bluuebunny/crossref_metadata_2025 huggingface dataset:
Measures of lung function and their relationship with advanced glycation end-products
Authors: Zaigham Suneela , Persson Margaretha , Jujic Amra , Frantz Sophia , Borné Yan , Malinovschi Andrei , Wollmer Per , Engström Gunnar
Published: June 2020

Background

Advanced glycation end-products (AGEs) have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the association between AGE accumulation in the skin measured by skin autofluorescence (SAF) and lung function in healthy subjects has not been explored in detail. We use a population-based study of 50–64-year-olds to assess spirometry, diffusing capacity of the lung for carbon monoxide (DLCO) and impulse oscillometry (IOS) in relation to SAF.

Methods

Participants with information on SAF, lung function and potential confounding variables were included from the Swedish Cardiopulmonary Bioimage Study (SCAPIS) cohort (spirometry, n=4111;DLCO, n=3889; IOS, n=3970). Linear regression was used to assess changes in lung function (as measured by spirometry (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC),DLCOand IOS (resistance measured at 5 (R5) and 20 Hz (R20),R5−R20, area of reactance, reactance measured at 5 Hz (X­5), and resonant frequency)) by a 1-sdincrease in SAF.

Results

FEV1, FVC andDLCOwere significantly and inversely associated with SAF after adjustment for potential confounding factors (per 1-sdincrease in SAF: FEV1−0.03 L (95% CI −0.04– −0.02 L), p<0.001; FVC −0.03 L (95% CI −0.05– −0.02 L), p<0.001;DLCO−0.07 mmol·min−1·kPa−1(95% CI −0.11– −0.03 mmol·min−1·kPa−1), p<0.001). This association was also found in nonsmokers and in non-COPD subjects. Pulmonary reactance (X5) but not pulmonary resistance (R5,R20andR5−R20) was significantly associated with SAF (per 1-sdincrease in SAF:X5−0.001 kPa·L−1·s (95% CI −0.003–0.00 kPa·L−1·s), p=0.042), which was mirrored in non-COPD patients but not in current nonsmokers.

Conclusions

AGE accumulation, as measured by SAF, is significantly associated with lung function decrements indicative of changes in the lung parenchyma
Disequilibrium evolution of the Fructose-1,6-bisphosphatase gene family leads to their functional biodiversity in Gossypium species
Authors: Gě Qún , Cūi Yànli , Lǐ Jùnwén , Gōng Jǔwǔ , Lú Quánwěi , Lǐ Péngtāo , Shí Yùzhēn , Shāng Hǎihóng , Liú Àiyīng , Dèng Xiǎoyīng , Pān Jìngtāo , Chén Qúanjiā , Yuán Yǒulù , Gǒng Wànkuí
Published: June 2020

Background

Fructose-1,6-bisphosphatase (FBP) is a key enzyme in the plant sucrose synthesis pathway, in the Calvin cycle, and plays an important role in photosynthesis regulation in green plants. However, no systemic analysis of FBPs has been reported in Gossypium species.

Results

A total of 41 FBP genes from four Gossypium species were identified and analyzed. These FBP genes were sorted into two groups and seven subgroups. Results revealed that FBP family genes were under purifying selection pressure that rendered FBP family members as being conserved evolutionarily, and there was no tandem or fragmental DNA duplication in FBP family genes. Collinearity analysis revealed that a FBP gene was located in a translocated DNA fragment and the whole FBP gene family was under disequilibrium evolution that led to a faster evolutionary progress of the members in G. barbadense and in At subgenome than those in other Gossypium species and in the Dt subgenome, respectively, in this study. Through RNA-seq analyses and qRT-PCR verification, different FBP genes had diversified biological functions in cotton fiber development (two genes in 0 DPA and 1DPA ovules and four genes in 20–25 DPA fibers), in plant responses to Verticillium wilt onset (two genes) and to salt stress (eight genes).

Conclusion

The FBP gene family displayed a disequilibrium evolution pattern in Gossypium species, which led to diversified functions affecting not only fiber development, but also responses to Verticillium wilt and salt stress. All of these findings provide the foundation for further study of the function of FBP genes in cotton fiber development and in environmental adaptability.
Using the axillary reverse mapping technique to screen breast cancer patients with a high risk of lymphedema
Authors: Liu Siyao , Wang Nan , Gao Ping , Liu Peng , Yang Houpu , Xie Fei , Wang Siyuan , Liu Miao , Wang Shu
Published: June 2020

Background

Preventing breast cancer-related lymphedema (BCRL) by preserving upper lymphatic drainage is still controversial. Our study aimed to use the axillary reverse mapping (ARM) technique in patients who underwent axillary surgery to analyse the correlation between postoperative residual ARM nodes and the occurrence of lymphedema, select candidates at high risk of developing lymphedema, and analyse the oncologic safety of ARM nodes.

Methods

Patients undergoing sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) from October 2015 to February 2016 at the Peking University People’s Hospital Breast Center were prospectively recruited for the study. ARM was performed in all patients before surgery. ARM nodes were separated from SLNB and ALND specimens. Data were collected on the identification of ARM nodes before surgery, number of residual ARM nodes after surgery, nodal status, crossover rate, and correlation between residual ARM nodes and the occurrence of lymphedema.

Results

The analysis included 78 patients. Of the 53 patients who underwent SLNB, crossover between ARM nodes and breast sentinel lymph nodes (SLNs) was seen in 22 specimens. The incidence of ARM node metastasis was 1.89% (1/53) and 25% (9/36) in the SLNB and ALND groups, respectively. The number of positive axillary lymph nodes was associated with the involvement of ARM nodes (P= 0.036). The incidence of residual ARM nodes was significantly higher in the SLNB group than in the ALND group (67.6% vs. 37.9%,P= 0.016). The incidence of lymphedema was significantly higher in the ALND group than in the SLNB group (33.3% vs. 5.4%,P= 0.003).

Conclusions

For SLNB, the ARM technique can help to resect SLNs more accurately. However, we do not recommend using the ARM technique to preserve ARM nodes in patients undergoing ALND due to oncologic safety issues. Nevertheless, we can predict patients undergoing axillary surgery who are more likely to have a high risk of lymphedema by assessing residual ARM nodes.

Trial registration

This study was registered onClinicalTrials.govin February 2016.

The clinical trial registration number isNCT02691624.
Geographical variations of early age sexual initiation among reproductive-age women in Ethiopia: evidence from EDHS 2016
Authors: Nigatu Araya Mesfin , Birhanu Abraham Yeneneh , Endehabtu Berhanu Fikadie
Published: June 2020

Background

The early age of sexual initiation contribute a lot for various risks such as mistimed pregnancy followed by insecure termination, developing fistula and contracting sexually transmitted infections which are currently the major public health concerns for low-income countries. Therefore, the purpose of this study was to detect spatial clusters and identify factors associated with an early age sexual initiation of women in the reproductive age group.

Methods

We used a population-based nationwide representative Ethiopian Demographic and Health Survey (EDHS) 2016 data.. A total of 12,033 respondents of reproductive age (15–49 years) women who had at least one event of sexual intercourse was retrieved and included for the analysis. Spatial cluster detection and autocorrelation analysis were also done to explore the patterns of early age sexual initiation.

Results

The median age at first sexual intercourse among respondents was 16 (±3.3) years and more than half (66.2%) had their first sexual intercourse before the age of 18 years. The spatial variations of the age of sexual initiation was nonrandom and clustered with a Moran’s I = 0.413 (P-value < 0.001). In addition, five significant spatial clusters were also identified. Moreover, the probability of starting sex at an earlier age was associated with the respondent’s residence, marital status, educational attainment and wealth index.

Conclusion

This study found a higher proportion of an early age sexual initiation of women. Respondent’s residence, marital status, educational attainment and wealth index were significantly associated with early sexual initiation. The SaTScan analysis identified five statistical significant spatial clusters which indicate that there were geographical variations. Therefore, integrated interventions focusing on the identified high spot clustered areas are recommended to reduce early age sexual initiation.
Comparison of the protective effects of resveratrol and pterostilbene against intestinal damage and redox imbalance in weanling piglets
Authors: Zhang Hao , Chen Yanan , Chen Yueping , Ji Shuli , Jia Peilu , Li Yue , Wang Tian
Published: June 2020

Background

Evidence indicates that early weaning predisposes piglets to intestinal oxidative stress and increases the risk of intestinal dysfunction; however, there are minimal satisfactory treatment strategies for these conditions. This study investigated the potential of resveratrol and its analog, pterostilbene, as antioxidant protectants for regulating intestinal morphology, barrier function, and redox status among weanling piglets.

Methods

A total of 144 piglets were selected at 21 days of age and randomly allocated into one of four treatment groups, each of which included six replicates. Piglets in a sow-reared control group were suckling normally between ages 21 and 28 days, while those in weaned groups were fed a basal diet, supplemented with either 300 mg/kg of resveratrol or with 300 mg/kg of pterostilbene. Parameters associated with intestinal injury and redox status were analyzed at the end of the feeding trial.

Results

Early weaning disrupted the intestinal function of young piglets, with evidence of increased diamine oxidase activity and D-lactate content in the plasma, shorter villi, an imbalance between cell proliferation and apoptosis, an impaired antioxidant defense system, and severe oxidative damage in the jejunum relative to suckling piglets. Feeding piglets with a resveratrol-supplemented diet partially increased villus height (P = 0.056) and tended to diminish apoptotic cell numbers (P = 0.084) in the jejunum compared with those fed a basal diet. Similarly, these beneficial effects were observed in the pterostilbene-fed piglets. Pterostilbene improved the feed efficiency of weanling piglets between the ages of 21 and 28 days; it also resulted in diminished plasma diamine oxidase activity and D-lactate content relative to untreated weaned piglets (P < 0.05). Notably, pterostilbene restored jejunal antioxidant capacity, an effect that was nearly absent in the resveratrol-fed piglets. Pterostilbene reduced the malondialdehyde and 8-hydroxy-2´-deoxyguanosine contents of jejunal mucosa possibly through its regulatory role in facilitating the nuclear translocation of nuclear factor erythroid-2-related factor 2 and the expression levels of NAD(P)H quinone dehydrogenase 1 and superoxide dismutase 2 (P < 0.05).

Conclusions

The results indicate that pterostilbene may be more effective than its parent compound in alleviating early weaning-induced intestinal damage and redox imbalance among young piglets.
Study of a hysteresis window of FinFET and fully-depleted silicon-on-insulator (FDSOI) MOSFET with ferroelectric capacitor
Authors: Yoon Chankeun , Moon Seungjun , Shin Changhwan
Published: June 2020

In this work, the measured electrical characteristics of a fully depleted silicon-on-insulator (FDSOI) device and fin-shaped field-effect transistor (FinFET), whose gate electrode is connected in series to the bottom electrode of a ferroelectric capacitor (FE-FDSOI/FE-FinFET), are experimentally studied. The hysteretic property in input transfer characteristic of those devices is desirable for memory device applications, so that the understanding and modulating the hysteresis window is a key knob in designing the devices. It is experimentally observed that the hysteresis window of FE-FDSOI/FE-FinFET is decreased with (i) increasing the area of the ferroelectric capacitor and/or (ii) decreasing the gate area of baseline FET. The way how to control the hysteresis window of FE-FDSOI/FE-FinFET is proposed and discussed in detail.
Morphological changes in intraretinal microvascular abnormalities after anti-VEGF therapy visualized on optical coherence tomography angiography
Authors: Sorour Osama A. , Mehta Nihaal , Baumal Caroline R. , Ishibazawa Akihiro , Liu Keke , Konstantinou Eleni K. , Martin Sarah , Braun Phillip , Alibhai A. Yasin , Arya Malvika , Witkin Andre J. , Duker Jay S. , Waheed Nadia K.
Published: June 2020

Background

To examine the baseline morphological characteristics and alterations in intraretinal microvascular abnormalities (IRMAs) in response to anti-vascular endothelial growth factor (anti-VEGF) treatment, documented by optical coherence tomography angiography (OCTA) in diabetic eyes.

Methods

In this retrospective study, IRMAs were evaluated with multimodal imaging (fundus photography, fluorescein angiography, OCTA) in treatment-naïve diabetic eyes before and after anti-VEGF treatment for diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR) and compared to diabetic control eyes with similar diabetic retinopathy (DR) severity that did not receive anti-VEGF therapy. The morphological characteristics of IRMAs on enface OCTA imaging were graded by masked readers at baseline, then after anti-VEGF therapy in treated eyes or after observation in control eyes. Characterization of interval changes in an IRMA were based on the following parameters: branching, vessel caliber and area of adjacent capillary non-perfusion.

Results

The treated group included 45 IRMA foci from 15 eyes of 11 patients, while the control group included 27 IRMA foci from 15 eyes of 14 patients. Following anti-VEGF treatment, enface OCTA demonstrated that 14 foci of IRMA (31%) demonstrated regression with normalization of appearance of the capillary bed, 20 IRMAs (44%) remained unchanged, six IRMAs (13%) progressed with enlargement or development of new IRMAs and five IRMAs (11%) demonstrated complete obliteration defined as IRMA disappearance with advancing capillary drop-out. In the control group, 17 IRMA (63%) remained stable, 8 IRMAs (29.6%) progressed and 2 experienced total obliteration (7.4%). The difference in rank order between the two groups was statistically significant (p = 0.022).

Conclusions

In eyes with DR status post anti-VEGF therapy, foci of IRMAs have a variable course demonstrating one of four possible outcomes: regression, stability, progression or complete obliteration. In contrast, none of the untreated control diabetic eyes demonstrated regression of IRMAs, consistent with known progression of DR severity in high risk eyes. Morphologic evaluation of IRMAs with OCTA may help to monitor changes in retinal blood flow as well as the response to anti-VEGF treatment.
Improvement of a delayed swallowing reflex following treatment for advanced head and neck cancer
Authors: Ohkoshi Akira , Kato Kengo , Ogawa Takenori , Nakanome Ayako , Ishii Ryo , Katori Yukio
Published: June 2020

Background

The latency of the swallowing reflex is an important factor causing dysphagia in head and neck cancer patients. Although there are many reports comparing voluntary swallowing function before and after treatment, few studies have focused on the latency of the swallowing reflex, which is a risk factor for pneumonia due to silent aspiration. The aim of this retrospective study was to clarify the changes in the latency of the swallowing reflex before and after treatment.

Methods

The latency of the swallowing reflex was quantified using the time from the injection of 1 ml of distilled water into the pharynx through a nasal catheter to the onset of swallowing.

Results

The latency time of the swallowing reflex was significantly decreased 3 months after treatment compared to before treatment. A significant reduction was also observed in patients with pharyngeal cancer who underwent chemoradiation therapy.

Conclusions

This retrospective study showed that a delayed swallowing reflex improved with treatment in advanced head and neck cancer patients.

Trial registration

The Institutional Review Board of Tohoku University Hospital (Number 2014–1-274).
Executive Perspectives
Authors: Koehr John
Published: June 2020

I am closing out my first year with SEG as executive director, and I wanted to share some of the highlights of my journey thus far. In previous issues of TLE, I have shared observations from my first 90 days (see October 2019 President's Page) and a report on the year 2019 (see April 2020 Executive Perspectives). Noteworthy accomplishments over my first year included realigning staff resources with SEG's new portfolio structure; refreshing the SEG strategy; completing the sale of SEG's Tulsa, Oklahoma, real estate; expanding SEG's international presence; convening a successful SEG 2019 Annual Meeting; enhancing operational rigor; and launching new products such as a new partner event, new early-career and membership programs, an open-access journal, and a new platform for the SEG Library.
An effective data processing workflow for broadband single-sensor single-source land seismic data
Authors: Cordery Simon
Published: June 2020

Examples of raw and processed broadband single-sensor single-source land seismic data acquired in the Middle East region have been found to be significantly noisy, and very low-frequency signal has been either missing or unrecoverable. In response, an effective and pragmatic processing workflow has been developed that substantially improves the quality of the final processed data, to the extent where we can say that original survey objectives can be met. The new workflow includes early deterministic deconvolution for a number of filtering effects in the recorded signal wavelet, with the aim of flattening the signal wavelet amplitude spectrum over the vibroseis sweep frequencies and zeroing the wavelet phase. This includes the key innovative step of converting the recorded particle motion to that of the vibroseis far-field signal, those respectively being particle acceleration and particle displacement. This significantly boosts low-frequency amplitudes relative to higher frequencies such that it becomes possible to deterministically compensate for earth's absorption using a large gain limit with less concern for overamplifying high-frequency noise. An application of a source designature compensates for the nonflat design of the pilot sweep, further increasing signal amplitudes over the low-frequency ramp-up portion of the sweep. With the flattened signal spectrum, it is possible to better assess trace noise characteristics across the full bandwidth and perform better QC for its removal. Subsequent statistical deconvolution becomes more of a correction for residual effects on the signal wavelet, and the use of trace supergrouping further mitigates the effect of noise on statistical deconvolution and other data-adaptive processes.
The role of integrated mental and community physical healthcare trusts in responding to the COVID-19 pandemic in the UK
Authors: Tracy Derek , Forrest Anna , Underwood Benjamin R.
Published: June 2020

For several decades, mental health services within the UK's National Health Service were provided by specialist mental health trusts. More recently many of these trusts have integrated community physical health services into their operations. We describe here how two integrated mental health trusts in England were able to make an enhanced response to the COVID-19 pandemic.
The social psychological impact of the COVID-19 pandemic on medical staff in China: A cross-sectional study
Authors: Dong Zai-Quan , Ma Jing , Hao Yan-Ni , Shen Xiao-Ling , Liu Fang , Gao Yuan , Zhang Lan
Published: June 2020

Background.

The COVID-19 outbreak required the significantly increased working time and intensity for health professionals in China, which may cause stress signs.

Methods.

From March 2–13 of 2020, 4,618 health professionals in China were included in an anonymous, self-rated online survey regarding their concerns on exposure to the COVID-19 outbreak. The questionnaires consisted of five parts: basic demographic information and epidemiological exposure; occupational and psychological impact; concerns during the episode; coping strategies; and the Huaxi Emotional-Distress Index (HEI).

Results.

About 24.2% of respondents experienced high levels of anxiety or/and depressive symptoms since the COVID-19 outbreak. Respondents who worried about their physical health and those who had COVID-19 infected friends or close relatives were more likely to have high HEI levels, than those without these characteristics. Further, family relationship was found to have an independent protective effect against high HEI levels. Their main concerns were that their families would not be cared for and that they would not be able to work properly. Compared to respondents with clear emotional problems, those with somewhat hidden emotional issues adopted more positive coping measures.

Conclusions.

About a quarter of medical staff experienced psychological problems during the pandemic of COVID-19. The psychological impact of stressful events was related to worrying about their physical health, having close COVID-19 infected acquaintances and family relationship issues. Therefore, the psychological supprot for medical staff fighting in the COVID-19 pandemic may be needed.
The term “physical distancing” is recommended rather than “social distancing” during the COVID-19 pandemic for reducing feelings of rejection among people with mental health problems
Authors: Wasserman Danuta , van der Gaag Rutger , Wise Jan
Published: June 2020

As COVID-19 has plagued our world, the term “social distancing” has been widely used with the aim to encourage the general population to physically distance themselves from others in order to reduce the spread of the virus. However, this term can have unintended but detrimental effects, as it evokes negative feelings of being ignored, unwelcome, left alone with one's own fears, and even excluded from society. These feelings may be stronger in people with mental illnesses and in socio-economically disadvantaged groups, such as stigmatized minorities, migrants, and homeless persons [1], many of them also having high risk for suicidal behaviors [2]. Mental health disorders are pervasive worldwide; the global burden accounting for approximately 21.2–32.4% of years lived with disability—more than any other group of illnesses [3]. So, the vulnerable group of people with mental health disorders represents a considerable share of the total global population.
Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 Study.
Authors: Andre Thierry , Shiu Kai-Keen , Kim Tae Won , Jensen Benny Vittrup , Jensen Lars Henrik , Punt Cornelis J. A. , Smith Denis Michel , Garcia-Carbonero Rocio , Benavides Manuel , Gibbs Peter , De La Fouchardiere Christelle , Rivera Fernando , Elez Elena , Bendell Johanna C. , Le Dung T. , Yoshino Takayuki , Yang Ping , Farooqui Mohammed Zulfiqar Husain , Marinello Patricia , Diaz Luis A.
Published: June 2020

LBA4

Background: KEYNOTE-177 (NCT02563002) is a phase 3, randomized open-label study evaluating the efficacy and safety of pembrolizumab (pembro) versus standard of care chemotherapy ± bevacizumab or cetuximab (chemo) as first-line therapy for patients (pts) with microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). We present results of the final PFS analysis. Methods: A total of 307 pts with MSI-H/dMMR mCRC as determined locally and ECOG PS 0 or 1 were randomly assigned 1:1 to first-line pembro 200 mg Q3W for up to 2 years or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab (chemo chosen prior to randomization). Treatment continued until PD, unacceptable toxicity, pt/investigator decision to withdraw, or completion of 35 cycles (pembro only). Patients receiving chemo could crossover to pembro for up to 35 cycles after confirmed PD. Primary end points were PFS (RECIST v1.1, central review) and OS. Key secondary end points included ORR (RECIST v1.1, central review), and safety. The data cutoff date for this interim analysis was Feb 19, 2020. The study will continue without changes to evaluate OS. Results: At data cutoff, 153 pts were randomized to pembro and 154 to chemo. Median (range) study follow-up was 28.4 mo (0.2-48.3) with pembro vs 27.2 mo (0.8-46.6) with chemo. Pembro was superior to chemo for PFS (median 16.5 mo vs 8.2 mo; HR 0.60; 95% CI, 0.45-0.80; P=0.0002). The 12- and 24-mo PFS rates were 55.3% and 48.3% with pembro vs 37.3% and 18.6% with chemo. Confirmed ORR was 43.8% vs 33.1%; median (range) duration of response was not reached (2.3+ to 41.4+) with pembro vs 10.6 mo (2.8 to 37.5+) with chemo. Grade 3-5 treatment related adverse event (AE) rates were 22% vs 66% for pembro vs chemo. One pt in the chemo arm died due to a treatment-related AE. Conclusions: Pembro provided a clinically meaningful and statistically significant improvement in PFS versus chemo as first-line therapy for pts with MSI-H/dMMR mCRC, with fewer treatment-related AEs observed and should be the new standard of care for these pts. Clinical trial information: NCT02563002 .
Avelumab in patients with gestational trophoblastic tumors resistant to monochemotherapy: Final outcomes of TROPHIMMUN phase II trial, cohort A.
Authors: You Benoit , Bolze Pierre-Adrien , Lotz Jean-Pierre , Massardier Jerome , Gladieff Laurence , Joly Florence , Hajri Touria , Maucort-Boulch Delphine , Bin Sylvie , Rousset Pascal , Villeneuve Laurent , Roux Adeline , Alves-Ferreira Marine , Grazziotin Daniele , Mercier Catherine , Freyer Gilles , Golfier Francois
Published: June 2020

LBA6008

Background: Patients with gestational trophoblastic tumors (GTT) resistant to monochemotherapy are treated with historic chemotherapy regimens known to be effective, but toxic. PD-L1 is constitutively expressed in all GTT subtypes (Bolze et al. Int J Gynecol Cancer 2017). HLA-G and natural killer (NK) cells are involved in GTT immune-surveillance. The anti-PD-L1 monoclonal antibody avelumab (Pfizer & Merck KGaA) triggers cytotoxicity through NK cells. The objective of TROPHIMMUN trial was to assess the efficacy of avelumab in patients with chemoresistant GTT. Methods: In the cohort A of this academic multicenter trial (NCT03135769), avelumab was given at 10 mg/kg Q2W in patients with GTT resistant to monochemotherapy. Avelumab was prescribed until hCG normalization, and then for 3 consolidation cycles. The primary objective was the rate of patients with hCG normalization, with a 2 step Simon design. Results: 15 patients (median 34 y old) followed by the French Gestational Trophoblastic Center were treated from Dec 2016 to Sept 2019 (stage I/III: 53%/47%; FIGO score 0-4: 33%; score 5-6: 47%; score >6: 20%). They all had progressed with previous methotrexate, and 1 patient with actinomycin-D. They received median 8 avelumab cycles (range: 2-11). The tolerability was favorable. 93 % of patients developed drug-related grade 1-2 toxicities (86% grade 1), mainly including fatigue (33% patients); nausea-vomiting (33%); infusion-related reactions (27%); thyroid disorder (20%); dry eyes (20%) & diarrhea (20%). A grade 3 uterus bleeding (treatment unrelated) was observed in 1 patient. Median follow-up was 30 months. Successful hCG normalizations were obtained in 8 patients (53%, median 9 avelumab cycles), either during avelumab treatment in 7 patients, or after avelumab discontinuation in 1 patient. None presented relapse afterwards, and 1 patient had a subsequent healthy pregnancy. Avelumab resistances requiring switch to chemotherapy were observed in 7 patients (47%), who normalized hCG with subsequent actinomycin-D (42%), or surgery/polychemotherapy (57%). The likelihood of success with avelumab was not related to the FIGO score, or disease stages. Conclusions: TROPHIMMUN is the first trial of immunotherapy in GTT patients. The anti-PD-L1 monoclonal antibody avelumab was effective, with a favorable safety profile compared to chemotherapy, in patients with resistance to mono-chemotherapy. About 50 % patients could be cured of their chemoresistant diseases. Avelumab may be a new therapeutic option. Clinical trial information: NCT03135769 .
Comparison of atomic force microscopy and zeta potential derived surface charge density
Authors: Herzberg M. , Dobberschütz S. , Okhrimenko D. , Bovet N. E. , Andersson M. P. , Stipp S. L. S. , Hassenkam T.
Published: June 2020

Surface charge density can be derived from atomic force microscopy (AFM) by using Derjaguin, Landau, Vervey and Overbeek (DLVO) theory. The sub-micrometer data allows observation of local differences in charge density and changes with time or solution composition, which has interesting applications in crystal growth and inhibition, bone formation and colloid behavior. To calibrate this type of AFM data and verify DLVO assumptions, it has to be correlated with an established technique. We successfully matched AFM derived surface charge densities with zeta potential measurements on a mica surface within one order of magnitude. A reproducible difference between surface charge of the mica substrate exposed to solutions cations with monovalent and divalent charge was also observed. The results provide confidence that the AFM method is valid for obtaining local surface charge information.
Near-Adult Height After Growth Hormone Treatment in Children Born Prematurely—Data From KIGS
Authors: Boguszewski Margaret C S , Carlsson Martin , Lindberg Anders , Dahlgren Jovanna , Aydin Ferah , Camacho-Hübner Cecilia , Hokken-Koelega Anita C S
Published: June 2020

Context

Children born prematurely have been treated with growth hormone (GH), and a significant improvement in height during the first years of treatment has been described.

Objective

To evaluate the influence of prematurity on near-adult height (NAH) after GH treatment.

Design

KIGS (Pfizer International Growth Database) was queried for children born preterm treated with GH.

Setting

KIGS database.

Patients

A total of 586 children short in stature born preterm with various GH status and with available gestational age (GA), birth weight, and NAH, all treated with GH.

Intervention

GH treatment.

Main Outcome Measure

NAH.

Results

Values were expressed as median. From the 586 children included, 482 born appropriate for GA (AGA; median age 8.26 years) and 104 born small for gestational age (SGA) (median age 8.54 years); 66.6% of preterm AGA had GH peak < 7 µg/L during a provocation test, whereas only 8.6% of preterm SGA. Change in height standard deviation scores (SDS) from GH start to NAH after 8.04 years of GH treatment was 1.82 in preterm AGA. Respective values were 7.08 years and 1.08 SDS for preterm SGA (P < 0.001); 57% of the variability of the growth response to NAH could be explained, and the distance to parental height was the strongest predictor. No significant changes in height SDS were observed from puberty start to NAH. No correlation was found with GA. GH treatment was well tolerated.

Conclusion

GH treatment resulted in significant improvement in height in children born preterm, particularly during prepubertal years and for those with GH deficiency. The degree of prematurity did not influence the growth response.
Metformin Biodistribution: A Key to Mechanisms of Action?
Authors: Sundelin Elias , Jensen Jonas Brorson , Jakobsen Steen , Gormsen Lars C , Jessen Niels
Published: June 2020

Metformin has undisputed glucose-lowering effects in diabetes and an impressive safety record. It has also shown promising effects beyond diabetes, and several hundred clinical trials involving metformin are currently planned or active. Metformin targets intracellular effectors, but exactly which remain to be established, and in an era of precision medicine, an incomplete understanding of mechanisms of action may limit the use of metformin. Distribution of metformin depends on specific organic cation transporter proteins that are organ- and species-specific. Therefore, target tissues of metformin can be identified by cellular uptake of the drug, and exploring the biodistribution of the drug in humans becomes an attractive strategy to assist the many investigations into the mechanisms of action of metformin performed in animals. In this review, we combine the emerging evidence from the use of 11C-labeled metformin in humans to discuss metformin action in liver, intestines, and kidney, which are the organs with the most avid uptake of the drug.
Estradiol and Progesterone Levels are Related to Redox Status in the Follicular Fluid During In Vitro Fertilization
Authors: Pizarro Bartira Marques , Cordeiro Aline , Reginatto Mila Weydtt , Campos Samir P C , Mancebo Ana Cristina A , Areas Patricia C F , Antunes Roberto Azevedo , Souza Maria do Carmo Borges , Oliveira Karen Jesus , Bloise Flavia Fonseca , Bloise Enrrico , Fortunato Rodrigo Soares , Ortiga-Carvalho Tania Maria
Published: June 2020

Studies have reported a possible association between the levels of oxidative stress biomarkers in follicular fluid (FF) and infertility treatment outcomes. FF analysis can provide important information about oocyte quality. This study aimed to evaluate the possible correlation between oxidative stress biomarker and intrafollicular hormone levels and clinical and laboratory parameters in women during controlled ovarian stimulation. These women were undergoing in vitro fertilization with intracytoplasmic sperm injection (ICSI).The FF samples were acquired from September 2012 to February 2014 from women undergoing private fertility treatment in Rio de Janeiro, Brazil. A total of 196 women who were undergoing ICSI and had different infertility diagnoses were recruited. The FF from each patient (average patient age of 36.3 ± 4.3 years) was collected following puncture of just one follicle with the largest diameter. After ruling out blood contamination by spectrophotometry, 163 patient samples were utilized in the study. In the FF, the progesterone levels were negatively correlated with (a) hydrogen peroxide scavenging capacity (HPSC) (r = −0.294, P < 0.0001), (b) total number of follicles (r = −0.246, P < 0.001) and (c) total number of oocytes punctured (r = −0.268, P = 0.0001). The concentration of serum estradiol exhibited a positive correlation with intrafollicular HPSC (r = 0.165, P = 0.037). Our data indicate that the FF levels of estradiol and progesterone are related to the FF redox status, which is closely associated with the number of oocytes obtained during ICSI procedures.
Drugs of Abuse and the Nervous System
Authors: Stitt Derek , Kumar Neeraj
Published: June 2020

PURPOSE OF REVIEW

This article discusses the neurologic complications of traditional, nontraditional, and emerging drugs of abuse.

RECENT FINDINGS

The manufacture, distribution, and use of so-called designer drugs are increasing. These agents can induce dramatic neurologic manifestations and can evade identification on conventional drug-screening assays. Additionally, gabapentinoids, drug agents that are very familiar to neurologists, are being abused in the general population at increasing rates to achieve euphoric highs and potentiate the effects of opiates. Furthermore, even well-known illicit narcotics such as heroin are posing dangers above their baseline because of “lacing” with additives or substitutes such as fentanyl and related compounds. These clandestine agents increase the potency of what are thought to be typical dosages to lethal levels, thus leading to more unintentional overdose deaths.

The potential for short- and long-term nervous system injury from drug abuse is well established. However, it is important for the practicing neurologist to possess awareness of the features and observed sequelae of the toxidromes of both traditional and nontraditional drugs of abuse. This is because the use of both is widespread in our society and conventional drug screening can miss detection of some powerful agents, thus forcing us to maintain a high index of suspicion based on recognition of the clinical features.
The Performance of an Artificial Neural Network Model in Predicting the Early Distribution Kinetics of Propofol in Morbidly Obese and Lean Subjects
Authors: Ingrande Jerry , Gabriel Rodney A. , McAuley Julian , Krasinska Karolina , Chien Allis , Lemmens Hendrikus J. M.
Published: June 2020

BACKGROUND:

Induction of anesthesia is a phase characterized by rapid changes in both drug concentration and drug effect. Conventional mammillary compartmental models are limited in their ability to accurately describe the early drug distribution kinetics. Recirculatory models have been used to account for intravascular mixing after drug administration. However, these models themselves may be prone to misspecification. Artificial neural networks offer an advantage in that they are flexible and not limited to a specific structure and, therefore, may be superior in modeling complex nonlinear systems. They have been used successfully in the past to model steady-state or near steady-state kinetics, but never have they been used to model induction-phase kinetics using a high-resolution pharmacokinetic dataset. This study is the first to use an artificial neural network to model early- and late-phase kinetics of a drug.

METHODS:

Twenty morbidly obese and 10 lean subjects were each administered propofol for induction of anesthesia at a rate of 100 mg/kg/h based on lean body weight and total body weight for obese and lean subjects, respectively. High-resolution plasma samples were collected during the induction phase of anesthesia, with the last sample taken at 16 hours after propofol administration for a total of 47 samples per subject. Traditional mammillary compartment models, recirculatory models, and a gated recurrent unit neural network were constructed to model the propofol pharmacokinetics. Model performance was compared.

RESULTS:

A 4-compartment model, a recirculatory model, and a gated recurrent unit neural network were assessed. The final recirculatory model (mean prediction error: 0.348; mean square error: 23.92) and gated recurrent unit neural network that incorporated ensemble learning (mean prediction error: 0.161; mean square error: 20.83) had similar performance. Each of these models overpredicted propofol concentrations during the induction and elimination phases. Both models had superior performance compared to the 4-compartment model (mean prediction error: 0.108; mean square error: 31.61), which suffered from overprediction bias during the first 5 minutes followed by under-prediction bias after 5 minutes.

CONCLUSIONS:

A recirculatory model and gated recurrent unit artificial neural network that incorporated ensemble learning both had similar performance and were both superior to a compartmental model in describing our high-resolution pharmacokinetic data of propofol. The potential of neural networks in pharmacokinetic modeling is encouraging but may be limited by the amount of training data available for these models.
Integration of the Intrinsic Surgical Risk With Patient Comorbidities and Severity of Congenital Cardiac Disease Does Not Improve Risk Stratification in Children Undergoing Noncardiac Surgery
Authors: Faraoni David , Zou Xue , DiNardo James A. , Nasr Viviane G.
Published: June 2020

BACKGROUND:

The objective of this study is to estimate the surgical risk of noncardiac procedures on the incidence of 30-day mortality in children with congenital heart disease.

METHODS:

Children with congenital heart disease undergoing noncardiac surgery from 2012 to 2016 and included in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Pediatric database were included in the derivation cohort, while the 2017 database was used as a validation cohort. Intrinsic surgical risk quartiles were built utilizing 30-day mortality rates for each Current Procedural Terminology code and relative value units to create 2 groups defined as low surgical risk (quartiles 1–3) and high surgical risk procedures (quartile 4). We used multivariable logistic regression to determine the predictors for 30-day mortality including patient comorbidities and intrinsic surgical risk. A partially external validation of the model was performed using the 2017 version of the database.

RESULTS:

We included 37,658 children with congenital heart disease undergoing noncardiac surgery with an incidence of overall 30-day mortality of 1.7% in the derivation cohort and 1.5% in the validation cohort (n = 13,129). Intrinsic surgical risk of procedures represented by Current Procedural Terminology procedural codes and relative value units risk quartiles was significantly associated with 30-day mortality (unadjusted P < .001). Predicted probability of 30-day mortality ranges from 0.2% (95% confidence interval [CI], 0.2–0.2) with no comorbidities to 39.6% (95% CI, 23.2–56.0) when all comorbidities were present among high surgical risk procedures and from 0.3% (95% CI, 0.3–0.3) to 54.8% (95% CI, 39.4–70.1) among low surgical risk procedures. An excellent discrimination was reported for the multivariable model with area under the curve (AUC) of 0.86 (95% CI, 0.85–0.88). High surgical risk was not associated with increased odds of 30-day mortality after adjustment for all other predictors (adjusted odds ratio [OR]: 0.75, 95% CI, 0.62–0.91). We also estimated the discriminative ability of a model that does not include the surgical risk (0.86 [95% CI, 0.84–0.88], with P value for the direct comparison of the AUC of the 2 models = 0.831). The multivariable model obtained from an external validation cohort reported an optimism corrected AUC of 0.88 (95% CI, 0.85–0.91).

CONCLUSIONS:

Our study demonstrates that integration of intrinsic surgical risk to comorbidities and severity of cardiac disease does not improve prediction of 30-day mortality in children undergoing noncardiac surgery. In children with congenital heart disease, patient comorbidities, and severity of the cardiac lesion are the predominant predictors of 30-day mortality.
Anticolonial Uprising and Communal Justice in Twentieth-Century Palestine
Authors: Winder Alex
Published: June 2020

This article examines the strategies, structures, and practices that allowed for the emergence of communities without police institutions during two Palestinian uprisings, the 1936–39 revolt and the 1987–91 intifada. For each period, the article identifies efforts to disengage from and disempower the state police, to establish alternative systems of anticolonial justice, and to employ disciplinary violence to serve the imperatives and enforce the decisions of Palestinian nationalist bodies. In particular, Palestinian systems of anticolonial justice drew on communal reconciliation (sulh) and other preexisting local iterations of communal justice. These local forms relied on discourses of egalitarianism and consensus, which produced stability in periods of upheaval but also obscured the inequalities they reproduced. Ultimately, the anticolonial structures that Palestinians established proved unable to withstand intense internal and external pressure, and some elements of the coercive forces that served them were absorbed into state police institutions.
A non-catalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage
Authors: Lupieri Adrien , Blaise Régis , Ghigo Alessandra , Smirnova Natalia , Sarthou Marie-Kerguelen , Malet Nicole , Limon Isabelle , Vincent Pierre , Hirsch Emilio , Gayral Stéphanie , Ramel Damien , Laffargue Muriel
Published: June 2020

Arterial remodeling in hypertension and intimal hyperplasia involves inflammation and disrupted flow, both of which contribute to smooth muscle cell dedifferentiation and proliferation. In this context, our previous results identified phosphoinositide 3-kinase γ (PI3Kγ) as an essential factor in inflammatory processes of the arterial wall. Here, we identify for the first time a kinase-independent role of nonhematopoietic PI3Kγ in the vascular wall during intimal hyperplasia using PI3Kγ-deleted mice and mice expressing a kinase-dead version of the enzyme. Moreover, we found that the absence of PI3Kγ in vascular smooth muscle cells (VSMCs) leads to modulation of cell proliferation, associated with an increase in intracellular cAMP levels. Real-time analysis of cAMP dynamics revealed that PI3Kγ modulates the degradation of cAMP in primary VSMCs independently of its kinase activity through regulation of the enzyme phosphodiesterase 4. Importantly, the use of an N-terminal competing peptide of PI3Kγ blocked primary VSMC proliferation. These data provide evidence for a kinase-independent role of PI3Kγ in arterial remodeling and reveal novel strategies targeting the docking function of PI3Kγ for the treatment of cardiovascular diseases.
Does anthropomorphic model design in ex vivo studies affect diagnostic accuracy for dental root fracture using CBCT?
Authors: Andraws Yalda Fedil , Clarkson Rosalyn J , Davies Jonathan , Rout Peter G J , Sengupta Anita , Horner Keith
Published: June 2020

Objectives:

The evidence for diagnostic accuracy using cone beam computed tomography (CBCT) for dental applications depends heavily on ex vivo research, but there is little knowledge of whether the model used affects the diagnostic accuracy results. The objective of this study was to determine the impact of different designs of anthropomorphic models on diagnostic accuracy for the specific task of dental root fracture detection.

Methods:

Horizontal or oblique root fracture was induced in 24 of 48 permanent maxillary incisors. The 48 teeth were scanned by CBCT using standard clinical exposure factors on five occasions, each with a different model design. Scans were viewed by five dental and maxillofacial radiologists, who each made a forced diagnosis of fracture or no fracture in each root and a judgment on root fracture using a five-point confidence scale. Sensitivity (Se), specificity (Sp) and areas under receiver operating characteristic (ROC) curve (Az) were calculated for each observer for each model.

Results:

There were no significant differences between the diagnostic accuracy measurements recorded using different models. There were, however, numerous significant differences between observers using the same anthropomorphic model.

Conclusions:

Despite the differences in X-ray attenuation between the five model designs, the results suggest that the anthropomorphic model does not affect the results of diagnostic accuracy studies on root fracture using this CBCT machine at standard clinical exposures. This provides some confidence in the previously published evidence. The interobserver diagnosis differences indicate that research using only two observers could provide misleading results.