graduation demonstrated gender effects for 4 patient care subcompetencies. For these subcompetencies, males were rated as performing better than females; differences ranged from 0.048 to 0.074 milestone ratings.

Conclusions

In this national dataset of EM resident milestone assessments by CCCs, males and females were rated similarly at the end of their training for the majority of subcompetencies. Statistically significant but small absolute differences were noted in 4 patient care subcompetencies.
Intergenerational Effects of Sevoflurane in Young Adult Rats
Authors: Ju Ling-Sha , Yang Jiao-Jiao , Xu Ning , Li Jia , Morey Timothy E. , Gravenstein Nikolaus , Seubert Christoph N. , Setlow Barry , Martynyuk Anatoly E.
Published: September 2019

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New

Background

Sevoflurane administered to neonatal rats induces neurobehavioral abnormalities and epigenetic reprogramming of their germ cells; the latter can pass adverse effects of sevoflurane to future offspring. As germ cells are susceptible to reprogramming by environmental factors across the lifespan, the authors hypothesized that sevoflurane administered to adult rats could induce neurobehavioral abnormalities in future offspring, but not in the exposed rats themselves.

Methods

Sprague-Dawley rats were anesthetized with 2.1% sevoflurane for 3 h every other day between postnatal days 56 and 60. Twenty-five days later, exposed rats and nonexposed controls were mated to produce offspring.

Results

Adult male but not female offspring of exposed parents of either sex exhibited deficiencies in elevated plus maze (mean ± SD, offspring of both exposed parents vs. offspring of control parents, 35 ± 12 vs. 15 ± 15 s, P < 0.001) and prepulse inhibition of acoustic startle (offspring of both exposed parents vs. offspring of control parents, 46.504 ± 13.448 vs. 25.838 ± 22.866%, P = 0.009), and increased methylation and reduced expression of the potassium ion-chloride ion cotransporter KCC2 gene (Kcc2) in the hypothalamus. Kcc2 was also hypermethylated in sperm and ovary of the exposed rats. Surprisingly, exposed male rats also exhibited long-term abnormalities in functioning of the hypothalamic-pituitary-gonadal and -adrenal axes, reduced expression of hypothalamic and hippocampal Kcc2, and deficiencies in elevated plus maze (sevoflurane vs. control, 40 ± 24 vs. 25 ± 12 s, P = 0.038) and prepulse inhibition of startle (sevoflurane vs. control, 39.905 ± 21.507 vs. 29.193 ± 24.263%, P < 0.050).

Conclusions

Adult sevoflurane exposure affects brain development in male offspring by epigenetically reprogramming both parental germ cells, while it induces neuroendocrine and behavioral abnormalities only in exposed males. Sex steroids may be required for mediation of the adverse effects of adult sevoflurane in exposed males.
Factors Affecting Time NICU Nurses Spend With Fathers
Authors: Clarkson Gina , Gilmer Mary Jo
Published: September 2019

Background:

Father involvement in the neonatal intensive care unit (NICU) is important for outcomes of children and should be encouraged. Neonatal nurses have been identified as a major source of support for fathers; yet, nurses have identified obstacles to family-centered care of the father.

Purpose:

The purpose of this article is to present results that broaden the knowledge of factors that affect time NICU nurses spend with fathers. The information presented here is a portion of results from a larger survey that examined factors affecting NICU nurse caring beliefs of fathers.

Methods:

This survey study included NICU nurses and was administered anonymously online. Content analysis was completed on responses to open-ended questions.

Results:

Questions asked nurses about the time they spend with fathers. Nurses described problems with workflow and encouraged family bonding. Some nurses described spending equal amounts of time with both parents, whereas others focused on either the mother or the father. Paternal attributes that affected time nurses spent with fathers included confidence, motivation, level of competence, beliefs, attitudes, and availability. Maternal factors included culture and gatekeeping. Infant factors were level of illness and tolerance to activity.

Implications for Practice:

Unmotivated fathers may benefit from encouragement from nurses to participate in the care of their infants. Nurses can encourage parental partnerships in caring for their infants.

Implications for Research:

Factors identified in this study can help guide future studies. Understanding the relationship between NICU fathers and nurses can help improve interactions and communication.
A roadmap for a comprehensive control of cervical cancer in Poland: integration of available solutions into current practice in primary and secondary prevention
Authors: Nowakowski Andrzej , Arbyn Marc , Turkot Maryla H. , Wieszczy Paulina , Miłosz Kinga , Kamiński Michał F. , Didkowska Joanna , Bidziński Mariusz , Olszewski Włodzimierz , Wielgoś Mirosław , Krzakowski Maciej , Kuchar Ernest , Walewski Jan
Published: September 2019

In Poland, cervical cancer incidence and mortality still remain considerably higher than in Western European countries or North America. Recent data indicate decreasing trends in women younger than 60 years and stable trends in older women. In this article, we identified obstacles in primary and secondary prevention of cervical cancer in Poland. We analysed local legislation, management structure and organization of cervical cancer prevention in Poland and reviewed solutions available and implemented in other European countries. The main weaknesses include: (i) very low coverage of organized screening; concurrent unregistered opportunistic screening with unknown coverage and high test consumption (ii) suboptimal quality assurance in organized screening and no external quality assurance in opportunistic screening (iii) very low coverage of human papillomavirus vaccination that is not centrally reimbursed (iv) absence of pilot evaluation of (a) interventions that may improve population coverage and (b) performance of new preventive strategies. The proposed solutions are multifaceted and involve: (i) legislative and organizational regulation of cervical cancer screening aimed at comprehensive registration of procedures, data access and quality assurance (ii) pilot testing and implementation of new ways to increase coverage of cervical cancer screening, in particular among older women (iii) pilot evaluation with possible introduction of human papillomavirus-based screening and (iv) inclusion of human papillomavirus vaccination into the reimbursed national immunization program.
Autophagy-related Proteins as a Prognostic Factor of Patients With Colorectal Cancer
Authors: Koustas Evangelos , Sarantis Panagiotis , Theoharis Stamatios , Saetta Angelica A. , Chatziandreou Ilenia , Kyriakopoulou Georgia , Giannopoulou Ioanna , Michelli Maria , Schizas Dimitrios , Papavassiliou Athanasios G. , Karamouzis Michalis V.
Published: September 2019

Objectives:

Autophagy plays a dual role in tumorigenesis. In the initial stages, it promotes cell survival and suppresses carcinogenesis, whereas in cancer development, it induces cancer cell survival. In this study, we investigate the role of autophagy as a protective or tumor suppressor mechanism in colorectal cancer (CRC) cell lines and evaluate its role as a potential biomarker in human tumor samples.

Materials and Methods:

The data of 68 patients with CRC treated at our Department from January 1 to December 31, 2016 were analyzed. Immunohistochemistry evaluation of p62, LC3B, Beclin-1, and Rab-7 in formalin-fixed paraffin-embedded tissue samples was performed and their expression was correlated with clinicopathologic characteristics, mutation status, and therapeutic approach. The χ2 was used to test an association among categorical variables. Survival curves were estimated using the Kaplan-Meier method and differences were assessed using the log-rank test. Colo-205, HT29, SW-480, and Caco-2 cell lines were also used so as to test the autophagy markers with oxaliplatin, irinotecan, hydroxychloroquine, and 3-methyladenine.

Results:

Overexpression of Beclin-1 is associated with poor survival (P=0.001) in patients with CRC treated with chemotherapy, irrespective of the stage and mutational status. Rab-7 is also correlated with progression-free survival (PFS) (P=0.088). Oxaliplatin (10 and 20 μΜ) and irinotecan (10 and 20 μΜ) inhibit autophagy in microsatellite stable (MSS) CRC cell lines. The inhibition of autophagy in MSS CRC cell lines after treatment with oxaliplatin and irinotecan is further identified through monodancylcadaverine staining. Moreover, inhibition of autophagy with molecules such as hydroxychloroquine (20 μΜ) and 3-methyladenine (5 mM) was identified by the accumulation of p62 and LC3B.

Conclusions:

Beclin-1 is an independent prognostic factor of overall survival and PFS. Also, Rab-7 is identified as an independent prognostic factor of PFS. Besides, several chemotherapeutic drugs such as oxaliplatin and irinotecan inhibit autophagy in MSS CRC cell lines in a similar way like hydroxychloroquine and 3-methyladenine. Thus, in MSS patients who develop chemoresistance, a combination of other therapies that include an autophagy inhibitor could be more beneficial. Further clinical trials are needed to investigate these therapeutic strategies.