bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and 3-month follow-up of cerebrovascular MRI markers in hospitalized COVID-19 patients: the CORONIS study
Authors: van Lith Theresa J. , Sluis Wouter M. , Wijers Naomi T. , Meijer Frederick J.A. , Ulzen Karin Kamphuis-van , de Bresser Jeroen , Dankbaar Jan Willem , de Mast Quirijn , Klok Frederikus A. , Cannegieter Suzanne C. , Wermer Marieke J. H. , Huisman Menno V. , Tuladhar Anil M. , van der Worp H. Bart , de Leeuw Frank-Erik
Published: July 2024

Purpose

To investigate the prevalence of cerebrovascular MRI markers in unselected patients hospitalized for COVID-19 (Coronavirus disease 2019), we compared these with healthy controls without previous SARS-CoV-2 infection or hospitalization and subsequently, investigated longitudinal (incidental) lesions in patients after three months.

Methods

CORONIS (CORONavirus and Ischemic Stroke) was an observational cohort study in adult hospitalized patients for COVID-19 and controls without COVID-19, conducted between April 2021 and September 2022. Brain MRI was performed shortly after discharge and after 3 months. Outcomes included recent ischemic (DWI-positive) lesions, previous infarction, microbleeds, white matter hyperintensities (WMH) and intracerebral hemorrhage and were analysed with logistic regression to adjust for confounders.

Results

125 patients with COVID-19 and 47 controls underwent brain MRI a median of 41.5 days after symptom onset. DWI-positive lesions were found in one patient (1%) and in one (2%) control, both clinically silent. WMH were more prevalent in patients (78%) than in controls (62%) (adjusted OR: 2.95 [95% CI: 1.07–8.57]), other cerebrovascular MRI markers did not differ. Prevalence of markers in ICU vs. non-ICU patients was similar. After three months, five patients (5%) had new cerebrovascular lesions, including DWI-positive lesions (1 patient, 1.0%), cerebral infarction (2 patients, 2.0%) and microbleeds (3 patients, 3.1%).

Conclusion

Overall, we found no higher prevalence of cerebrovascular markers in unselected hospitalized COVID-19 patients compared to controls. The few incident DWI-lesions were most likely to be explained by risk-factors of small vessel disease. In the general hospitalized COVID-19 population, COVID-19 shows limited impact on cerebrovascular MRI markers shortly after hospitalization.
Numerical and Thermal Response of the Bacterivorous Ciliate Colpidium kleini, a Species Potentially at Risk of Extinction by Rising Water Temperatures
Authors: Weisse Thomas , Pröschold Thomas , Kammerlander Barbara , Sonntag Bettina , Schicker Laura
Published: July 2024

We investigated the food-dependent growth and thermal response of the freshwater ciliate Colpidium kleini using numerical response (NR) experiments. This bacterivorous ciliate occurs in lotic water and the pelagial of lakes and ponds. The C. kleini strain used in this work was isolated from a small alpine lake and identified by combining detailed morphological inspections with molecular phylogeny. Specific growth rates (rmax) were measured from 5 to 21 °C. The ciliate did not survive at 22 °C. The threshold bacterial food levels (0.3 − 2.2 × 106 bacterial cells mL−1) matched the bacterial abundance in the alpine lake from which C. kleini was isolated. The food threshold was notably lower than previously reported for C. kleini and two other Colpidium species. The threshold was similar to levels reported for oligotrich and choreotrich ciliates if expressed in terms of bacterial biomass (0.05 − 0.43 mg C L−1). From the NR results, we calculated physiological mortality rates at zero food concentration. The mean mortality (0.55 ± 0.17 d−1) of C. kleini was close to the mean estimate obtained for other planktonic ciliates that do not encyst. We used the data obtained by the NR experiments to fit a thermal performance curve (TPC). The TPC yielded a temperature optimum at 17.3 °C for C. kleini, a maximum upper thermal tolerance limit of 21.9 °C, and a thermal safety margin of 4.6 °C. We demonstrated that combining NR with TPC analysis is a powerful tool to predict better a species’ fitness in response to temperature and food.
Engineered polyethylene terephthalate hydrolases: perspectives and limits
Authors: Kawai Fusako , Iizuka Ryo , Kawabata Takeshi
Published: July 2024

Polyethylene terephthalate (PET) is a major component of plastic waste. Enzymatic PET hydrolysis is the most ecofriendly recycling technology. The biorecycling of PET waste requires the complete depolymerization of PET to terephthalate and ethylene glycol. The history of enzymatic PET depolymerization has revealed two critical issues for the industrial depolymerization of PET: industrially available PET hydrolases and pretreatment of PET waste to make it susceptible to full enzymatic hydrolysis. As none of the wild-type enzymes can satisfy the requirements for industrialization, various mutational improvements have been performed, through classical technology to state-of-the-art computational/machine-learning technology. Recent engineering studies on PET hydrolases have brought a new insight that flexibility of the substrate-binding groove may improve the efficiency of PET hydrolysis while maintaining sufficient thermostability, although the previous studies focused only on enzymatic thermostability above the glass transition temperature of PET. Industrial biorecycling of PET waste is scheduled to be implemented, using micronized amorphous PET. Next stage must be the development of PET hydrolases that can efficiently degrade crystalline parts of PET and expansion of target PET materials, not only bottles but also textiles, packages, and microplastics. This review discusses the current status of PET hydrolases, their potential applications, and their profespectal goals.

Key points

• PET hydrolases must be thermophilic, but their operation must be below 70 °C

• Classical and state-of-the-art engineering approaches are useful for PET hydrolases

• Enzyme activity on crystalline PET is most expected for future PET biorecycling

Graphical Abstract
Halophilic archaea as tools for bioremediation technologies
Authors: Martínez-Espinosa Rosa María
Published: July 2024

Haloarchaea are extremophilic microorganisms belonging to the Archaea domain that require high salt concentrations to be alive, thus inhabiting ecosystems like salty ponds, salty marshes, or extremely salty lagoons. They are more abundantly and widely distributed worldwide than initially expected. Most of them are grouped into two families: Halobacteriaceae and Haloferacaceae. The extreme conditions under which haloarchaea survive contribute to their metabolic and molecular adaptations, thus making them good candidates for the design of bioremediation strategies to treat brines, salty water, and saline soils contaminated with toxic compounds such as nitrate, nitrite, oxychlorates such as perchlorate and chlorate, heavy metals, hydrocarbons, and aromatic compounds. New advances in understanding haloarchaea physiology, metabolism, biochemistry, and molecular biology suggest that biochemical pathways related to nitrogen and carbon, metals, hydrocarbons, or aromatic compounds can be used for bioremediation proposals. This review analyses the novelty of the most recent results showing the capability of some haloarchaeal species to assimilate, modify, or degrade toxic compounds for most living beings. Several examples of the role of these microorganisms in the treatment of polluted brine or salty soils are also discussed in connection with circular economy-based processes.

Key points

• Haloarchaea are extremophilic microorganisms showing genuine metabolism

• Haloarchaea can metabolise compounds that are highly toxic to most living beings

• These metabolic capabilities are useful for designing soil and water bioremediation strategies
Long-term responders to nivolumab in previously treated advanced renal cell carcinoma: a sub-analysis of meet-URO15 study
Authors: Messina Carlo , Catalano Martina , Roviello Giandomenico , Gandini Annalice , Maruzzo Marco , De Giorgi Ugo , Pedrazzoli Paolo , Sbrana Andrea , Zucal Paolo Andrea , Masini Cristina , Naglieri Emanuele , Procopio Giuseppe , Milella Michele , Catalano Fabio , Fratino Lucia , Pipitone Stefania , Ricotta Riccardo , Panni Stefano , Mollica Veronica , Soraru Mariella , Prati Veronica , Atzori Francesco , Di Napoli Marilena , Messina Marco , Morelli Franco , Prati Giuseppe , Nole Franco , Malgeri Andrea , Tudini Marianna , Vignani Francesca , Cavo Alessia , Signori Alessio , Banna Giuseppe Luigi , Rescigno Pasquale , Buti Sebastiano , Rebuzzi Sara Elena , Fornarini Giuseppe
Published: July 2024

Background

Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment.

Materials and methods

A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses.

Results

A total of 571 patients with a median age of 61 years (range 17–85) were included in the analysis. With a median follow-up of 22.1 (1.0–89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders.

Conclusion

This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy.
In vitro CAR-T cell killing: validation of the potency assay
Authors: Piccinini Claudia , Carloni Silvia , Arienti Chiara , Pancisi Elena , Fanini Francesca , Pignatta Sara , Soldati Valentina , Stefanelli Monica , Granato Anna Maria , Martinelli Giovanni , Ridolfi Laura , Petrini Massimiliano
Published: July 2024

For advanced therapy medicinal products, the development and validation of potency assays are required, in accordance with international guidelines, to characterise the product and obtain reliable and consistent data. Our purpose was to validate the killing assay for the evaluation of autologous anti-CD19 chimeric antigen receptor (CAR) T potency. We used CD4 + and CD8 + lymphocytes or anti-CD19 CAR-T cells as effector cells and REH (CD19 +) or MOLM-13 (CD19 −) cell lines as target cells. After co-culturing target and effector cells (1:1 ratio) for 24 h, samples were labelled with 7-AAD, anti-CD3 and anti-CD19 antibodies and the frequency of CD19 + dead cells was evaluated by flow cytometry. In order to verify the CAR-T specificity for the CD19 + target, the co-culture between CAR-T and REH or MOLM-13 at different effector-to-target ratios was scheduled. Moreover, not transduced CD4 + and CD8 + lymphocytes were tested in comparison with CAR-T from the same donor to demonstrate the assay specificity. Linearity and accuracy were evaluated, and established acceptance criteria were compiled for both parameters (r2 ≥ 0.97 for linearity and average relative error ≤ 10% for accuracy). Furthermore, the method was considered robust when performed between 23 and 25 h of co-culture, and the intra-assay, inter-assay and inter-day precision was obtained. Finally, in order to verify the inter-analyst precision, the test was executed by three different operators and the intra-class correlation coefficient was > 0.4 in both cases. In conclusion, we consider this CAR-T potency assay as validated and usable in all steps of product development and quality control.
Monocyte infiltration is an independent positive prognostic biomarker in vulvar squamous cell carcinoma
Authors: Abdulrahman Ziena , Kortekaas Kim E. , Welters Marij J. P. , van Poelgeest Mariette I. E. , van der Burg Sjoerd H.
Published: July 2024

Background

Vulvar squamous cell carcinoma (VSCC) arises after an HPV infection or the mutation of p53 or other driver genes and is treated by mutilating surgery and/or (chemo) radiation, with limited success and high morbidity. In-depth information on the immunological make up of VSCC is pivotal to assess whether immunotherapy may form an alternative treatment.

Methods

A total of 104 patient samples, comprising healthy vulva (n = 27) and VSCC (n = 77), were analyzed. Multispectral immunofluorescence (15 markers) was used to study both the myeloid and lymphoid immune cell composition, and this was linked to differences in transcriptomics (NanoString nCounter, 1258 genes) and in survival (Kaplan–Meier analyses).

Results

Healthy vulva and VSCC are both well infiltrated but with different subpopulations of lymphoid and myeloid cells. In contrast to the lymphoid cell infiltrate, the density and composition of the myeloid cell infiltrate strongly differed per VSCC molecular subtype. A relative strong infiltration with epithelial monocytes (HLADR−CD11c−CD14+CD68−CD163−CD33−) was prognostic for improved survival, independent of T cell infiltration, disease stage or molecular subtype. A strong infiltration with T cells and/or monocytes was associated with drastic superior survival: 5-year survival > 90% when either one is high, versus 40% when both are low (p < 0.001).

Conclusion

A hot myeloid and/or lymphoid infiltrate predicts excellent survival in VSCC. Based on the response of similarly high-infiltrated other tumor types, we have started to explore the potential of neoadjuvant checkpoint blockade in VSCC.
Systemic delivery of oncolytic herpes virus using CAR-T cells enhances targeting of antitumor immuno-virotherapy
Authors: Zhang Zongliang , Yang Nian , Xu Long , Lu Huaqing , Chen Yongdong , Wang Zeng , Lu Qizhong , Zhong Kunhong , Zhu Zhixiong , Wang Guoqing , Li Hexian , Zheng Meijun , Zhou Liangxue , Tong Aiping
Published: July 2024

Recent studies have indicated that combining oncolytic viruses with CAR-T cells in therapy has shown superior anti-tumor effects, representing a promising approach. Nonetheless, the localized delivery method of intratumoral injection poses challenges for treating metastatic tumors or distal tumors that are difficult to reach. To address this obstacle, we employed HSV-1-infected CAR-T cells, which systemically delivery HSV into solid tumors. The biological function of CAR-T cells remained intact after loading them with HSV for a period of three days. In both immunocompromised and immunocompetent GBM orthotopic mouse models, B7-H3 CAR-T cells effectively delivered HSV to tumor lesions, resulting in enhanced T-cell infiltration and significantly prolonged survival in mice. We also employed a bilateral subcutaneous tumor model and observed that the group receiving intratumoral virus injection exhibited a significant reduction in tumor volume on the injected side, while the group receiving intravenous infusion of CAR-T cells carrying HSV displayed suppressed tumor growth on both sides. Hence, CAR-THSV cells offer notable advantages in the systemic delivery of HSV to distant tumors. In conclusion, our findings emphasize the potential of CAR-T cells as carriers for HSV, presenting significant advantages for oncolytic virotherapy targeting distant tumors.
γδ T cells in human colon adenocarcinomas comprise mainly Vδ1, Vδ2, and Vδ3 cells with distinct phenotype and function
Authors: Rodin William , Szeponik Louis , Rangelova Tsvetanka , Tamiru Kebede Firaol , Österlund Tobias , Sundström Patrik , Hogg Stephen , Wettergren Yvonne , Cosma Antonio , Ståhlberg Anders , Bexe Lindskog Elinor , Quiding Järbrink Marianne
Published: July 2024

Γδ T cell infiltration into tumours usually correlates with improved patient outcome, but both tumour-promoting and tumoricidal effects of γδ T cells have been documented. Human γδ T cells can be divided into functionally distinct subsets based on T cell receptor (TCR) Vδ usage. Still, the contribution of these different subsets to tumour immunity remains elusive. Here, we provide a detailed γδ T cell profiling in colon tumours, using mass and flow cytometry, mRNA quantification, and TCR sequencing. δ chain usage in both the macroscopically unaffected colon mucosa and tumours varied considerably between patients, with substantial fractions of Vδ1, Vδ2, and non-Vδ1 Vδ2 cells. Sequencing of the Vδ complementarity-determining region 3 showed that almost all non-Vδ1 Vδ2 cells used Vδ3 and that tumour-infiltrating γδ clonotypes were unique for every patient. Non-Vδ1Vδ2 cells from colon tumours expressed several activation markers but few NK cell receptors and exhaustion markers. In addition, mRNA analyses showed that non-Vδ1 Vδ2 cells expressed several genes for proteins with tumour-promoting functions, such as neutrophil-recruiting chemokines, Galectin 3, and transforming growth factor-beta induced. In summary, our results show a large variation in γδ T cell subsets between individual tumours, and that Vδ3 cells make up a substantial proportion of γδ T cells in colon tumours. We suggest that individual γδ T cell composition in colon tumours may contribute to the balance between favourable and adverse immune responses, and thereby also patient outcome.
Engineered CD147-CAR macrophages for enhanced phagocytosis of cancers
Authors: Chupradit Koollawat , Muneekaew Saitong , Wattanapanitch Methichit
Published: July 2024

Chimeric antigen receptor (CAR) T cell therapy has shown promising results in hematologic malignancies, but its effectiveness in solid cancers remains challenging. Macrophages are immune cells residing within the tumor microenvironment. They can phagocytose tumor cells. Recently, CAR macrophages (CAR-M) have been a promising candidate for treating solid cancers. One of the common cancer antigens overexpressed in various types of cancer is CD147. CAR-T and NK cells targeting CD147 antigen have shown significant efficacy against hepatocellular carcinoma. Nevertheless, CAR-M targeting the CD147 molecule has not been investigated. In this study, we generated CAR targeting the CD147 molecule using the THP-1 monocytic cell line (CD147 CAR-M). The CD147 CAR-M exhibited typical macrophage characteristics, including phagocytosis of zymosan bioparticles and polarization ability toward M1 and M2 phenotypes. Furthermore, the CD147 CAR-M demonstrated enhanced anti-tumor activity against K562 and MDA-MB-231 cells without exhibiting off-target cytotoxicity against normal cells. Our research provides valuable insights into the potential of CD147 CAR-M as a promising platform for cancer immunotherapy, with applications in both hematologic malignancies and solid cancers.

Graphical abstract
Spatial Variation in Agricultural BMPs and Relationships with Nutrient Yields Across New York State Watersheds
Authors: Schewe Rebecca , Iavorivska Lidiia , Kelleher Christa
Published: July 2024

Agricultural nutrients nitrogen and phosphorus can subsequently be transported to waterways and are often managed through the adoption of best management practices (BMPs). However, we have a poor understanding of how the use of BMPs varies spatially and how BMP adoption might be related to nutrient yields in surface waters. To address this, we performed a survey of agricultural landowners across New York State and compared this with estimates of annual incremental nitrogen and phosphorus yields of agricultural origin from the Spatially Referenced Regressions On Watershed attributes (SPARROW) model. Using these socio-behavioral data and SPARROW predictions, we perform colocation analysis to identify areas where watersheds with high nutrient yield from agriculture are collocated with non-use of agricultural BMPs. This colocation analysis offers a novel methodology for identifying areas where monitoring of waterways and promotion of best management practices could be targeted to achieve the greatest benefits.
A sub-pharmacological test dose does not predict individual docetaxel exposure in prostate cancer patients
Authors: Heerma van Voss Marise R , Notohardjo Jessica , van Dodewaard-de Jong Joyce , Bloemendal Haiko J , ter Heine Rob
Published: July 2024

Purpose

Docetaxel is a cytotoxic drug used for first-line treatment of various malignancies. It has a narrow therapeutic index and shows wide interpatient variability in clearance and toxicity. Tools for individual dose optimization are needed to maximize efficacy and avoid toxicity.

Methods

We performed a proof-of-concept study (EudraCT 2016-003785-77) to evaluate whether pharmacokinetics after a sub-pharmacological test dose of 1000 µg docetaxel (millidose) could be used to predict therapeutic dose exposure. Thirty prostate cancer patients eligible for treatment with docetaxel as part of routine clinical care were included. An intravenous docetaxel millidose was administered 1–7 days prior to therapeutic docetaxel. After both doses plasma docetaxel concentrations were measured by ultra- high performance liquid chromatography-tandem mass spectrometry. The docetaxel clearance was estimated with non-linear mixed effects modeling.

Results

Geometric mean docetaxel clearance was 57.9 L/h (GCV 78.6%) after admission of a millidose and 40.3 L/h (GCV 60.7%) after admission of a therapeutic dose. The millidose and therapeutic dose in a single patient were not significantly correlated (Spearman’s rho R = 0.02, P = 0.92).

Conclusion

Docetaxel pharmacokinetics at milli- and therapeutic dose level showed insufficient correlation for individual dose optimization. However, the clearance of a docetaxel millidose and full dose are within the same order of magnitude. Therefore, docetaxel millidose pharmacokinetics could potentially facilitate prediction of docetaxel pharmacokinetics at a population level in situations where therapeutic dose levels are impractical, such as pharmacokinetic drug-drug interaction studies or pediatric studies.
The persistence of bipartite ecological communities with Lotka–Volterra dynamics
Authors: Dopson Matt , Emary Clive
Published: July 2024

The assembly and persistence of ecological communities can be understood as the result of the interaction and migration of species. Here we study a single community subject to migration from a species pool in which inter-specific interactions are organised according to a bipartite network. Considering the dynamics of species abundances to be governed by generalised Lotka–Volterra equations, we extend work on unipartite networks to we derive exact results for the phase diagram of this model. Focusing on antagonistic interactions, we describe factors that influence the persistence of the two guilds, locate transitions to multiple-attractor and unbounded phases, as well as identifying a region of parameter space in which consumers are essentially absent in the local community.
Decision support for prioritizing critical societal services in optimal post-disaster critical lifeline recovery
Authors: Shahverdi Bahar , Miller-Hooks Elise , Isaac Shabtai
Published: July 2024

Critical societal services, such as health care, education, law enforcement, and emergency response, are key to societal well-being and safety. Disruption to these services may arise from direct damage to the buildings from which the services are provided, or indirectly as a consequence of damage to supporting lifelines. The order in which lifeline elements are restored post-disaster affects not only the timing for restoring the lifeline services to its customers, but also the timing for restoring critical services that rely on these lifelines. In this paper, a mathematical formulation of the problem of prioritizing critical societal services in lifeline service restoration treated by multiple, specialized crews and exact algorithmic approach for its solution are proposed. Two approaches to accelerate the solution algorithm for use in realistic settings, where efficiency and scalability are essential, are presented. The developed techniques can be embedded in a decision support tool for real-time application with real-time information. To illustrate the proposed modeling and solution methodology and assess its efficiency for large, complex multi-lifeline applications, numerical experiments were run on a synthetic yet real-world network involving three key lifelines, including power, water, and transportation, as well as two hospitals that rely on them. The analysis of this case study shows that cross-lifeline collaboration in prioritization and scheduling in restoration action affects not only the return of services from the individual lifelines, but also of critical services on which, particularly in disaster settings, lives may depend.
Complex Fluid Models of Mixed Quantum–Classical Dynamics
Authors: Gay-Balmaz François , Tronci Cesare
Published: July 2024

Several methods in nonadiabatic molecular dynamics are based on Madelung’s hydrodynamic description of nuclear motion, while the electronic component is treated as a finite-dimensional quantum system. In this context, the quantum potential leads to severe computational challenges and one often seeks to neglect its contribution, thereby approximating nuclear motion as classical. The resulting model couples classical hydrodynamics for the nuclei to the quantum motion of the electronic component, leading to the structure of a complex fluid system. This type of mixed quantum–classical fluid models has also appeared in solvation dynamics to describe the coupling between liquid solvents and the quantum solute molecule. While these approaches represent a promising direction, their mathematical structure requires a certain care. In some cases, challenging higher-order gradients make these equations hardly tractable. In other cases, these models are based on phase-space formulations that suffer from well-known consistency issues. Here, we present a new complex fluid system that resolves these difficulties. Unlike common approaches, the current system is obtained by applying the fluid closure at the level of the action principle of the original phase-space model. As a result, the system inherits a Hamiltonian structure and retains energy/momentum balance. After discussing some of its structural properties and dynamical invariants, we illustrate the model in the case of pure-dephasing dynamics. We conclude by presenting some invariant planar models.
„Klick“-Phänomen beim erworbenen Jaensch-Brown-Syndrom und schnellenden Finger/Daumen: dem Notta-Syndrom
Authors: Mühlendyck Hermann
Published: July 2024

Krankheitsbild

Zu einem „Klick-Phänomen“ kommt es beim forcierten Überwinden einer erworbenen mechanischen Einschränkung der Hebung in Adduktion beim Auge bzw. Strecken des Fingers/Daumens bei der Hand. Die gemeinsame Ursache ist ein Knoten: Beim Auge hinter der Trochlea; der Hand vor dem Ringband A1. Wobei es zu dem „Klick“ über den gleichen Pathomechanismus kommt.

Ergebnisse

Aufgrund dieser identischen Befunde beim Auge und der Hand kann bei kleinen Kindern angenommen werden, dass die durch Studien bei der Hand bei Neugeborenen und kleinen Kindern mit einem „Trigger thumb/finger“ gewonnenen Erkenntnisse auch auf die Situation beim Auge zutreffen: 1. Im frühen Kindesalter kommt es zu dieser Motilitätsstörung nicht kongenital. Hierzu kommt es höchstwahrscheinlich durch bei der Geburt noch nicht voll entwickelte Gleitverhältnisse, die für eine glatte Passage der Sehne durch die Trochlea/das Ringband A1 erforderlich sind. 2. Bei dieser Motilitätsstörung muss zwischen den Stadien 0–3 unterschieden werden: Stadium 0 = keine Einschränkung der Motilität und kein „Klick-Phänomen“ mehr; Stadium 1 = forciert aktiv; Stadium 2 = nur passiv Strecken/Hebung möglich – mit jeweils einem „Klick-Phänomen“; Stadium 3 = kein Strecken/Hebung möglich und kein „Klick-Phänomen“. 3. Bei den meisten frühkindlichen Fällen kommt es ohne Therapie (75 % nach 6 bis 7 Jahren) zu einer spontanen vollständigen Rückbildung: Was beim Auge nur begrenzt durch Motilitätsübungen in Kombination mit einer Sektorokklusion verkürzt werden kann.

Schlussfolgerung

Das „Klick-Phänomen“ ist ein Symptom beim Stadium 1 und 2 der erworbenen mechanischen Einschränkung der Hebung in Adduktion bzw. Strecken des Fingers/Daumens. Es ist kein „Syndrom“, nach dem diese Motilitätsstörung bezeichnet werden kann.
A New Look at the Dirichlet Distribution: Robustness, Clustering, and Both Together
Authors: Tomarchio Salvatore D. , Punzo Antonio , Ferreira Johannes T. , Bekker Andriette
Published: July 2024

Compositional data have peculiar characteristics that pose significant challenges to traditional statistical methods and models. Within this framework, we use a convenient mode parametrized Dirichlet distribution across multiple fields of statistics. In particular, we propose finite mixtures of unimodal Dirichlet (UD) distributions for model-based clustering and classification. Then, we introduce the contaminated UD (CUD) distribution, a heavy-tailed generalization of the UD distribution that allows for a more flexible tail behavior in the presence of atypical observations. Thirdly, we propose finite mixtures of CUD distributions to jointly account for the presence of clusters and atypical points in the data. Parameter estimation is carried out by directly maximizing the maximum likelihood or by using an expectation-maximization (EM) algorithm. Two analyses are conducted on simulated data to illustrate the effects of atypical observations on parameter estimation and data classification, and how our proposals address both aspects. Furthermore, two real datasets are investigated and the results obtained via our models are discussed.
Inference on Weibull inverted exponential distribution under progressive first-failure censoring with constant-stress partially accelerated life test
Authors: Fathi Abdullah , Farghal Al-Wageh A. , Soliman Ahmed A.
Published: July 2024

Accelerated life tests (ALTs) play a pivotal role in life testing experiments as they significantly reduce costs and testing time. Hence, this paper investigates the statistical inference issue for the Weibull inverted exponential distribution (WIED) under the progressive first-failure censoring (PFFC) data with the constant-stress partially ALT (CSPALT) under progressive first-failure censoring (PFFC) data for Weibull inverted exponential distribution (WIED). For classical inference, maximum likelihood (ML) estimates for both the parameters and the acceleration factor are derived. Making use of the Fisher information matrix (FIM), asymptotic confidence intervals (ACIs) are constructed for all parameters. Besides, two parametric bootstrap techniques are implemented. For Bayesian inference based on a proposed technique for eliciting the hyperparameters, the Markov chain Monte Carlo (MCMC) technique is provided to acquire Bayesian estimates. In this context, the Bayesian estimates are obtained under symmetric and asymmetric loss functions, and the corresponding credible intervals (CRIs) are constructed. A simulation study is carried out to assay the performance of the ML, bootstrap, and Bayesian estimates, as well as to compare the performance of the corresponding confidence intervals (CIs). Finally, real-life engineering data is analyzed for illustrative purposes.
Deal.t: an implementation of multivariate analysis suitable T-splines within the deal.ii framework
Authors: Beuchler Sven , Hiniborch Robin , Morgenstern Philipp
Published: July 2024

We present a numerical framework for solving partial differential equations within an isogeometric context using T-splines in two and three space dimensions. Within this paper, we explain the data structures used for the implementation of ( with T-splines) and main differences when using in contrast to . The authors present numerical experiments with error-based refinement (2D) and a priori refinement (3D) for scalar-valued problems. A full tutorial is given in the appendix. Since the new framework is based on , T-splines may be applied to various different PDEs.
Measurement of energy availability in highly trained male endurance athletes and examination of its associations with bone health and endocrine function
Authors: McGuire Amy , Warrington Giles , Walsh Adam , Byrne Thomas , Doyle Lorna
Published: July 2024

Purpose

Despite the introduction of Relative Energy Deficiency in Sport (RED-s) in 2014, there is evidence to suggest that male endurance athletes still present with a high prevalence of low energy availability (LEA). Previous findings suggest that energy availability (EA) status is strongly correlated with impairments in endocrine function such as reduced leptin, triiodothyronine (T3), and insulin, and elevated bone loss. This study aimed to report the current EA status, endocrine function and bone health of highly trained Irish male endurance athletes.

Methods

In this cross-sectional study, participants (n = 3 triathletes; n = 10 runners) completed a 7-day testing period during the competition season using lab-based measures, to ascertain EA status, hormone level and rates of bone metabolism. Serum blood samples were obtained to assess hormone levels and markers of bone metabolism.

Results

Mean EA was < 30 kcal/kg lean body mass (LBM)/day in 76.9% of athletes. There was a strong association between LEA and low carbohydrate intake, and lower LBM. Mean levels of insulin, IGF-1 and leptin were significantly lower than their reference ranges. Elevated mean concentrations of β-CTX and a mean P1NP: β-CTX ratio < 100, indicated a state of bone resorption.

Conclusion

The EA level, carbohydrate intake, hormone status and bone metabolism status of highly trained male endurance athletes are a concern. Based on the findings of this study, more frequent assessment of EA across a season is recommended to monitor the status of male endurance athletes, in conjunction with nutritional education specific to EA and the associated risks.
Nusinersen effectiveness and safety in pediatric patients with 5q-spinal muscular atrophy: a multi-center disease registry in China
Authors: Yao Xiaoli , Peng Jing , Luo Rong , Wang Xiuxia , Lu Xinguo , Wu Liwen , Jin Ruifeng , Zhong Jianmin , Liang Jianmin , Hong Siqi , Yang Lin , Zhang Xiaoli , Mao Shanshan , Hu Jun , Tao Zhe , Sun Dan , Wang Hua , Zhang Li , Xia Yanyan , Chen Ken , Wang Yi
Published: July 2024

Objective

To evaluate the effectiveness and safety of nusinersen for the treatment of 5q-spinal muscular atrophy (SMA) among Chinese pediatric patients.

Methods

Using a longitudinal, multi-center registry, both prospective and retrospective data were collected from pediatric patients with 5q-SMA receiving nusinersen treatment across 18 centers in China. All patients fulfilling the eligibility criteria were included consecutively. Motor function outcomes were assessed post-treatment by SMA type. Safety profile was evaluated among patients starting nusinersen treatment post-enrollment. Descriptive analyses were used to report baseline characteristics, effectiveness, and safety results.

Results

As of March 2nd, 2023, 385 patients were included. Most patients demonstrated improvements or stability in motor function across all SMA types. Type II patients demonstrated mean changes [95% confidence interval (CI)] of 4.4 (3.4–5.4) and 4.1 (2.8–5.4) in Hammersmith Functional Motor Scale-Expanded (HFMSE), and 2.4 (1.7–3.1) and 2.3 (1.2–3.4) in Revised Upper Limb Module (RULM) scores at months 6 and 10. Type III patients exhibited mean changes (95% CI) of 3.9 (2.5–5.3) and 4.3 (2.6–6.0) in HFMSE, and 2.1 (1.2–3.0) and 1.5 (0.0–3.0) in RULM scores at months 6 and 10. Of the 132 patients, 62.9% experienced adverse events (AEs). Two patients experienced mild AEs (aseptic meningitis and myalgia) considered to be related to nusinersen by the investigator, with no sequelae.

Conclusions

These data underscore the significance of nusinersen in Chinese pediatric patients with SMA regarding motor function improvement or stability, and support recommendations on nusinersen treatment by Chinese SMA guidelines and continuous coverage of nusinersen by basic medical insurance.
External validation of clinical risk prediction score for elderly treated with endovascular thrombectomy
Authors: Enriquez Brian Anthony B. , Skattør Thor Håkon , Laugesen Nicolaj Grønbæk , Truelsen Thomas , Lund Christian Georg , Nome Terje , Beyer Mona K. , Skjelland Mona , Aamodt Anne Hege
Published: July 2024

Background and aim

The thrombectomy in the elderly prediction score (TERPS) for functional outcome after anterior circulation endovascular therapy (EVT) in patients ≥ 80 years was recently developed. The aim of this study was to assess predictors of functional outcome in the elderly and validate the prediction model.

Methods

Consecutive patients treated with EVT from the Oslo Acute Reperfusion Stroke Study were evaluated for inclusion. Clinical and radiological parameters were used to calculate the TERPS, and functional outcome were assessed at 3-month follow-up.

Results

Out of 1028 patients who underwent EVT for acute ischemic stroke from January 2017 to July 2022, 218 (21.2%) patients ≥ 80 years with anterior ischemic stroke were included. Fair outcome, defined as modified Rankin scale ≤ 3 (mRS), was achieved in 117 (53.7%). In bivariate analyses, male sex (p 0.035), age (p 0.025), baseline National Institute of Health Stroke Scale (NIHSS, p < 0.001), pre-stroke mRS (p 0.002) and Alberta Stroke Program Early Computed Tomography score (ASPECTS, p 0.001) were associated with fair outcome. Significant predictors for fair outcome in regression analyses were lower pre-stroke mRS, adjusted odd ratio, (aOR) 0.67 (95% CI 0.50–0.91, p 0.01), NIHSS, aOR 0.92 (95% CI 0.87–0.97, p 0.002), and higher ASPECTS, aOR 1.22 (95% CI 1.03–1.44, p 0.023). The area under the curve (AUC) using TERPS was 0.74 (95% CI 0.67–0.80).

Conclusions

The risk prediction score TERPS showed moderate performance in this external validation. Other variables may still be included to improve the model and validation using other cohorts is recommended.

Trial registration

NCT06220981.
Impact of heat waves on human morbidity and hospital admissions in a city of the western mediterranean area
Authors: Bujosa Mateu Adrián , Alegre Latorre Luis , Comas María Villalonga , Salom Jaume , García Gasalla Mercedes , Planas Bibiloni Lluis , Orfila Timoner Jaime , Murillas Angoiti Javier
Published: July 2024

Purpose

The effect of heat waves on mortality is well known, but current evidence on morbidity is limited. Establishing the consequences of these events in terms of morbidity is important to ensure communities and health systems can adapt to them.

Methods

We thus collected data on total daily emergency hospital admissions, admissions to critical care units, emergency department admissions, and emergency admissions for specific diagnoses to Hospital Universitario de Son Espases from 1 January 2005 to 31 December 2021. A heat wave was defined as a period of ≥ 2 days with a maximum temperature ≥ 35 °C, including a 7 day lag effect (inclusive). We used a quasi-Poisson generalized linear model to estimate relative risks (RRs; 95%CI) for heat wave-related hospital admissions.

Results

Results showed statistically significant increases in total emergency admissions (RR 1.06; 95%CI 1 – 1.12), emergency department admissions (RR 1.12; 95%CI 1.07 – 1.18), and admissions for ischemic stroke (RR 1.26; 95%CI 1.02 – 1.54), acute kidney injury (RR 1.67; 95%CI 1.16 – 2.35), and heat stroke (RR 18.73, 95%CI 6.48 – 45.83) during heat waves.

Conclusion

Heat waves increase hospitalization risk, primarily for thromboembolic and renal diseases and heat strokes.
The diagnostic and prognostic role of cerebrospinal fluid biomarkers in glucose transporter 1 deficiency: a systematic review
Authors: Mastrangelo Mario , Manti Filippo , Ricciardi Giacomina , Cinnante Elisa Maria Colacino , Cameli Noemi , Beatrice Annachiara , Tolve Manuela , Pisani Francesco
Published: July 2024

The purpose of this study is to investigate the diagnostic and prognostic role of cerebrospinal fluid (CSF) biomarkers in the diagnostic work-up of glucose transporter 1 (GLUT1) deficiency. Reported here is a systematic review according to PRISMA guidelines collecting clinical and biochemical data about all published patients who underwent CSF analysis. Clinical phenotypes were compared between groups defined by the levels of CSF glucose (≤ 2.2 mmol/L versus > 2.2 mmol/L), CSF/blood glucose ratio (≤ 0.45 versus > 0.45), and CSF lactate (≤ 1 mmol/L versus > 1 mmol/L). Five hundred sixty-two patients fulfilled the inclusion criteria with a mean age at the diagnosis of 8.6 ± 6.7 years. Patients with CSF glucose ≤ 2.2 mmol/L and CSF/blood glucose ratio ≤ 0.45 presented with an earlier onset of symptoms (16.4 ± 22.0 versus 54.4 ± 45.9 months, p < 0.01; 15.7 ± 23.8 versus 40.9 ± 38.0 months, p < 0.01) and received an earlier molecular genetic confirmation (92.1 ± 72.8 versus 157.1 ± 106.2 months, p < 0.01). CSF glucose ≤ 2.2 mmol/L was consistently associated with response to ketogenic diet (p = 0.018) and antiseizure medications (p = 0.025). CSF/blood glucose ratio ≤ 0.45 was significantly associated with absence seizures (p = 0.048), paroxysmal exercise‐induced dyskinesia (p = 0.046), and intellectual disability (p = 0.016) while CSF lactate > 1 mmol/L was associated with a response to antiseizure medications (p = 0.026) but not to ketogenic diet.

Conclusions:This systematic review supported the diagnostic usefulness of lumbar puncture for the early identification of patients with GLUT1 deficiency responsive to treatments especially if they present with co-occurring epilepsy, movement, and neurodevelopmental disorders.

What is Known:

• Phenotypes of GLUT1 deficiency syndrome range between early epileptic and developmental encephalopathy to paroxysmal movement disorders and developmental impairment

What is New:

• CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with early onset absences

• CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with paroxysmal exercise induced dyskinesia and intellectual disability.

• CSF glucose may predict better than CSF blood/glucose and lactate the response to ketogenic diet and antiseizure medications.
Spatial distribution, pollution level and human health risk assessment of heavy metals in urban street dust at neighbourhood scale
Authors: Isinkaralar Oznur , Isinkaralar Kaan , Nguyen Tuyet Nam Thi
Published: July 2024

Urban street dust (UStD) is a vital issue for human health and is crucial for urban sustainability. This study aims to enhance the creation of safe, affordable, and resilient cities by examining environmental contamination and health risks in urban residential areas. Specifically, it investigates the concentrations and spatial distribution of chromium (Cr), cadmium (Cd), nickel (Ni), copper (Cu), lead (Pb), and zinc (Zn) in UStD in Yenimahalle, Ankara. The mean concentrations of Zn, Cr, Pb, Cd, Ni, and Cu in UStD were 97.98, 66.88, 55.22, 52.45, 38.37, and 3.81 mg/kg, respectively. The geoaccumulation pollution index (Igeo) values for these elements were: Cd (5.12), Ni (1.61), Cr (1.21), Pb (1.13), Cu (0.78), and Zn (0.24). These indices indicate that the area is moderately polluted with Cr, Pb, and Ni, uncontaminated to moderately contaminated with Cu and Zn, and extremely polluted with Cd. The hazard index (HI) values for Cr, Cd, Ni, Cu, Pb, and Zn were below the non-carcinogenic risk threshold for adults, indicating no significant risk. However, for children, the HI values for Pb, Ni, Cd, and Zn were 3.37, 1.80, 1.25, and 1.25, respectively, suggesting a higher risk. Carcinogenic risk (RI) of Cd, Ni, and Pb was significant for both children and adults, indicating that exposure through ingestion, inhalation, and dermal contact is hazardous. The findings highlight the need for strategic mitigation measures for both natural and anthropogenic activities, providing essential insights for residents, policymakers, stakeholders, and urban planners.
The impact of continuous lenalidomide maintenance treatment on people living with multiple myeloma—a single-centre, qualitative service evaluation study
Authors: Buck Caroline , Brenes Castillo Francisco , Bettio Elena , Land Joanne , McCourt Orla , Poole Helen , Tarling Rachel , Yong Kwee , Popat Rakesh , Lee Lydia , McMillan Annabel , Papanikolaou Xenofon , Xu Ke , Kyriakou Chara , Rabin Neil , Wechalekar Ashu , Fisher Abigail , Sive Jonathan
Published: July 2024

Purpose

Continuous lenalidomide maintenance treatment after autologous stem cell transplantation delivers improvement in progression free and overall survival among newly diagnosed multiple myeloma patients and has been the standard of care in the UK since March 2021. However, there is scant information about its impact on patients’ day-to-day lives. This service evaluation aimed to qualitatively assess patients receiving lenalidomide treatment at a cancer centre in London, in order that the service might better align with needs and expectations of patients.

Methods

We conducted 20 semi-structured interviews among myeloma patients who were on continuous lenalidomide maintenance treatment at a specialist cancer centre in London. Members of the clinical team identified potentially eligible participants to take part, and convenience sampling was used to select 10 male and 10 female patients, median age of 58 (range, 45–71). The median treatment duration was 11 months (range, 1–60 months). Participants were qualitatively interviewed following the same semi-structured interview guide, which was designed to explore patient experience and insights of lenalidomide. Reflexive thematic analysis was used for data analysis.

Results

Four overarching themes were as follows: (i) lenalidomide: understanding its role and rationale; (ii) reframing the loss of a treatment-free period to a return to normal life; (iii) the reality of being on lenalidomide: balancing hopes with hurdles; (iv) gratitude and grievances: exploring mixed perceptions of care and communication. Results will be used to enhance clinical services by tailoring communication to better meet patients’ preferences when making treatment decisions.

Conclusion

This study highlights that most patients feel gratitude for being offered continuous lenalidomide and perceive it as alleviating some fears concerning relapse. It reveals variations in side effects in different age groups; younger patients reported no/negligible side effects, whilst several older patients with comorbidities described significant symptom burden, occasionally leading to treatment discontinuation which caused distress at the perceived loss of prolonged remission. Future research should prioritise understanding the unique needs of younger patients living with multiple myeloma.