bluuebunny/crossref_metadata_2025 huggingface dataset:
Substrate integrated waveguide based class‐F power amplifier
Authors: Yang Fei , Yu Hongxi , Li Jun , Xu Kai‐Da , Zhang Anxue , Jin Zhonghe
Published: October 2021

This work outlines the design, implementation, and experimental results of a Class‐F power amplifier (PA) with a novel output matching topology by utilizing substrate integrated waveguide (SIW). The design methodology is first proposed with one highly integrated SIW matching structure. The impedances at fundamental, second harmonic and third harmonic frequencies are analysed to explain good impedance matching for the PA as well as the isolation mechanism of the direct current (DC) and radio frequency (RF). For demonstration, an S‐band 10‐W Class‐F PA is fabricated and tested. The simulation and measurement results agree very well with each other, which verifies the proposed technology of SIW output matching. To the authors’ knowledge, this is the first time to use a highly integrated SIW matching in Class‐F PA, which simplifies the output matching for third‐order harmonics and DC/RF isolation structures.
„Eine integrativmedizinische Praxis und EbM passen gut zueinander“
Authors: Kühne Rolf
Published: October 2021

Komplementärmedizin und Naturheilverfahren sind primär ein Gewinn für die Patient*innen und das ist in jedem Fall auch ein Gewinn für die Praxis.

Ein Gespräch mit Dr. Rolf Kühne
Medicinal Plants for the Treatment of Mental Diseases in Pregnancy: An In Vitro Safety Assessment
Authors: Spiess Deborah , Winker Moritz , Chauveau Antoine , Abegg Vanessa Fabienne , Potterat Olivier , Hamburger Matthias , Gründemann Carsten , Simões-Wüst Ana Paula
Published: October 2021

Pregnancy is a critical period for medical care, during which the well-being of woman and fetus must be considered. This is particularly relevant in managing non-psychotic mental disorders since treatment with central nervous system-active drugs and untreated NMDs may have negative effects. Some well-known herbal preparations (phytopharmaceuticals), including St. Johnʼs wort, California poppy, valerian, lavender, and hops, possess antidepressant, sedative, anxiolytic, or antidepressant properties and could be used to treat mental diseases such as depression, restlessness, and anxiety in pregnancy. Our goal was to assess their safety in vitro, focusing on cytotoxicity, induction of apoptosis, genotoxicity, and effects on metabolic properties and differentiation in cells widely used as a placental cell model (BeWo b30 placenta choriocarcinoma cells). The lavender essential oil was inconspicuous in all experiments and showed no detrimental effects. At low-to-high concentrations, no extract markedly affected the chosen safety parameters. At an artificially high concentration of 100 µg/mL, extracts from St. Johnʼs wort, California poppy, valerian, and hops had minimal cytotoxic effects. None of the extracts resulted in genotoxic effects or altered glucose consumption or lactate production, nor did they induce or inhibit BeWo b30 cell differentiation. This study suggests that all tested preparations from St. Johnʼs wort, California poppy, valerian, lavender, and hops, in concentrations up to 30 µg/mL, do not possess any cytotoxic or genotoxic potential and do not compromise placental cell viability, metabolic activity, and differentiation. Empirical and clinical studies during pregnancy are needed to support these in vitro data.
GOÄneu
Authors: Stör Wolfram , Irnich Dominik
Published: October 2021

Die Gebührenordnung für Ärzte (GOÄ) ist eine von der Bundesregierung mit Zustimmung des Bundesrates erlassene Rechtsverordnung. Die aktuell verbindliche GOÄ ist mehr als ein Vierteljahrhundert nicht reformiert worden und entspricht nicht mehr dem aktuellen Wissenstand der Medizin und den Patientenbedürfnissen. Bundesärztekammer und Verband der Privaten Krankenversicherungen haben gemeinsamen einen neuen Entwurf erarbeitet, dessen Eckpunkte im Beitrag dargestellt werden mit besonderem Blick auf die komplementärmedizinischen Verfahren.
Abrechnung der ärztlichen Homöopathie
Authors: Geiger Michaela
Published: October 2021

Ob in der hausärztlichen Versorgung oder in einer fachärztlichen Praxis, die Homöopathie lässt sich in jedes Praxismodell integrieren. Homöopathie kann integrativ oder komplementär zur konventionellen Medizin eingesetzt werden. Durch die Homöopathie entstehen neue Therapieoptionen bei der Behandlung von akuten bis hin zu schweren chronischen Erkrankungen. Die Therapie ist in der PKV und der GKV verankert.
Efficacy of Norway Spruce Ointments and Bacterial and Fungal Alterations in the Treatment of Castration Wounds in Piglets
Authors: Prokop Désirée , Spergser Joachim , Hagmüller Werner , Tichy Alexander , Zitterl-Eglseer Karin
Published: October 2021

This study aimed to evaluate the efficacy of Norway spruce ointments on wound healing of castration wounds in piglets. This study included 95 male pigs randomly divided into five treatment groups: Norway spruce balm (Vulpuran), Norway spruce resin (Abilar), pork lard (ointment base of Vulpuran), no treatment (negative control) and antibiotic blue spray (Cyclo spray, positive control). Wound healing parameters (such as healing time, wound size, reddening of wound edges and surrounding, swelling, secretion and wound contamination), microbiological status and the haptoglobin level as an inflammation parameter were investigated. In the Norway spruce groups, some positive effects on wound healing parameters were found. In the first 6 days of treatment, Abilar or Vulpuran showed the smallest means of wound areas, and at the end of the study (day 15 + 17), the highest rates of completely closed wounds compared to the other groups. Vulpuran treatment led to significantly lower
wound secretion (p = 0.003) and wound contamination (p = 0.015) than the untreated control did. Furthermore, the microbiological status was determined using MALDI-TOF-MS and partial 16S rRNA gene sequencing at different days of treatment. A comparison of the five treatment groups on day 3 revealed that Norway spruce led to the lowest rate of wounds colonised with fungi, mainly classified into genus Candida, (Abilar 77%, Vulpuran 70%) in comparison with blue spray (89%), lard (100%) and untreated control (100%). Fungi could only be detected in one of the 13 samples treated with Vulpuran on day 8, which nearly reached significance (p = 0.055).
Gut Microbiota of Pigs Metabolizes Extracts of Filipendula ulmaria and Orthosiphon aristatus–Herbal Remedies Used in Urinary Tract Disorders
Authors: Popowski Dominik , Zentek Jürgen , Piwowarski Jakub P. , Granica Sebastian
Published: October 2021

Urinary tract infections influence the mortality rate in pigs and are linked to extensive antibiotic usage in the farm industry. Filipendula ulmaria (L.) Maxim. and Orthosiphon aristatus (Blume) Miq. are widespread medicinal plants traditionally used to treat urinary tract disorders. As their preparations are orally administered, the metabolism of their constituents by gut microbiota before absorption should be considered. Until now, no experiments had been performed to describe the biotransformation of tthose plantsʼ extracts by animal gut microbiota. The study evaluates the influence of pig intestinal microbiota on the structure of active compounds in flowers of F. ulmaria and leaves of O. aristatus. The incubations of the extracts with piglet gut microbiota were performed in anaerobic conditions, and the samples of the batch culture were collected for 24 h. In F. ulmaria, the main metabolites were quercetin and kaempferol, which were products of the deglycosylation of flavonoids. After 24 h incubation of O. aristatus extract with the piglet gut microbiota, 2 main metabolites were observed. One, tentatively identified as 3-(3-dihydroxyphenyl)propionic acid, is likely the primary metabolite of the most abundant depsides and phenolic acids. The results confirm the formation of the compounds with anti-inflammatory and diuretic activity in the microbiota cultures, which might suggest F. ulmaria and O. aristatus for treating urinary tract disorders in piglets. Based on the similarities of human and pig gut microbiota, the pig model can help estimate the metabolic pathways of natural products in humans.
Successful Use of Intravenous Methylnaltrexone for Opioid-Induced Constipation in Critically Ill Pediatric Patients
Authors: Mills Kimberly P. , McPherson Christopher C. , Said Ahmed S. , Lahart Michael A.
Published: October 2021

Objectives Methylnaltrexone is U.S. Food and Drug Administration (FDA) approved as a subcutaneous injection for adults with opioid-induced constipation (OIC). Case series have described the use of methylnaltrexone for OIC in the pediatric oncology population. There are limited data describing its intravenous use in critically ill pediatric patients.

Methods We conducted a retrospective observational study at St. Louis Children's Hospital. Patients less than 18 years old who received at least one dose of intravenous methylnaltrexone while admitted to an intensive care unit between January 2016 and August 2019 were included. The primary outcome was documented laxation within 24 hours of methylnaltrexone administration.

Results Sixteen patients received a total of 34 doses of intravenous methylnaltrexone. Patients received a median of 1.69 (interquartile range [IQR], 0.9–4.86) morphine milligram equivalents per kilogram per 24 hours, over a median of 14 days (IQR, 11–30), before methylnaltrexone administration. The median dose of methylnaltrexone was 0.15 mg/kg (IQR, 0.15–0.16). Ten patients (63%) responded to the first dose of methylnaltrexone, and 14 patients (88%) responded to at least one dose. Overall, 26 doses (76%) led to patient response. Four patients (25%) experienced adverse events (emesis, abdominal pain) after methylnaltrexone administration. No signs or symptoms of opioid withdrawal were documented.

Conclusions Intravenous methylnaltrexone appears to be safe and effective in treating OIC in critically ill pediatric patients. No serious adverse events or signs of opioid withdrawal were observed after single and repeat dosing. Patients responded to methylnaltrexone with varying opioid dosing and durations prior to administration.
How do contract types and incentives influence driver behavior?−An analysis of the Kigali bus network
Authors: Sörensen Leif , Schlüter Jan
Published: October 2021

The rapidly growing city of Kigali has a bus network that is undergoing increased development as underlined in its Transport Master Plan. Two schemes of bus driver remuneration coexist in the city: One constitutes a hybrid salary and commission system, while the other pays a fixed monthly salary. This paper examines the effect of these differing compensation schemes on driver behavior in Kigali using survey data from 2019. The analysis applies linear models incorporating various aspects of driver behavior in a principal-agent framework. The results indicate that the performance-based compensation scheme is associated with higher per-trip passenger fluctuation and faster driving (possibly due to drivers aiming to accrue a higher income) compared to the fixed-wage system. Policy implications comprise the inclusion of further criteria in incentive contracts to internalize potential negative externalities on society, e.g., to hinder the endangerment of passenger safety by appropriately incentivizing drivers. In conclusion, bus drivers who are compensated by performance are more likely to alter their behavior, responding to the incentive scheme through several channels.
Commissioning experiment of the high-contrast SILEX-Ⅱ multi-petawatt laser facility
Authors: Hong Wei , He Shukai , Teng Jian , Deng Zhigang , Zhang Zhimeng , Lu Feng , Zhang Bo , Zhu Bin , Dai Zenghai , Cui Bo , Wu Yuchi , Liu Dongxiao , Qi Wei , Jiao Jinlong , Zhang Faqiang , Yang Zuhua , Zhang Feng , Bi Bi , Zeng Xiaoming , Zhou Kainan , Zuo Yanlei , Huang Xiaojun , Xie Na , Guo Yi , Su Jingqin , Han Dan , Mao Ying , Cao Leifeng , Zhou Weimin , Gu Yuqiu , Jing Feng , Zhang Baohan , Cai Hongbo , He Minqing , Zheng Wudi , Zhu Shaoping , Ma Wenjun , Wang Dahui , Shou Yinren , Yan Xueqing , Qiao Bin , Zhang Yi , Zhong Congling , Yuan Xiaohui , Wei Wenqing
Published: October 2021

The results of a commissioning experiment on the SILEX-Ⅱ laser facility (formerly known as CAEP-PW) are reported. SILEX-Ⅱ is a complete optical parametric chirped-pulse amplification laser facility. The peak power reached about 1 PW in a 30 fs pulse duration during the experiment. The laser contrast was better than 1010 at 20 ps ahead of the main pulse. In the basic laser foil target interaction, a set of experimental data were collected, including spatially resolved x-ray emission, the image of the coherent transition radiation, the harmonic spectra in the direction of reflection, the energy spectra and beam profile of accelerated protons, hot-electron spectra, and transmitted laser energy fraction and spatial distribution. The experimental results show that the laser intensity reached 5 × 1020 W/cm2 within a 5.8 µm focus (FWHM). Significant laser transmission did not occur when the thickness of the CH foil was equal to or greater than 50 nm. The maximum energy of the accelerated protons in the target normal direction was roughly unchanged when the target thickness varied between 50 nm and 15 µm. The maximum proton energy via the target normal sheath field acceleration mechanism was about 21 MeV. We expect the on-target laser intensity to reach 1022 W/cm2 in the near future, after optimization of the laser focus and upgrade of the laser power to 3 PW.
A simple and effective attachment to prevent dome diffraction reaching 2D or 1D detectors in x-ray diffractometers
Authors: van der Pers N. M. , Hendrikx R. W. A. , Böttger A. J.
Published: October 2021

An attachment has been developed for x-ray diffractometer systems equipped with a domed stage when using a 2D or 1D detector. It consists of a single screen in front of the detector positioned such that it blocks diffraction from the dome. This results in measured data free of disturbing spurious peaks and background, thereby greatly facilitating further data analysis. Its working principle is universally applicable and allows for all specimen orientation movements needed for x-ray diffraction measurements, including texture, stress, and mapping.
Pressure-induced hydride superconductors above 200 K
Authors: Zhang Xiaohua , Zhao Yaping , Li Fei , Yang Guochun
Published: October 2021

Although it was proposed many years ago that compressed hydrogen should be a high-temperature superconductor, the goal of room-temperature superconductivity has so far remained out of reach. However, the successful synthesis of the theoretically predicted hydrides H3S and LaH10 with high superconducting transition temperatures TC provides clear guidance for achieving this goal. The existence of these superconducting hydrides also confirms the utility of theoretical predictions in finding high-TC superconductors. To date, numerous hydrides have been studied theoretically or experimentally, especially binary hydrides. Interestingly, some of them exhibit superconductivity above 200 K. To gain insight into these high-TC hydrides (>200 K) and facilitate further research, we summarize their crystal structures, bonding features, and electronic properties, as well as their superconducting mechanism. Based on hydrogen structural motifs, covalent H3S with isolated hydrogen and several clathrate superhydrides (LaH10, YH9, and CaH6) are highlighted. Other predicted hydrides with various H-cages and two-dimensional H motifs are also discussed. Finally, we present a systematic discussion of the common features, current problems, and future challenges of these high-TC hydrides.
Reformulation on Chinese EFL learners’ email literacy
Authors: Chen Yuan-shan , Liu Chin-Ting
Published: October 2021

This study explored the effect of reformulation on Chinese EFL learners’ email pragmatic performance. Two high-intermediate learners of English collaboratively wrote an email (pretest), compared their original email to a reformulated version of it and to a native speaker model in the noticing stage, and revised the pretest email individually (posttest). The results indicated that (a) most of the problems found in pragmatic-related episodes in the pretest were appropriately resolved based on peer discussion; (b) the participants predominantly noticed pragmalinguistic features in the noticing stage; and (c) in the posttest, the number of changes matching the reformulation was higher than the number of those matching the native speaker model. This study closes by providing pedagogical implications for language teachers.
The effect of first language pragmatics on second language email performance
Authors: Economidou-Kogetsidis Maria
Published: October 2021

The present study is a comparative production study which investigates the effect of L1 email pragmatics on L2 email performance and examines the extent to which the L2 email production of advanced, Greek learners of English shows agreement with their L1 email production. The study identified culture-specific pragmatic norms and aspects of L1 pragmatic behaviours that learners transferred to their L2 emails. A preference for formality and direct strategies was confirmed in both data sets suggesting that the learners’ emails converge with those of NS of Greek and approximate native Greek norms. Results further pointed towards a high degree of agreement in the majority of the modifiers employed by the two groups.
Email communication in English and in German
Authors: Schauer Gila A.
Published: October 2021

This semi-longitudinal investigation examines greetings and closings in emails written by German university students in their native and foreign language. The results reveal students’ preference for formal greetings in both English and German. However, the data also suggest that not all students were aware of appropriate address term combinations in formal English emails. Regarding closings, the students used a limited set of standard formal closings in English but employed a greater variety of closing strategies in German. The results further revealed the importance of micro-analysing individual students’ contributions in a corpus, as this provides insights into an individual’s language use over time and also shows the impact individual students’ routine preferences can have on group scores.
“You are the best!”
Authors: Savić Milica , Đorđević Miodrag
Published: October 2021

This study investigates relational practices in developing email conversations between interactants performing various institutional roles at a Norwegian university. Three variables were examined: conversational progression, institutional roles, and social distance. Conversational progression was found to exert an influence on increasing familiarity in closing sequences. The openings and closings in the conversations between faculty members tended to orient to familiarity to a greater extent than in most other institutional role dyads, while the widest variety and the highest frequency of relational moves outside the framing moves appeared in faculty – PhD fellow conversations. Social distance was identified as a driver of deference in both openings and closings, while its influence on the frequency of occurrence of other relational moves was limited.
Maternal gut microbiome regulates immunity to RSV infection in offspring
Authors: Fonseca Wendy , Malinczak Carrie-Anne , Fujimura Kei , Li Danny , McCauley Kathryn , Li Jia , Best Shannon K.K. , Zhu Diana , Rasky Andrew J. , Johnson Christine C. , Bermick Jennifer , Zoratti Edward M. , Ownby Dennis , Lynch Susan V. , Lukacs Nicholas W. , Ptaschinski Catherine
Published: October 2021

Development of the immune system can be influenced by diverse extrinsic and intrinsic factors that influence the risk of disease. Severe early life respiratory syncytial virus (RSV) infection is associated with persistent immune alterations. Previously, our group had shown that adult mice orally supplemented with Lactobacillus johnsonii exhibited decreased airway immunopathology following RSV infection. Here, we demonstrate that offspring of mice supplemented with L. johnsonii exhibit reduced airway mucus and Th2 cell–mediated response to RSV infection. Maternal supplementation resulted in a consistent gut microbiome in mothers and their offspring. Importantly, supplemented maternal plasma and breastmilk, and offspring plasma, exhibited decreased inflammatory metabolites. Cross-fostering studies showed that prenatal Lactobacillus exposure led to decreased Th2 cytokines and lung inflammation following RSV infection, while postnatal Lactobacillus exposure diminished goblet cell hypertrophy and mucus production in the lung in response to airway infection. These studies demonstrate that Lactobacillus modulation of the maternal microbiome and associated metabolic reprogramming enhance airway protection against RSV in neonates.
Barbed Polydioxanone Sutures for Face Recontouring: Six-Month Safety and Effectiveness Data Supported by Objective Markerless Tracking Analysis
Authors: Preibisz Lukasz , Boulmé Florence , Paul Lorenc Z
Published: October 2021

Background

Barbed polydioxanone (PDO) sutures allowing for minimally invasive skin lifting are broadly and increasingly used in aesthetic dermatology.

Objectives

To describe utilization of diverse barbed PDO sutures for aesthetic facial corrections in Caucasian patients, to evaluate long-term safety and to demonstrate effectiveness in skin tightening, redefinition of facial contours, and tissue elevation.

Methods

A retrospective chart review of patients routinely treated with barbed PDO sutures on face was performed. Aesthetic improvement was evaluated at 6-, 12- and 24-week posttreatment by the treating physician, patients, and an independent photographic reviewer. Patient’s satisfaction with treatment outcome was evaluated. Procedure effects were also objectively measured by markerless tracking analysis.

Results

Sixty patients were treated with a total of 388 barbed sutures in various anatomical areas and followed-up for 24 weeks. At Week 24, the aesthetic improvement rate was 80% to 100% (depending on the evaluator), skin movements related to pre-treatment photographs showed significant changes across several different anatomical regions, and 97% of patients were satisfied with the overall treatment outcome. Transient, mild, and short-lasting adverse events, mostly pain and hematoma, occurred in 15% of patients.

Conclusions

Barbed PDO sutures are safe and highly effective for aesthetic corrections, with results lasting for at least 24 weeks.

Level of Evidence: 4
Do taxon-specific DNA barcodes improve species discrimination relative to universal barcodes in Lauraceae?
Authors: Liu Zhi-Fang , Ma Hui , Zhang Xiao-Yan , Ci Xiu-Qin , Li Lang , Hu Jian-Lin , Zhang Can-Yu , Xiao Jian-Hua , Li His-Wen , Conran John G , Twyford Alex D , Hollingsworth Peter M , Li Jie
Published: October 2021

The aim of DNA barcoding is to enable fast and accurate species identification. However, universal plant DNA barcodes often do not provide species-level discrimination, especially in taxonomically complex groups. Here we use Lauraceae for the design and evaluation of DNA barcoding strategies, considering: (1) the efficacy of taxon-specific DNA barcode regions compared with universal barcodes for species discrimination; and (2) how the extent of intra- and interspecific sampling affects species discrimination rates. To address these areas, we targeted the highly polymorphic, taxon-specific barcode regions ycf1 + ndhH–rps15 + trnL–ycf2 for Lauraceae and compared them against the suite of standard plastid loci used for DNA barcoding (rbcL + matK + trnH–psbA) and the standard nuclear barcode ITS. The highest discrimination success came from nrDNA ITS, whereas the plastid regions (rbcL + matK + trnH–psbA) and the taxon-specific regions (ycf1 + ndhH–rps15 + trnL–ycf2) showed limited and inconsistent resolution. These results highlight that taxon-specific plastid barcodes may provide limited gains in discriminatory power in complex, closely related groups like Lauraceae. Moreover, our study showed that species discrimination greatly depends on the taxon sampling scheme, with relatively lower species discrimination observed where there is more comprehensive intra- and interspecific sampling. The outstanding challenge for plant DNA barcoding is the development of assays that allow routine low-cost access to large numbers of nuclear markers to facilitate the sequencing of large numbers of individuals.
Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach
Authors: Yeo Tianrong , Probert Fay , Sealey Megan , Saldana Luisa , Geraldes Ruth , Höckner Sebastian , Schiffer Eric , Claridge Timothy D W , Leppert David , DeLuca Gabriele , Kuhle Jens , Palace Jacqueline , Anthony Daniel C
Published: October 2021

Accurate determination of relapses in multiple sclerosis is important for diagnosis, classification of clinical course and therapeutic decision making. The identification of biofluid markers for multiple sclerosis relapses would add to our current diagnostic armamentarium and increase our understanding of the biology underlying the clinical expression of inflammation in multiple sclerosis. However, there is presently no biofluid marker capable of objectively determining multiple sclerosis relapses although some, in particular neurofilament-light chain, have shown promise. In this study, we sought to determine if metabolic perturbations are present during multiple sclerosis relapses, and, if so, identify candidate metabolite biomarkers and evaluate their discriminatory abilities at both group and individual levels, in comparison with neurofilament-light chain. High-resolution global and targeted 1H nuclear magnetic resonance metabolomics as well as neurofilament-light chain measurements were performed on the serum in four groups of relapsing-remitting multiple sclerosis patients, stratified by time since relapse onset: (i) in relapse (R); (ii) last relapse (LR) ≥ 1 month (M) to < 6 M ago; (iii) LR ≥ 6 M to < 24 M ago; and (iv) LR ≥ 24 M ago. Two hundred and one relapsing-remitting multiple sclerosis patients were recruited: R (n = 38), LR 1–6 M (n = 28), LR 6–24 M (n = 34), LR ≥ 24 M (n = 101). Using supervised multivariate analysis, we found that the global metabolomics profile of R patients was significantly perturbed compared to LR ≥ 24 M patients. Identified discriminatory metabolites were then quantified using targeted metabolomics. Lysine and asparagine (higher in R), as well as, isoleucine and leucine (lower in R), were shortlisted as potential metabolite biomarkers. ANOVA of these metabolites revealed significant differences across the four patient groups, with a clear trend with time since relapse onset. Multivariable receiver operating characteristics analysis of these four metabolites in discriminating R versus LR ≥ 24 M showed an area under the curve of 0.758, while the area under the curve for serum neurofilament-light chain was 0.575. Within individual patients with paired relapse–remission samples, all four metabolites were significantly different in relapse versus remission, with the direction of change consistent with that observed at group level, while neurofilament-light chain was not discriminatory. The perturbations in the identified metabolites point towards energy deficiency and immune activation in multiple sclerosis relapses, and the measurement of these metabolites, either singly or in combination, are useful as biomarkers to differentiate relapse from remission at both group and individual levels.
Carboxylesterase-1 Assisted Targeting of HDAC Inhibitors to Mononuclear Myeloid Cells in Inflammatory Bowel Disease
Authors: Elfiky Ahmed M I , Ghiboub Mohammed , Li Yim Andrew Y F , Hageman Ishtu L , Verhoeff Jan , de Krijger Manon , van Hamersveld Patricia H P , Welting Olaf , Admiraal Iris , Rahman Shafaque , Garcia-Vallejo Juan J , Wildenberg Manon E , Tomlinson Laura , Gregory Richard , Rioja Inmaculada , Prinjha Rab K , Furze Rebecca C , Lewis Huw D , Mander Palwinder K , Heinsbroek Sigrid E M , Bell Matthew J , de Jonge Wouter J
Published: October 2021

Background and Aims

Histone deacetylase inhibitors [HDACi] exert potent anti-inflammatory effects. Because of the ubiquitous expression of HDACs, clinical utility of HDACi is limited by off-target effects. Esterase-sensitive motif [ESM] technology aims to deliver ESM-conjugated compounds to human mononuclear myeloid cells, based on their expression of carboxylesterase 1 [CES1]. This study aims to investigate utility of an ESM-tagged HDACi in inflammatory bowel disease [IBD].

Methods

CES1 expression was assessed in human blood, in vitro differentiated macrophage and dendritic cells, and Crohn’s disease [CD] colon mucosa, by mass cytometry, quantitative polymerase chain reaction [PCR], and immunofluorescence staining, respectively. ESM-HDAC528 intracellular retention was evaluated by mass spectrometry. Clinical efficacy of ESM-HDAC528 was tested in dextran sulphate sodium [DSS]-induced colitis and T cell transfer colitis models using transgenic mice expressing human CES1 under the CD68 promoter.

Results

CES1 mRNA was highly expressed in human blood CD14+ monocytes, in vitro differentiated and lipopolysaccharide [LPS]-stimulated macrophages, and dendritic cells. Specific hydrolysis and intracellular retention of ESM-HDAC528 in CES1+ cells was demonstrated. ESM-HDAC528 inhibited LPS-stimulated IL-6 and TNF-α production 1000 times more potently than its control, HDAC800, in CES1high monocytes. In healthy donor peripheral blood, CES1 expression was significantly higher in CD14++CD16- monocytes compared with CD14+CD16++ monocytes. In CD-inflamed colon, a higher number of mucosal CD68+ macrophages expressed CES1 compared with non-inflamed mucosa. In vivo, ESM-HDAC528 reduced monocyte differentiation in the colon and significantly improved colitis in a T cell transfer model, while having limited potential in ameliorating DSS-induced colitis.

Conclusions

We demonstrate that monocytes and inflammatory macrophages specifically express CES1, and can be preferentially targeted by ESM-HDAC528 to achieve therapeutic benefit in IBD.
Reel syndrome, a diagnostic conundrum: a case report
Authors: Bellinge Jamie W , Petrov George P , Taggu Wasing
Published: October 2021

Background

Pacemaker lead dislodgement and failure, related to device manipulation, is a rare complication of permanent pacemaker (PPM) insertion. Reel’s, Twiddler’s, and Ratchet syndrome are rare causes of pacemaker failure with varying mechanisms, defined by their classical lead and generator findings on chest X-ray imaging. Misleading patient presentations may be attributed to lead stimulation of surrounding structures.

Case summary

A 77-year-old female was admitted with abdominal wall pulsations, abdominal pain, and lower limb jerking 3 months following PPM insertion. Following exclusion of a ruptured abdominal aortic aneurysm, the presence of Reel syndrome was noted on the patient’s chest X-ray and the electrocardiogram showed inappropriate pacing. Deactivation of the pacemaker resulted in immediate symptom cessation and urgent repositioning of pacemaker leads was undertaken.

Discussion

This case highlights the importance of considering pacemaker complications causing non-cardiac symptomatology. Pacemaker lead stimulation of surrounding structures can present in an unconventional fashion, veiling the diagnosis. However, a structured approach to undifferentiated neuromuscular presentations in patients with PPMs should consider lead dislodgement as a differential diagnosis. Rapid recognition of lead dislodgement, device deactivation, and re-implantation or repositioning of the leads are critical in preventing potentially life-threatening complications.
RNAseq-based gene expression profiling of the Anopheles funestus pyrethroid-resistant strain FUMOZ highlights the predominant role of the duplicated CYP6P9a/b cytochrome P450s
Authors: Wondji Charles S , Hearn Jack , Irving Helen , Wondji Murielle J , Weedall Gareth
Published: October 2021

Insecticide-based interventions, notably long-lasting insecticidal nets, against mosquito vectors of malaria are currently threatened by pyrethroid resistance. Here, we contrasted RNAseq-based gene expression profiling of laboratory-resistant (FUMOZ) and susceptible (FANG) strains of the major malaria vector Anopheles funestus. Cytochrome P450 genes were the predominant over-expressed detoxification genes in FUMOZ, with high expression of the duplicated CYP6P9a (fold-change of 82.23 vs FANG) and CYP6P9b (FC 11.15). Other over-expressed P450s belonged to the same cluster of P450s corresponding to the resistance to pyrethroid 1 (rp1) quantitative trait loci (QTL) on chromosome 2R. Several Epsilon class glutathione S-transferases were also over-expressed in FUMOZ, as was the ATP-binding cassette transporter AFUN019220 (ABCA) which also exhibited between-strain alternative splicing events at exon 7. Significant differences in single-nucleotide polymorphism frequencies between strains occurred in resistance QTLs rp1 (CYP6P9a/b and CYP6AA1), rp2 on chromosome 2L (CYP6Z1, CYP6M7, and CYP6Z3), and rp3 on chromosome 3R (CYP9J5, CYP9J4, and CYP9J3). Differences were also detected in CYP4G17 and CYP4G16 genes on the X chromosome, both of which are associated with cuticular resistance in Anopheles gambiae. A close analysis of nonsynonymous diversity at the CYP6P9a/b loci revealed a drastic loss of diversity in FUMOZ with only a single polymorphism and 2 haplotypes vs 18 substitutions and 8 haplotypes in FANG. By contrast, a lowly expressed cytochrome P450 (CYP4C36) did not exhibit diversity differences between strains. We also detected the known pyrethroid resistance conferring amino acid change N384S in CYP6P9b. This study further elucidates the molecular bases of resistance in An. funestus, informing strategies to better manage widespread resistance across Africa.
Metformin Protects Against Inflammation, Oxidative Stress to Delay Poly I:C-Induced Aging-Like Phenomena in the Gut of an Annual Fish
Authors: Li Shasha , Hou Yanhan , Liu Keke , Zhu Hongyan , Qiao Mengxue , Sun Xiaowen , Li Guorong
Published: October 2021

Metformin, a clinical agent of type 2 diabetes, is reported as a potential geroprotector. Viral infection induces phenotypes of senescence in human T cells, and polyinosinic:polycytidylic acid (poly I:C), a viral mimic, induces upregulation of senescence-associated beta-galactosidase (SA-β-gal) activity in the ovary of the annual fish Nothobranchius guentheri. However, the effects and mechanisms of metformin on poly I:C-induced aging-like phenomena are poorly understood in vertebrates. In this study, the activity of SA-β-gal increased in the gut of 12-month-old fish and poly I:C-injected 6-month-old fish, compared to 6-month-old control fish, indicating that poly I:C induces aging-like phenomena in the gut of the fish. Metformin supplementation retarded accumulation of SA-β-gal in the gut of old fish and poly I:C-treated young fish. The results of qPCR analysis showed that metformin reduced NF-κB-mediated inflammatory response including the decreased level of proinflammatory cytokine IL-8 and increased expression of anti-inflammatory cytokine IL-10 in the gut of the fish with natural aging and poly I:C-injected 6-month-old fish. Metformin also exhibited antioxidant effects, as it reduced reactive oxygen species production that is associated with the upregulation of FoxO3a and PGC-1α in the gut of 6-month-old fish with poly I:C injection. Expression of AMPK and SIRT1 was reduced in the gut of 6-month-old fish with poly I:C treatment, and feeding metformin reversed these declines. Taken together, the present study suggested that poly I:C injection led to aging-like phenomena in the gut and metformin activated AMPK and SIRT1 to reduce NF-κB-mediated inflammation and resist oxidative stress via enhanced expression of FoxO3a and PGC-1α and finally delayed gut aging in vertebrates.
Care Challenges Due to COVID-19 and Mental Health Among Caregivers of U.S. Adults With a Chronic or Disabling Condition
Authors: Leggett Amanda N , Carmichael Alicia , Leonard Natalie , Jackson Jeannette , Kirch Matthias , Solway Erica , Kullgren Jeffrey T , Singer Dianne , Malani Preeti N , Gonzalez Richard
Published: October 2021

Background and Objectives

The coronavirus disease 2019 (COVID-19) pandemic poses new challenges for caregivers of adults with chronic or disabling conditions. This study uses nationally representative data to examine the prevalence of pandemic care challenges and supports and their associations with caregiver mental health and interpersonal well-being.

Research Design and Methods

Participants include 311 caregivers aged 50–80 in the United States who were providing care for an adult with a chronic or disabling condition from the June 2020 National Poll on Healthy Aging. Five care challenges (e.g., confusion on public health guidelines) and 2 supports (e.g., physician offered information on care during COVID-19) are treated as predictors of caregiver mental health (care-related stress, self-reported mental health, and depressive symptoms) and interpersonal well-being (interpersonal conflicts, lack of companionship, and isolation).

Results

Each care challenge/support was endorsed by 13%–23% of caregivers. In adjusted models, difficulty getting needed medical care was associated with greater caregiver stress, depressive symptoms, and lower interpersonal well-being. All care challenges universally predicted greater caregiver stress. Caregiving supports were not independently associated with caregiver’ mental health and interpersonal well-being.

Discussion and Implications

Care challenges were associated with caregivers’ mental health and interpersonal well-being during the early months of the pandemic. Some of these challenges may be attributed to changing public health guidelines and practices as the pandemic unfolded, whereas others are relevant to all care contexts (e.g., less support from family). Tools and supports for caregivers must consider both changing policies and care needs.
Predictors of Hospitalization and Superinfection in Viral Respiratory Tract Infections Between Influenza and Paramyxoviruses: The SUPERFLUOUS Study
Authors: Lemarie Benoit , Boussaid Ghilas , Gault Elyanne , Prigent Helene , Beaune Sebastien , Moreau Frederique , Dumoulin Jennifer , Pepin Marion , Greffe Segolene , De Truchis Pierre , Davido Benjamin
Published: October 2021

Background

Viral respiratory tract infections (VRTIs) are among the most common diseases, but the risks of superinfection for different virus species have never been compared.

Methods

Multicenter retrospective study conducted among adults who tested positive for VRTIs with reverse-transcription polymerase chain reaction. We compared characteristics between influenza (A or B) and paramyxoviruses (respiratory syncytial virus, parainfluenza virus types 1 and 3, and human metapneumovirus) and identified predictors of superinfection and hospitalization.s

Results

Five hundred ninety patients had VRTI, including 347 (59%) influenza and 243 paramyxovirus infections with comparable rates of superinfections (53% vs 60%). In multivariate analyses, the predictors of superinfections were age >75 years (adjusted odds ratio, 2.37 [95% confidence interval, 1.65–3.40]), chronic respiratory disease (1.79 [1.20–2.67]), and biological abnormalities, including neutrophil count >7000/µL (1.98 [1.34–2.91)], eosinophil count <50/µL (2.53 [1.61–3.98], and procalcitonin level >0.25ng/mL (2.8 [1.65–4.73]). The predictors of hospitalization were age >75 years old (adjusted odds ratio, 3.49 [95% confidence interval, 2.17–5.63]), paramyxovirus infection (2.28 [1.39–3.75]), long-term use of inhaled corticosteroids (2.49 [1.13–5.49]), and biological abnormalities, including neutrophil count >7000/µL (2.38 [1.37–4.12)] and procalcitonin level >0.25ng/mL (2.49 [1.23–5.02]). Kaplan-Meier survival curves showed that influenza-infected patients had a higher mortality rate than those with paramyxovirus infections (8.9% vs 4.5%, respectively; P = .02).

Conclusions

Our study revealed a high rate of superinfection (56%), not related to viral species. However influenza virus was associated with a poorer prognosis than paramyxoviruses, pleading for a broader and large-scale vaccination of individual at risk of VRTIs.
Polar auxin transport dynamics of primary and secondary vein patterning in dicot leaves
Authors: Holloway David M , Wenzel Carol L
Published: October 2021

The growth regulator auxin plays a central role in the phyllotaxy, shape and venation patterns of leaves. The auxin spatial localization underlying these phenomena involves polar auxin transport (PAT) at the cellular level, particularly the preferential allocation of PINFORMED (PIN) efflux proteins to certain areas of the plasma membrane. Two general mechanisms have been studied: an up-the-gradient (UTG) allocation dependent on neighbouring-cell auxin concentrations, and a with-the-flux (WTF) allocation dependent on the flow of auxin across walls. We have developed a combined UTG+WTF model to quantify the observed auxin flows both towards (UTG) and away from (WTF) auxin maxima during primary and secondary vein patterning in leaves. The model simulates intracellular and membrane kinetics and intercellular transport, and is solved for a 2D leaf of several hundred cells. In addition to normal development, modelling of increasing PAT inhibition generates, as observed experimentally: a switch from several distinct vein initiation sites to many less distinct sites; a delay in vein canalization; inhibited connection of new veins to old; and finally loss of patterning in the margin, loss of vein extension and confinement of auxin to the margin. The model generates the observed formation of discrete auxin maxima at leaf vein sources and shows the dependence of secondary vein patterning on the efficacy of auxin flux through cells. Simulations of vein patterning and leaf growth further indicate that growth itself may bridge the spatial scale from the cell–cell resolution of the PIN-auxin dynamics to vein patterns on the whole-leaf scale.
Ensemble learning to predict opioid-related overdose using statewide prescription drug monitoring program and hospital discharge data in the state of Tennessee
Authors: Ripperger Michael , Lotspeich Sarah C , Wilimitis Drew , Fry Carrie E , Roberts Allison , Lenert Matthew , Cherry Charlotte , Latham Sanura , Robinson Katelyn , Chen Qingxia , McPheeters Melissa L , Tyndall Ben , Walsh Colin G
Published: October 2021

Objective

To develop and validate algorithms for predicting 30-day fatal and nonfatal opioid-related overdose using statewide data sources including prescription drug monitoring program data, Hospital Discharge Data System data, and Tennessee (TN) vital records. Current overdose prevention efforts in TN rely on descriptive and retrospective analyses without prognostication.

Materials and Methods

Study data included 3 041 668 TN patients with 71 479 191 controlled substance prescriptions from 2012 to 2017. Statewide data and socioeconomic indicators were used to train, ensemble, and calibrate 10 nonparametric “weak learner” models. Validation was performed using area under the receiver operating curve (AUROC), area under the precision recall curve, risk concentration, and Spiegelhalter z-test statistic.

Results

Within 30 days, 2574 fatal overdoses occurred after 4912 prescriptions (0.0069%) and 8455 nonfatal overdoses occurred after 19 460 prescriptions (0.027%). Discrimination and calibration improved after ensembling (AUROC: 0.79–0.83; Spiegelhalter P value: 0–.12). Risk concentration captured 47–52% of cases in the top quantiles of predicted probabilities.

Discussion

Partitioning and ensembling enabled all study data to be used given computational limits and helped mediate case imbalance. Predicting risk at the prescription level can aggregate risk to the patient, provider, pharmacy, county, and regional levels. Implementing these models into Tennessee Department of Health systems might enable more granular risk quantification. Prospective validation with more recent data is needed.

Conclusion

Predicting opioid-related overdose risk at statewide scales remains difficult and models like these, which required a partnership between an academic institution and state health agency to develop, may complement traditional epidemiological methods of risk identification and inform public health decisions.
Breast Arterial Calcifications: Reporting Preferences and Impact on Screening for Coronary Artery Disease
Authors: Zaki-Metias Kaitlin M , MacLean Jeffrey J , Mergo Paul A , Ogunde Barakat , Al-Hameed Mohammed , Trivax Cory Z
Published: October 2021

Objective

Breast arterial calcifications (BAC) have been shown to correlate with measures of coronary artery disease risk stratification, although reporting of BAC is optional by BI-RADS guidelines. The purpose of this study is to determine referring provider preferences in BAC reporting on mammography reports and if such reporting has any impact on patient management.

Methods

This study was approved by the local institutional review board. A voluntary eight-question survey regarding the preferences and outcomes of BAC reporting on mammography was distributed to 1085 primary care physicians, obstetrics and gynecologists, medical oncologists, and breast and general surgeons in our health system via a secure online platform. Data analysis including Pearson chi-square was performed with a P-value of <0.05 for significance.

Results

A response rate of 19.1% (207/1085) was attained, with 21/207 (10.1%) of respondents indicating they do not routinely order mammograms excluded from further analysis. A total of 62.4% (116/186) of ordering physicians indicated a preference for reporting of BAC in both the body and impression of the radiology report, with 82.3% (153/186) of respondents placing importance on the quantity of atherosclerotic calcifications. Most participants (148/186, 79.6%) reported that the presence of BAC would prompt further investigation for coronary artery disease and associated risk factors.

Conclusion

The majority of responding physicians indicated a preference for detailed reporting of BAC and that such reporting would impact patient care. Understanding referring provider preferences regarding ancillary findings of BAC will allow for improved communication and value in mammography.
From Smart Contract Litigation to Blockchain Arbitration, a New Decentralized Approach Leading Towards the Blockchain Arbitral Order
Authors: Chevalier Maxime
Published: October 2021

Blockchain dispute resolution has led the crypto economy to the surge of a new form of dispute resolution: blockchain arbitration. Resolving disputes on-chain is becoming necessary as national and international legal frameworks are not adapted to the characteristics of blockchain transactions. More importantly, the legality of smart contracts is highly debated under various national laws. This new sui generis form of arbitration should not be assimilated with traditional arbitration. Indeed, blockchain arbitration might not fit within the traditional international arbitration framework, and it does not have to. Because blockchain arbitration operates as an oracle, the decision from the jurors automatically triggers or modifies the smart contract. Through the blockchain technology, arbitration has reached the possibility to automatically enforce arbitral awards with no need to rely on state courts’ authority. Observing the legal theories of international arbitration, blockchain arbitration enshrines the representation of delocalized arbitration, but simultaneously leaves room for a new representation of arbitration: decentralized arbitration. In the next decades, we will see the surge of the blockchain arbitral order, an independent legal order anchored in the Lex Cryptographia. This essay advocates for the recognition of the blockchain arbitral legal order and tries to draw its contours.