bluuebunny/crossref_metadata_2025 huggingface dataset:
Testing the nonclinical Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm with an established anti‐seizure medication: Levetiracetam case study
Authors: Delaunois Annie , Mathy François‐Xavier , Cornet Miranda , Gryshkova Vitalina , Korlowski Chloé , Bonfitto François , Koch Juliane , Schlit Anne‐Françoise , Hebeisen Simon , Passini Elisa , Rodriguez Blanca , Valentin Jean‐Pierre
Published: February 2023

Levetiracetam (LEV), a well‐established anti‐seizure medication (ASM), was launched before the original ICH S7B nonclinical guidance assessing QT prolongation potential and the introduction of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm. No information was available on its effects on cardiac channels. The goal of this work was to “pressure test” the CiPA approach with LEV and check the concordance of nonclinical core and follow‐up S7B assays with clinical and post‐marketing data. The following experiments were conducted with LEV (0.25–7.5 mM): patch clamp assays on hERG (acute or trafficking effects), NaV1.5, CaV1.2, Kir2.1, KV7.1/mink, KV1.5, KV4.3, and HCN4; in silico electrophysiology modeling (Virtual Assay® software) in control, large‐variability, and high‐risk human ventricular cell populations; electrophysiology measurements in human induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes and dog Purkinje fibers; ECG measurements in conscious telemetered dogs after single oral administration (150, 300, and 600 mg/kg). Except a slight inhibition (<10%) of hERG and KV7.1/mink at 7.5 mM, that is, 30‐fold the free therapeutic plasma concentration (FTPC) at 1500 mg, LEV did not affect any other cardiac channels or hERG trafficking. In both virtual and real human cardiomyocytes, and in dog Purkinje fibers, LEV induced no relevant changes in electrophysiological parameters or arrhythmia. No QTc prolongation was noted up to 2.7 mM unbound plasma levels in conscious dogs, corresponding to 10‐fold the FTPC. Nonclinical assessment integrating CiPA assays shows the absence of QT prolongation and proarrhythmic risk of LEV up to at least 10‐fold the FTPC and the good concordance with clinical and postmarketing data, although this does not exclude very rare occurrence of QT prolongation cases in patients with underlying risk factors.
Lethal, transmission, behavioral, and physiological effects of Metarhizium anisopliae against gregarious larvae of Heortia vitessoides and synergistic effects between Metarhizium anisopliae and insecticides
Authors: Qian Chenyu , Ma Tao , Qiu Hualong , Lyu Hailong , Liang Shiping , Shao Yuhe , Yuan Pengyu , Shen Liming , Wen Xiujun , Wang Cai
Published: February 2023

BACKGROUND

Heortia vitessoides Moore is a severe pest of Aquilaria sinensis (Lour.) Gilg, an important source of agarwood. In recent years, large amounts of chemical insecticides have been applied in A. sinensis plantations to deal with the outbreak of H. vitessoides, causing residue problems that reduce the quality and price of agarwood. Herein, we hypothesize that the widely applied biocontrol agent, Metarhizium anisopliae (Metschn.) Sorokin, can effectively kill the gregarious larvae of H. vitessoides through direct contact and horizontal transmission.

RESULTS

At the concentration of 1 × 109 conidia/mL, the three M. anisopliae strains caused 100% mortality of H. vitessoides larvae. In addition, mixing donor larvae (previously treated with M. anisopliae conidia) with receptor larvae (which did not directly contact M. anisopliae conidia) caused significantly higher mortality of receptor larvae than the control receptors. This is due to the horizontal transmission of M. anisopliae conidia among live larvae, which was proven by pictures taken by scanning electron microscopy and induced activities of immunity‐related enzymes of donor and receptor larvae. Behavioral bioassays showed that M. anisopliae conidia had little effect on the aggregation tendency of H. vitessoides larvae but may trigger feeding‐avoidance behavior depending on M. anisopliae strains and concentrations. Interestingly, joint use of sublethal concentrations of M. anisopliae and chemical insecticides significantly increased larval mortality than each agent alone, indicating synergistic effects between M. anisopliae and insecticide against H. vitessoides.

CONCLUSION

This study may provide a new strategy to suppress H. vitessoides population and reduce the use of chemical insecticides. © 2023 Society of Chemical Industry.
A comparison of different methods to adjust survival curves for confounders
Authors: Denz Robin , Klaaßen‐Mielke Renate , Timmesfeld Nina
Published: February 2023

Treatment specific survival curves are an important tool to illustrate the treatment effect in studies with time‐to‐event outcomes. In non‐randomized studies, unadjusted estimates can lead to biased depictions due to confounding. Multiple methods to adjust survival curves for confounders exist. However, it is currently unclear which method is the most appropriate in which situation. Our goal is to compare forms of inverse probability of treatment weighting, the G‐Formula, propensity score matching, empirical likelihood estimation and augmented estimators as well as their pseudo‐values based counterparts in different scenarios with a focus on their bias and goodness‐of‐fit. We provide a short review of all methods and illustrate their usage by contrasting the survival of smokers and non‐smokers, using data from the German Epidemiological Trial on Ankle‐Brachial‐Index. Subsequently, we compare the methods using a Monte‐Carlo simulation. We consider scenarios in which correctly or incorrectly specified models for describing the treatment assignment and the time‐to‐event outcome are used with varying sample sizes. The bias and goodness‐of‐fit is determined by taking the entire survival curve into account. When used properly, all methods showed no systematic bias in medium to large samples. Cox regression based methods, however, showed systematic bias in small samples. The goodness‐of‐fit varied greatly between different methods and scenarios. Methods utilizing an outcome model were more efficient than other techniques, while augmented estimators using an additional treatment assignment model were unbiased when either model was correct with a goodness‐of‐fit comparable to other methods. These “doubly‐robust” methods have important advantages in every considered scenario.
Detecting and predicting countermeasures against clickjacking
Authors: Aryaman  , Naik Nenavath Srinivas , Vollala Satyanarayana , Amin Ruhul
Published: February 2023

Clickjacking is a fast‐growing threat for users online. Here, an attacker program shows a user‐interface (UI) which is entirely out of context, by concealing a very sensitive UI element and rendering it in such a way that it is not visible (transparent) to the end user. The user is then tricked into clicking on the hidden element. By exploiting cameras and publishing unwanted messages, these attacks have the potential to do significant harm. Many websites still lack server‐side minimum security (eg, X‐Frame‐Options header, Content‐Security‐Policy Header, etc) and are hence susceptible to clickjacking. Additionally, client‐side defense methods fare poorly and are ineffective against advanced clickjacking attack types. This paper focuses on dealing with the detection of a possibility of a website being clickjacked. It also predicts the Level of Security of a website against a clickjacking attack and the possible security countermeasures that could be taken to avoid a clickjacking attack on the website. Testing this approach on various websites has proved effective in detecting whether or not a website is vulnerable to clickjacking.
Shear strengthening of precast prestressed I‐girders using carbon fiber reinforced polymers and in‐fill concrete blocks
Authors: Yaqub Muhammad Arslan , Czaderski Christoph , Matthys Stijn
Published: February 2023

Due to the rapid increase in traffic volumes, existing infrastructure demands proper assessment and in some cases rehabilitation is needed. Prestressed concrete (PC) I‐shaped girders are widely used in prefabricated girder bridges. With sequel generations of shear design provisions their shear capacity might need to be increased in the framework of assessing safety of aging bridges. Earlier attempts in shear strengthening this specific type of girder with fiber reinforced polymers (FRP) has shown early debonding along the concrete surface at the web‐flange corner so that the increase in shear strength was very limited. This study presents the results of full scale PC I‐girders strengthened with CFRP through epoxy bonded concrete in‐fill blocks that locally transforms the I‐section to a rectangular section at the position of CFRP strips. This transformation eliminated the early debonding of CFRP shear reinforcement and for the studied configurations a 30%–40% increase in shear capacity was obtained with respect to the unstrengthened control specimen, without and with additional CFRP spike anchors, respectively. In comparison, similar configurations without in‐fill blocks reached 5% and 12% increase in shear capacity, respectively. As such, the use of in‐fill blocks appeared more effective than local anchorage of the CFRP at the web‐flange corner. Analytical verification of the experimental results confirmed that existing formulations lack ability to predict the shear capacity of strengthened I‐girders, and further work is needed in this respect.
Abnormal [18F]NIFENE binding in transgenic 5xFAD mouse model of Alzheimer's disease: In vivo PET/CT imaging studies of α4β2* nicotinic acetylcholinergic receptors and in vitro correlations with Aβ plaques
Authors: Liang Christopher , Nguyen Grace A. , Danh Tram B. , Sandhu Anoopraj K. , Melkonyan Lusine L. , Syed Amina U. , Mukherjee Jogeshwar
Published: February 2023

Since cholinergic dysfunction has been implicated in Alzheimer's disease (AD), the effects of Aβ plaques on nicotinic acetylcholine receptors (nAChRs) α4β2* subtype were studied using the transgenic 5xFAD mouse model of AD. Using the PET radiotracer [18F]nifene for α4β2* nAChRs, in vitro autoradiography and in vivo PET/CT studies in 5xFAD mice were carried out and compared with wild‐type (C57BL/6) mice. Ratios of [18F]nifene binding in brain regions versus cerebellum (CB) in 5xFAD mice brains were for thalamus (TH) = 17, hippocampus‐subiculum = 7, frontal cortex (FC) = 5.5, and striatum = 4.7. [125I]IBETA and immunohistochemistry (IHC) in 5xFAD brain slices confirmed Aβ plaques. Nicotine and acetylcholine displaced [18F]nifene in 5xFAD mice (IC50 nicotine = 31–73 nM; ACh = 38–83 nM) and C57BL/6 (IC50 nicotine = 16–18 nM; ACh = 34–55 nM). Average [18F]nifene SUVR (CB as reference) in 5xFAD mice was significantly higher in FC = 3.04 compared to C57BL/6 mice FC = 1.92 (p = .001), whereas TH difference between 5xFAD mice (SUVR = 2.58) and C57BL/6 mice (SUVR = 2.38) was not significant. Nicotine‐induced dissociation half life (t1/2) of [18F]nifene for TH were 37 min for 5xFAD mice and 26 min for C57BL/6 mice. Dissociation half life  for FC in C57BL/6 mice was 77 min , while no dissociation of [18F]nifene occurred in the medial prefrontal cortex (mFC) of 5xFAD mice. Coregistration of [18F]nifene PET with MR suggested that the mPFC, and anterior cingulate (AC) regions exhibited high uptake in 5xFAD mice compared to C57BL/6 mice. Ex vivo [18F]nifene and in vitro [125I]IBETA Aβ plaque autoradiography after in vivo PET/CT scan of 5xFAD mouse brain were moderately correlated (r2 = 0.68). In conclusion, 5xFAD mice showed increased non‐displaceable [18F]nifene binding in mPFC.
Nomenclatural type of the Linnaean name Sibthorpia africana and its synonym Sibthorpia balearica (Plantaginaceae, Sibthorpieae)
Authors: Ferrer‐Gallego P. Pablo , Sáez Llorenç
Published: February 2023

The nomenclatural type of the Linnaean name Sibthorpia africana (Plantaginaceae, Sibthorpieae) is discussed and revised. An illustration published by Shaw in 1738 is selected as the lectotype of the name. Sibthorpia balearica is another name in this group, published by Knoche in 1922, and treated in this paper as a heterotypic synonym of the Linnaean name. This name had previously been lectotypified by Hedberg in 1955 from a specimen kept at K. This typification is narrowed to a single specimen by a “second‐step” lectotypification.
Extramedullary plasmacytoma of the oral cavity metastasising to both kidneys in a dog
Authors: Park Kyung Ho , Kim Tae‐Un , Park Hyun‐Woo , Lee Seoung‐Woo , Baek Su‐Min , Noh Daji , Yim Jae‐Hyuk , Lee Young‐Jin , Kim Yeon‐Gyeong , Son Dong‐Ju , Park Sang‐Joon , Choi Seong‐Kyoon , Lee Kija , Park Larry Chong , Park Jin‐Kyu
Published: February 2023

Background

Most extramedullary plasmacytomas (EMPs) aresolitary and located in the head and neck region. They may also occur in the visceral parts of the body.

Objectives

Here, we report a case of oral EMP followed by neoplastic plasma cell metastasis to both kidneys in a neutered male Pomeranian.

Methods

Oral plasmacytoma recurred 11 months aftersurgical removal of an oral mass and partial maxillectomy was performed. Eighteen months after partial maxillectomy, neoplastic masses were detected in both kidneys on computed tomography. The dog died 12 months after detection of bilateral kidney neoplasms. The resected neoplastic masses were routinely processed for histopathological observation and immunohistochemistry against pan‐cytokeratin, desmin, CD3, and MUM‐1.

Results

The recurred mass mainly consisted of well‐differentiated plasma cells and contained a small portion of aggressive cells with malignant features. Monoclonal gammopathy was not observed on serumelectrophoresis performed to exclude multiple myeloma. The mass was composed of plasma cells with high nuclear pleomorphism and abundant mitotic figures. The neoplasm stained positive for MUM‐1 with a more aggressive morphology than in oral EMP.

Conclusion

Based on serum biomarker and pathological observations, a diagnosis of recurrence and metastasis of oral‐to‐renal EMP was established. To the best of our knowledge, metastasis of oral EMP into the bilateral kidneys, as described in the current case, has not been previously reported in dogs.
An overview of poly(vinyl alcohol) and poly(vinyl pyrrolidone) in pharmaceutical additive manufacturing
Authors: Bianchi Marica , Pegoretti Alessandro , Fredi Giulia
Published: February 2023

Recently, drug personalization has received noticeable attention. Problems arising from standard generalized drug treatments have aroused over the years, particularly among pediatric and geriatric patients. The growing awareness of the limitations of the “one‐size‐fits‐all” approach has progressively led to a rethinking of the current medicine's development, laying the basis of personalized medicine. Three‐dimensional printing is a promising tool for realizing personalized therapeutic solutions fitting specific patient needs. This technology offers the possibility to manufacture drug delivery devices with tailored doses, sizes, and release characteristics. Among additive manufacturing techniques, fused deposition modeling (FDM) is the most studied for oral drug delivery device production due to its high precision and cheapness. By playing with factors such as drug loading method, filament production, and printing parameters, the medication release profile of a drug delivery device produced by 3D printing can be tailored depending on the patient's requirements. This review focuses on the applications of FDM in drug fabrication using poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) as drug‐loaded matrices. The authors aim to provide an overview of the current trends in this research field, with special attention to the effect of the printing parameters, tablet shape, and drug distribution and concentration on drug customization and personalized drug release.
The mitochondrial BCKD complex interacts with hepatic apolipoprotein E in cultured cells in vitro and mouse livers in vivo
Authors: Rueter Johanna , Rimbach Gerald , Treitz Christian , Schloesser Anke , Lüersen Kai , Tholey Andreas , Huebbe Patricia
Published: February 2023

Background and aims

Apolipoprotein E (APOE) is known for its role in lipid metabolism and its association with age-related disease pathology. The aim of the present work was to identify previously unknown functions of APOE based on the detection of novel APOE protein–protein interaction candidates.

Approach and results

APOE targeted replacement mice and transfected cultured hepatocytes expressing the human isoforms APOE3 and APOE4 were used. For 7 months, APOE3 and APOE4 mice were fed a high-fat and high-sugar diet to induce obesity, while a subgroup was subjected to 30% dietary restriction. Proteomic analysis of coimmunoprecipitation products from APOE mouse liver extracts revealed 28 APOE-interacting candidate proteins, including branched-chain alpha-keto acid dehydrogenase (BCKD) complex subunit alpha (BCKDHA) and voltage-dependent anion-selective channel 1 (VDAC1). The binding of APOE and BCKDHA was verified in situ by proximity ligation assay in cultured cells. The activity of the BCKD enzyme complex was significantly higher in obese APOE4 mice than in APOE3 mice, while the plasma levels of branched-chain amino acids and mTOR signalling proteins were not different. However, the protein–protein interaction with VDAC1 was strongly induced in APOE3 and APOE4 mice upon dietary restriction, suggesting a prominent role of APOE in mitochondrial function.

Conclusions

The protein–protein interactions of APOE with BCKDHA and VDAC1 appear to be of physiological relevance and are modulated upon dietary restriction. Because these are mitochondrial proteins, it may be suggested that APOE is involved in mitochondria-related processes and adaptation to hepatic energy demands.
Cardiac radioablation of incessant ventricular tachycardia in patients with terminal heart failure under permanent left ventricular assist device therapy—description of two cases
Authors: Mehrhof Felix , Bergengruen Paula , Gerds-Li Jin-Hong , Jahn Andrea , Kluge Anne Kathrin , Parwani Abdul , Zips Daniel , Boldt Leif-Hendrik , Schönrath Felix
Published: February 2023

Purpose

Cardiac radioablation (cRA) using a stereotactic single-session radioablative approach has recently been described as a possible treatment option for patients with otherwise untreatable recurrent ventricular tachycardia (VT). There is very limited experience in cRA for patients undergoing left ventricular assist device (LVAD) therapy. We present clinical experiences of two patients treated with cRA for incessant VT under long-term LVAD therapy.

Methods

Two male patients (54 and 61 years old) with terminal heart failure under LVAD therapy (both patients for 8 years) showed incessant VT despite extensive antiarrhythmic drug therapy and repeated catheter ablation. cRA with a single dose of 25 Gy was applied as a last resort strategy under compassionate use in both patients following an electroanatomical mapping procedure.

Results

Both patients displayed ongoing VT during and after the cRA procedure. Repeated attempts at post-procedural rhythm conversion failed in both patients; however, one patient was hemodynamically stabilized and could be discharged home for several months before falling prey to a fatal bleeding complication. The second patient initially stabilized for a few days following cRA before renewed acceleration of running VT required bilateral ablation of the stellate ganglion; the patient died 50 days later. No immediate side effects of cRA were detected in either patient.

Conclusion

cRA might serve as a last resort strategy for patients with terminal heart failure undergoing LVAD therapy and displaying incessant VT. Intermediate- and long-term outcomes of these seriously ill patients often remain poor; therefore, best supportive care strategies should also be evaluated as long as no clear beneficial effects of cRA procedures can be shown. For patients treated with cRA under running ventricular rhythm abnormality, strategies for post-procedural generation of stabilized rhythm have to be established.
Strukturierte Patientenübergabe in Hochrisikobereichen
Authors: Fliegenschmidt J. , Merkel M. J. , von Dossow V. , Zwißler B.
Published: February 2023

Die perioperative Medizin ist ein Hochrisikobereich, der besonders anfällig für Kommunikationsdefizite und -fehler ist. Das Schema „situation, background, assessment, recommendation“ (SBAR) bietet einen einfach anzuwendenden Kommunikationsleitfaden, der mit einer verbesserten Qualität der Übergabe assoziiert ist. Im März 2022 ist die Verwendung des SBAR-Schemas in der Perioperativmedizin durch die DGAI schon in zweiter Auflage empfohlen worden. Darüber hinaus hat die moderne Kommunikationsforschung ein ganzes Bündel von Maßnahmen identifiziert, die essenzielle Voraussetzungen für eine effektive Teamarbeit und die Gewährleistung der Patientensicherheit schaffen. Das SBAR-Schema ist eine Möglichkeit, strukturierte Kommunikation im klinischen Alltag umzusetzen. Entscheidend sind die konsequente Nutzung und eine klare Definition der Handlungsabläufe. Nur so können Kommunikationsdefizite in Hochrisikobereichen schneller identifiziert und durch Einführung eines strukturierten Übergabekonzeptes reduziert werden. Unabdingbar bleibt das gemeinsame Verständnis für die Notwendigkeit, diese Konzepte zu erlernen, umzusetzen und als Team zu trainieren. Das übergeordnete Ziel einer Kultur der Patientensicherheit ist nur durch die konsequente Zusammenarbeit des interprofessionellen Teams und durch das Vorleben der Führungskräfte erreichbar.
Die Situation pflegender Angehöriger im erwerbsfähigen Alter in der COVID-19-Pandemie – Ergebnisse einer Onlinebefragung in Deutschland
Authors: Wiegelmann Henrik , Hess Moritz , Domhoff Dominik , Heinze Franziska , Schmidt Annika , Seibert Kathrin , Stolle Claudia , Preuß Benedikt , Rothgang Heinz , Wolf-Ostermann Karin
Published: February 2023

Hintergrund

Die Folgen der COVID-19-Pandemie haben verschiedene Personengruppen vor große Herausforderungen gestellt; eine dieser Gruppen sind pflegende Angehörige. Die vorliegende Studie untersucht, welche Veränderungen die Pandemie für pflegende Angehörige mit sich gebracht hat und in welchem Ausmaß sich Lebensqualität und Pflegebelastung subgruppenspezifisch verändert haben.

Methode

Die Datenerhebung erfolgte im Sommer 2020 in einer Querschnittsstudie mit pflegenden Angehörigen im erwerbsfähigen Alter (N = 1143). Neben soziodemografischen Daten wurden Angaben zu Versorgungssituation, Vereinbarkeit von Pflege und Beruf sowie Belastung und Lebensqualität in einer Onlinebefragung erhoben. Versorgungssituation und Vereinbarkeit von Pflege und Beruf wurden deskriptiv analysiert. Für die Analysen der Veränderung der Lebensqualität und der Belastung wurden logistische Regressionsmodelle verwendet.

Ergebnisse

Die Versorgungssituation hat sich für viele Befragte (54,7 %) während der Pandemie geändert und ist zeitlich aufwendiger geworden. Für 70,8 % ist die Vereinbarkeit von Pflege und Beruf schwieriger geworden. Mit dem Pandemiemanagement der eigenen Arbeitgeber:innen zeigt sich die Mehrheit zufrieden (65,9 %). Die Lebensqualität hat ab- und die Belastung zugenommen, besonders deutlich für jüngere Pflegende, Frauen und Pflegende von Personen mit hohem Pflegebedarf.

Diskussion

Die Ergebnisse weisen darauf hin, dass sich die Lebenssituationen pflegender Angehöriger während der COVID-19-Pandemie verschlechtert haben. Entscheidungsträger:innen sollten dies anerkennen und besonders betroffene Subgruppen pflegender Angehöriger unterstützen. Zukünftig ist es wichtig, die informelle häusliche Pflege ebenso wie Versorgungssettings der professionellen (Langzeit‑)Pflege in gesundheits- und sozialpolitische Pandemiekonzepte einzubeziehen.
Accountability in artificial intelligence: what it is and how it works
Authors: Novelli Claudio , Taddeo Mariarosaria , Floridi Luciano
Published: February 2023

Accountability is a cornerstone of the governance of artificial intelligence (AI). However, it is often defined too imprecisely because its multifaceted nature and the sociotechnical structure of AI systems imply a variety of values, practices, and measures to which accountability in AI can refer. We address this lack of clarity by defining accountability in terms of answerability, identifying three conditions of possibility (authority recognition, interrogation, and limitation of power), and an architecture of seven features (context, range, agent, forum, standards, process, and implications). We analyze this architecture through four accountability goals (compliance, report, oversight, and enforcement). We argue that these goals are often complementary and that policy-makers emphasize or prioritize some over others depending on the proactive or reactive use of accountability and the missions of AI governance.
The abuse potential of lemborexant, a dual orexin receptor antagonist, according to the 8 factors of the Controlled Substances Act
Authors: Moline Margaret , Asakura Shoji , Beuckman Carsten , Landry Ishani , Setnik Beatrice , Ashworth Judy , Henningfield Jack E.
Published: February 2023

Rationale

Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries including the USA, Japan, Canada, Australia, and several Asian countries for the treatment of insomnia in adults. As a compound with central nervous system activity, it is important to understand the abuse potential of LEM with respect to public health.

Objectives

This review discusses data for LEM relevant to each of the 8 factors of the United States Controlled Substances Act.

Results

LEM did not demonstrate abuse potential in nonclinical testing and was associated with a low incidence of abuse-related adverse events in clinical study participants with insomnia disorder. Similar to other DORAs that have been evaluated (eg., almorexant, suvorexant (SUV), and daridorexant), LEM and the positive controls (zolpidem and SUV) also showed drug liking in a phase 1 abuse potential study that enrolled subjects who used sedatives recreationally. However, internet surveillance of SUV and the FDA Adverse Events Reporting System suggests that drugs in the DORA class display very low abuse-related risks in the community. Additionally, as described in FDA-approved labeling, it does not carry physical dependence and withdrawal risks.

Conclusions

LEM, similar to most other prescription insomnia medications, was placed into Schedule IV. However, LEM and other drugs in the DORA class may have a lower potential for abuse as suggested by real-world postmarketing data from federal surveys and internet surveillance, and thus may have lower risks to public health than Schedule IV benzodiazepines and nonbenzodiazepine hypnotics that potentiate GABA signaling.
Analysis of milk with liquid chromatography–mass spectrometry: a review
Authors: Imperiale Sebastian , Morozova Ksenia , Ferrentino Giovanna , Scampicchio Matteo
Published: February 2023

As a widely consumed foodstuff, milk and dairy products are increasingly studied over the years. At the present time, milk profiling is used as a benchmark to assess the properties of milk. Modern biomolecular mass spectrometers have become invaluable to fully characterize the milk composition. This review reports the analysis of milk and its components using liquid chromatography coupled with mass spectrometry (LC–MS). LC–MS analysis as a whole will be discussed subdivided into the major constituents of milk, namely, lipids, proteins, sugars and the mineral fraction.
Effect of rosemary addition on the sensorial and physicochemical qualities of dry-cured ham slices. Measurement of camphor transfer
Authors: Gómez-Sáez Elena M. , Alonso Gonzalo L. , Vergara Herminia
Published: February 2023

This study determined the effect of three concentrations (R1: high, R2: medium and R3: low) of rosemary added to dry-cured ham slices vacuum packaged. pH and the colour parameters were evaluated at 0, 7, 14, 28 and 60 days of storage; visual appearance, odour, flavour and camphor content were assessed at days 7, 14, 28 and 60. The rosemary concentration changed the colour parameters, significantly altering the visual appearance (p < 0.001 at 7 and 14 days; p < 0.5 at day 28), but did not affect the pH, neither odour nor flavour. Nevertheless, significant differences were found with the time on R1 and R2 in odour (p < 0.01 and p < 0.001, respectively) and in flavour (p < 0.001). Camphor content was similar in all samples but changed over the time in R1 (p < 0.001) and R2 (p < 0.01). In conclusion, despite the differences observed, it is evident that the addition of this spice was to the liking of the panellists, in any of the concentrations used.
Incidence and concomitant chondral injuries in a consecutive cohort of primary traumatic patellar dislocations examined with sub-acute MRI
Authors: Isacsson Anders , Olsson Ola , Englund Martin , Frobell Richard B.
Published: February 2023

Purpose

To present age- and sex-specific cumulative annual incidences of primary traumatic lateral patellar dislocation (LPD) and to detail patient characteristics and concomitant chondral injuries including osteochondral fractures, as visualized on magnetic resonance imaging (MRI), in a large consecutive cohort of knee-injured individuals.

Methods

Data on primary traumatic lateral patellar dislocations were collected from a large consecutive cohort of knee injuries examined with sub-acute MRI in a single centre with a well-defined catchment area. Annual incidences for different age-groups in relation to gender were calculated together with the risk of concomitant chondral and osteochondral injury, during sports and in general.

Results

A total of 184 primary patellar dislocations were identified in the cohort of 1145 acute knee injuries (n=175) and surgical records (n=9). Knee MRI was performed within a median of six days of injury. Median age of patients with primary LPD was 16 years (interquartile range, 14–21; range, 9–47) and 41% were females. Males were significantly older than females at the time of injury (median age 17 vs. 15, P = 0.021) and sustained their primary LPD during sports more often than females (65 vs. 40%, P < 0.001). Primary LPD occurred most frequently at the age of 13 to 15 years where the annual incidence was 125 (95% CI, 96–160) per 100,000 persons. The overall annual incidence of primary LPD was 14 (95% CI, 12–16) per 100,000 persons, with a predominance of males versus females (17 vs. 11, P = 0.01). Concomitant lesions to joint surfaces were displayed on MRI or during surgery in 75 (43%) knees. Osteochondral fractures were seen in 32 knees (18%). We found no statistically significant difference in the risk of osteochondral fracture between those injured during sports or during leisure activity (14 vs. 24%, P = 0.08).

Conclusions

The annual incidence of first-time patellar dislocation was found to be 14 per 100,000 individuals with the highest incidence found among those aged 13–15 years. Primary LPD was more common among males and was sustained during sports activity in 55% of the cases. Associated injuries to the chondral surfaces should be expected in 43% of knees with primary LPD where 18% represent osteochondral fractures.
Evaluation of cannulated compression headless screws as an alternative implant for superior pubic ramus fracture fixation: a biomechanical study
Authors: Berk Till , Zderic Ivan , Schwarzenberg Peter , Pastor Tatjana , Lesche Felix , Halvachizadeh Sascha , Richards R. Geoff , Gueorguiev Boyko , Pape Hans-Christoph
Published: February 2023

Background/purpose

Pubic ramus fractures account for the most common types of pelvic fractures. The standard surgical approach for superior pubic ramus fractures (SPRF) is a minimally invasive percutaneous screw fixation. However, percutaneous closed reduction and internal fixation of anterior pelvic ring injuries have high failure rates of up to 15%. The aim of this biomechanical study was to evaluate the stability of SPRF following stabilization with retrograde placed cannulated compression headless screw (CCHS) versus conventional fully and partially threaded screws in an artificial pelvic bone model.

Methods

SPRF type II as described by Nakatani et al. was created by means of osteotomies in eighteen anatomical composite hemi-pelvises. Specimens were stratified into three groups of six specimens each (n = 6) for fixation with either a 7.3 mm partially threaded cannulated screw (group RST), a 7.3 mm fully threaded cannulated screw (group RSV), or a 7.5 mm partially threaded cannulated CCHS (group CCS). Each hemi-pelvic specimen was tested in an inverted upright standing position under progressively increasing cyclic axial loading. The peak load, starting at 200 N, was monotonically increased at a rate of 0.1 N/cycle until 10 mm actuator displacement.

Results

Total and torsional displacement were associated with higher values for RST versus CCS and RSV, with significant differences between RST and CCS for both these parameters (p ≤ 0.033). The differences between RST and RSV were significant for total displacement (p = 0.020), and a trend toward significance for torsional displacement (p = 0.061) was observed. For both failure criteria 2 mm total displacement and 5° torsional displacement, CCS was associated with significantly higher number of cycles compared to RST (p ≤ 0.040).

Conclusion

CCHS fixation presented predominantly superior stability to the standard surgical treatment and could therefore be a possible alternative implant for retrograde SPRF screw fixation, whereas partially threaded screws in group RST were associated with inferior biomechanical stability.
Aktiv und zufrieden? Körperliche Aktivität und berufsbezogene Lebensqualität bei Psycholog:innen
Authors: Bendau Antonia , Gerz George Oliver , Ströhle Andreas , Petzold Moritz Bruno
Published: February 2023

Hintergrund

Klinisch tätige Psycholog:innen sind in ihrer Arbeit mit Menschen mit psychischen Erkrankungen oft zahlreichen Stressoren ausgesetzt; diese können sich in psychischer Belastung und einer verringerten Lebensqualität niederschlagen. Körperliche Aktivität könnte eine protektive Ressource darstellen, diesbezüglich fehlen jedoch bisher empirische Befunde.

Methoden

Im Rahmen einer querschnittlichen Online-Befragung über SoSci-Survey (Januar bis April 2020) wurden die körperliche Aktivität und die berufsbezogene Lebensqualität (positive Dimension: Mitgefühlszufriedenheit; negative Dimension: Mitgefühlsmüdigkeit) einer Gelegenheitsstichprobe aus 443 klinisch tätigen Psycholog:innen mithilfe etablierter Selbstberichtfragebogen (International Physical Activity Questionnaire – Short Form [IPAQ-SF], Professional Quality of Life Scale [ProQOL]) erfasst.

Ergebnisse

Der Großteil der befragten Psycholog:innen erfüllte das von der Weltgesundheitsorganisation empfohlene Mindestmaß an körperlicher Aktivität. Die Mitgefühlszufriedenheit war im Schnitt relativ hoch, während eher geringe bis moderate Ausprägungen an Burn-out-Symptomatik sowie sekundärem traumatischem Stress (Facetten der Mitgefühlsmüdigkeit) berichtet wurden. Außer vereinzelten kleinen negativen Korrelationen zwischen körperlicher Inaktivität und Mitgefühlszufriedenheit bei Psycholog:innen in Weiterbildung sowie Burn-out-Symptomen und körperlicher Gesamtaktivität bei Psychologischen Psychotherapeut:innen waren keine Zusammenhänge zwischen körperlicher Aktivität und berufsbezogener Lebensqualität ersichtlich.

Schlussfolgerungen

Psycholog:innen scheinen zu großen Teilen eine körperlich aktive und tendenziell zufriedene Berufsgruppe darzustellen. Zusammenhänge zwischen körperlicher Aktivität und Lebensqualität könnten teilweise durch Deckeneffekte verdeckt sein. Des Weiteren könnte eine Analyse der Ursachen für diese adaptiven Ausprägungen in Aktivität und Lebensqualität Anhaltspunkte für Maßnahmen zur Förderung anderer Professionen liefern.
Ein Simulationsmodell zur Erfassung von Abflussrisiken in der Landwirtschaft
Authors: Wendland S. , Hankers B. , Bock M. , Böhner J. , Squar J. , Lembrich D. , Conrad O.
Published: February 2023

Digitale Informationstechniken gewinnen zunehmend an Bedeutung für Optimierungsstrategien in der landwirtschaftlichen Produktion, wobei einer Gewinnmaximierung die Minimierung kritischer Umweltwirkungen z. B. durch Oberflächenabfluss und Bodenerosion gegenübersteht. Mit dem hier vorgestellten Simulationsmodell lassen sich die an den Oberflächenabfluss gekoppelten Risiken der Stoffverlagerung räumlich explizit für frei wählbare Szenarien bezüglich der Niederschlagsmenge, Bodenwasseraufsättigung, Feldfrucht und verschiedenen Minderungsmaßnahmen abschätzen. Die Modellimplementierung erfolgte auf Basis der freien GIS Software SAGA, die federführend an der Universität Hamburg entwickelt wird. Die Konfiguration und operationelle Ausführung des Modells erfolgt typischerweise in einer Python Umgebung. Deutschlandweit prozessierte Simulationsergebnisse für repräsentative Szenarien mit einer räumlichen Auflösung von 10 m werden von der Geoinformationsdienst GmbH über eine Web-GIS Anwendung für Kunden bereitgestellt.
Comparison of plug-based versus suture-based vascular closure for large-bore arterial access: a collaborative meta-analysis of observational and randomized studies
Authors: Dumpies Oliver , Jobs Alexander , Obradovic Danilo , van Wiechen Maarten , Hartung Philipp , Rotta detto Loria Johannes , Wilde Johannes , Majunke Nicolas , Kiefer Philipp , Noack Thilo , Thiele Holger , van Mieghem Nicolas , Desch Steffen , Abdel-Wahab Mohamed
Published: February 2023

Background

Large-bore arteriotomies can be percutaneously closed with suture-based or plug-based vascular closure device (VCD) strategies. The efficacy of both techniques remains controversial.

Aims

We conducted a meta-analysis of comparative studies between both VCD strategies, focusing on the most commonly applied VCDs (MANTA and ProGlide).

Methods

We searched MEDLINE, the Cochrane Central Register of Controlled Trials and Google scholar for observational studies (OS) and randomized controlled trials (RCT) comparing vascular closure with the MANTA-based and the ProGlide-based technique. The principal endpoint of this analysis was access-site related vascular complications. Both study types were analyzed separately.

Results

Access-site related vascular complications were less frequent after vascular closure with the MANTA technique in the analysis of OS (RR 0.61 [95%CI 0.43–0.89], p = 0.01, I2 = 0%), but more frequent in the analysis of RCT data (RR 1.70 [95%CI 1.16–2.51], p = 0.01, I2 = 0%). Both data sets provided no significant difference between the VCD techniques in terms of overall bleeding events (OS: RR 0.57 [95%CI 0.32–1.02], p = 0.06, I2 = 70%; and RCT: RR 1.37 [95%CI 0.82–2.28], p = 0.23, I2 = 30%). RCT data showed that endovascular stenting or vascular surgery due to VCD failure occurred more often after MANTA application (RR 3.53 [95%CI 1.07–11.33], p = 0.04, I2 = 0%).

Conclusions

While OS point to favorable outcomes for large-bore vascular closure with the MANTA-based technique, RCT data show that this strategy is associated with more access-site related vascular complications as well as endovascular stenting or vascular surgery due to device failure compared with the ProGlide-based technique.

Graphical abstract
Systematic review to estimate the prevalence of inflammatory rheumatic diseases in Germany
Authors: Albrecht Katinka , Binder Sebastian , Minden Kirsten , Poddubnyy Denis , Regierer Anne C. , Strangfeld Anja , Callhoff Johanna
Published: February 2023

Objective

This study aimed to update the prevalence estimates of inflammatory rheumatic diseases (IRD) in Germany.

Methods

A systematic literature search in PubMed and Web of Science (last search 08 November 2022) identified original articles (regional and nationwide surveys and claims data analyses for arthritides, connective tissue diseases, and vasculitides) on prevalences for the period 2014–2022. Data sources, collection period, case definition, and risk of bias are reported. Prevalences were estimated from available national data, with consideration of international data.

Results

Screening by two authors yielded 263 hits, of which 18 claims data analyses and 2 surveys met the inclusion criteria. Prevalences ranged from 0.42 to 1.85% (rheumatoid arthritis), 0.32–0.5% (ankylosing spondylitis), 0.11–0.32% (psoriatic arthritis), 0.037–0.14% (systemic lupus erythematosus), 0.07–0.77% (Sjögren’s disease/sicca syndrome), 0.14–0.15% (polymyalgia rheumatica, ≥ 40 years), 0.04–0.05% (giant cell arteritis, ≥ 50 years), and 0.015–0.026% (ANCA-associated vasculitis). The risk of bias was moderate in 13 and high in 7 studies. Based on the results, we estimate the prevalence of IRD in Germany to be 2.2–3.0%, which corresponds to approximately 1.5–2.1 million affected individuals. The prevalence of juvenile idiopathic arthritis was reported to be around 0.10% (0.07–0.10%) of 0–18-year-olds, corresponding to about 14,000 children and adolescents in Germany.

Conclusion

This systematic review shows an increase in the prevalence of IRD in Germany, which is almost exclusively based on claims data analyses. In the absence of multistage population studies, the available data are, overall, uncertain sources for prevalence estimates, with a moderate to high risk of bias.
Periprosthetic knee infection in octogenarians: a single institution experience at midterm outcome
Authors: Karczewski Daniel , Schönnagel Lukas , Hipfl Christian , Akgün Doruk , Hardt Sebastian
Published: February 2023

Purpose

Periprosthetic joint infections (PJI) of total knee arthroplasties (TKAs) in the elderly is among the clinically most challenging scenarios given multimorbidity combined with poor bone and soft tissue quality. Despite increasing prevalence, limited is known on PJI among this unique group of patients. As such, this study analyzed PJI characteristics, implant survivorship and non-surgical complications of octogenarians revised PJI for the knee.

Methods

We identified 31 patients that were revised for PJIs of the knee between 2010 and 2019 using a single university-based registry. Mean age was 83 years (range 80–87), 48% were females, and mean BMI was 29 kg/m2. Mean age adjusted Charlson Comorbidity Index was 7, and mean ASA score was 3. Major causative pathogens included Coagulase-negative Staphylococci (26%), Staphylococcus aureus (13%), and Streptococci (13%). Two-stage exchange was performed in 30 patients, permanent resection arthroplasty in one joint. Kaplan–Meier survivorship analyses were performed. Mean follow-up was 4 years.

Results

The 2-year survivorship free of any recurrent PJI was 96%, and there was one PJI relapse noted at 6 months. Moreover, there were three additional revisions for aseptic loosening, and one further revision for fracture. As such, the 2-year survivorship free of any revision was 87%. In addition to the aforementioned revisions, there was one additional plate osteosynthesis for a Vancouver C fracture, resulting in a 79% survivorship free of any reoperation at 2 years. Mean perioperative complication score according to the Clavien–Dindo classification was 2 out of 5. A total of three patients died: one patient 40 days after resection arthroplasty, two others 4 months and 8 months after reimplantation.

Conclusions

Octogenarians revised for PJI of the knee are at low risk of recurrent infection and overall revision at 2 years. However, moderate rates of perioperative complications and mortality at short term must acknowledge before deciding upon procedure.

Level of evidence

Therapeutic level IV.
Vitamin C transporter SVCT1 serves a physiological role as a urate importer: functional analyses and in vivo investigations
Authors: Toyoda Yu , Miyata Hiroshi , Uchida Naohiro , Morimoto Keito , Shigesawa Ryuichiro , Kassai Hidetoshi , Nakao Kazuki , Tomioka Naoko H. , Matsuo Hirotaka , Ichida Kimiyoshi , Hosoyamada Makoto , Aiba Atsu , Suzuki Hiroshi , Takada Tappei
Published: February 2023

Uric acid, the end product of purine metabolism in humans, is crucial because of its anti-oxidant activity and a causal relationship with hyperuricemia and gout. Several physiologically important urate transporters regulate this water-soluble metabolite in the human body; however, the existence of latent transporters has been suggested in the literature. We focused on the Escherichia coli urate transporter YgfU, a nucleobase-ascorbate transporter (NAT) family member, to address this issue. Only SLC23A proteins are members of the NAT family in humans. Based on the amino acid sequence similarity to YgfU, we hypothesized that SLC23A1, also known as sodium-dependent vitamin C transporter 1 (SVCT1), might be a urate transporter. First, we identified human SVCT1 and mouse Svct1 as sodium-dependent low-affinity/high-capacity urate transporters using mammalian cell-based transport assays. Next, using the CRISPR-Cas9 system followed by the crossing of mice, we generated Svct1 knockout mice lacking both urate transporter 1 and uricase. In the hyperuricemic mice model, serum urate levels were lower than controls, suggesting that Svct1 disruption could reduce serum urate. Given that Svct1 physiologically functions as a renal vitamin C re-absorber, it could also be involved in urate re-uptake from urine, though additional studies are required to obtain deeper insights into the underlying mechanisms. Our findings regarding the dual-substrate specificity of SVCT1 expand the understanding of urate handling systems and functional evolutionary changes in NAT family proteins.
Predictors of favorable outcome after pyloroplasty for gastroparesis: should response to pyloric dilation or Botox injection be used as a marker of surgical outcome?
Authors: Eriksson Sven E. , Zheng Ping , Morton Scott , Maurer Nicole , Hoppo Toshitaka , Jobe Blair A. , Ayazi Shahin
Published: February 2023

Introduction

Pyloroplasty and gastric peroral endoscopic myotomy (G-POEM) are effective surgeries for gastroparesis. The primary aim of this study was to evaluate outcomes of pyloroplasty and G-POEM in patients with gastroparesis and determine factors associated with favorable outcome. The secondary aim was to assess the utility of clinical response to preoperative pyloric dilation or botulinum toxin injection (Botox) on surgical outcome, a factor conventionally used as a favorable marker.

Methods

There were 204 patients who underwent pyloroplasty (n = 177) or G-POEM (n = 27) for gastroparesis at our institution from 2014 to 2021. Demographic and clinical parameters were analyzed to assess their impact on surgical outcome. A subgroup of patients who had pyloric dilation or Botox injection were assessed separately. Favorable outcome was defined as patient reported complete resolution of the predominant gastroparesis symptom.

Results

Favorable outcome was achieved in 78.4% of patients (pyloroplasty: 79.7% and G-POEM: 70.4%, p = 0.274). Among 61 patients where pre- and postoperative gastric emptying studies (GES) were available, mean 4-hour retention significantly improved from 33.5 to 15.0% (p < 0.001) and 77.0% of patients achieved normalization.

Favorable outcome was not significantly impacted by etiology of gastroparesis (p = 0.120), GERD (p = 0.518), or primary gastroparesis symptom (p = 0.244). Age ≥ 40 was a significant predictor of favorable surgical outcome on multivariate analysis [OR: 2.476 (1.224–5.008), p = 0.012]. Among the patients who had preoperative dilation (n = 82) or Botox injection (n = 46), response to these interventions was not a predictor of favorable surgical outcome (p = 0.192 and 0.979, respectively). However, preoperative Botox injection, regardless of response to injection, was associated with favorable surgical outcome [OR: 3.205 (CI 1.105–9.299), p = 0.032].

Conclusion

Symptomatic improvement after pyloroplasty or G-POEM is independent of etiology of gastroparesis, GERD, and primary symptom. Response to dilation or Botox are not markers of response to surgery. However, patients who receive Botox are 3.2 times more likely to improve postoperatively.

Graphical abstract