bluuebunny/crossref_metadata_2025 huggingface dataset:
Interventionell-radiologische Behandlung als Therapieoption bei blutendem Analkarzinom
Authors: Schöttes Sophia , Haneberg Henrika , Feyen Ludger
Published: June 2024

In dem hier beschriebenen Fall stellte sich ein 75-jähriger Patienten mit starken analen Blutungen vor, der neben einem Hämorrhoidalleiden vierten Grades auch ein inoperables Analkarzinom sowie kardiopulmonale Morbidität aufwies. Da die Behandlungsmöglichkeiten aufgrund des hohen perioperativen Risikos begrenzt waren, wurde in einem minimal-invasiven Eingriff eine Embolisation der Äste der A. anorectalis superior durchgeführt, durch welche die analen Blutungen stark reduziert werden konnten.
Psychotherapeutische Sprechstunde am Arbeitsplatz: Zusammenhänge zwischen Unternehmensgröße und psychosomatischer Gesundheit
Authors: Hander Nicole R. , Krohn Julia , Kohl Fiona , Heming Meike , Erim Yesim , Herold Regina , Kröger Christoph , Hansmann Marieke , Köllner Volker , Chrysanthou Sophia , Wegewitz Uta , Schröder Ute B. , Feißt Manuel , Herrmann Kristin , Rothermund Eva
Published: June 2024

Hintergrund

Die Inanspruchnahme der psychotherapeutischen Sprechstunde am Arbeitsplatz (PT-A) wurde bislang in Großunternehmen (GU) untersucht. Diese unterscheiden sich strukturell von mittleren und Klein(st)unternehmen (KMU). Unterschiede der Nutzerprofile einer PT‑A hinsichtlich psychosomatischer Gesundheit, arbeitsbezogener Selbstwirksamkeit und Arbeitsfähigkeit sowie des psychosozialen Sicherheitsklimas (PSC) abhängig von der Unternehmensgröße wurden bisher kaum betrachtet.

Methoden

In der Interventionsstudie „Frühe Intervention am Arbeitsplatz“ (friaa) wurden zwischen 09/2021 und 01/2023 an einer PT‑A interessierte Beschäftigte aus GU und KMU deutschlandweit befragt. Mittels t‑ und χ2-Tests wurden Unterschiede zwischen Beschäftigten in GU (n = 439) und KMU (n = 109) hinsichtlich F‑Diagnosen nach ICD-10 („International Statistical Classification of Diseases and Related Health Problems“; psychische und Verhaltensstörungen), Depressivität (PHQ-9), Ängstlichkeit (GAD-2), allgemeinen Funktionsniveaus (GAF), somatischer Symptombelastung (SSS-8), Gesundheit (VR-12), Arbeitsfähigkeit (WAI), Selbstwirksamkeit (SOSES) und psychosozialen Sicherheitsklimas (PSC-4) geprüft und mittels Korrelationsanalyse explorativ deren Zusammenhänge untersucht.

Ergebnisse

Beide Gruppen zeigten sich ähnlich stark beansprucht. In GU wurden aus Sicht der Beschäftigten psychosoziale Themen signifikant häufiger thematisiert als in KMU mit einer mittleren Effektgröße. Die Studie lieferte erste Hinweise, dass in GU positive Zusammenhänge des PSC‑4 mit SOSES und WAI sowie negative mit PHQ‑9 und SSS‑8 vorliegen.

Diskussion

Die vergleichbare psychische Beanspruchung der Beschäftigten in GU und KMU weist auf den Bedarf von verhältnis- und verhaltenspräventiven Maßnahmen unabhängig von der Unternehmensgröße hin. Vor allem in KMU sollte die Thematisierung psychosozialer Gesundheit einen größeren Stellenwert einnehmen.
Fine mapping a QTL for BYDV-PAV resistance in maize
Authors: Schmidt Maria , Guerreiro Ricardo , Baig Nadia , Habekuß Antje , Will Torsten , Ruckwied Britta , Stich Benjamin
Published: June 2024

Barley yellow dwarf (BYD) is one of the economically most important virus diseases of cereals worldwide, causing yield losses up to 80%. The means to control BYD are limited, and the use of genetically resistant cultivars is the most economical and environmentally friendly approach. The objectives of this study were i) to identify the causative gene for BYD virus (BYDV)-PAV resistance in maize, ii) to identify single nucleotide polymorphisms and/or structural variations in the gene sequences, which may cause differing susceptibilities to BYDV-PAV of maize inbreds, and iii) to characterize the effect of BYDV-PAV infection on gene expression of susceptible, tolerant, and resistant maize inbreds. Using two biparental mapping populations, we could reduce a previously published quantitative trait locus for BYDV-PAV resistance in maize to ~ 0.3 Mbp, comprising nine genes. Association mapping and gene expression analysis further reduced the number of candidate genes for BYDV-PAV resistance in maize to two: Zm00001eb428010 and Zm00001eb428020. The predicted functions of these genes suggest that they confer BYDV-PAV resistance either via interfering with virus replication or by inducing reactive oxygen species signaling. The gene sequence of Zm00001eb428010 is affected by a 54 bp deletion in the 5`-UTR and a protein altering variant in BYDV-PAV-resistant maize inbreds but not in BYDV-PAV-susceptible and -tolerant inbreds. This finding suggests that altered abundance and/or properties of the proteins encoded by Zm00001eb428010 may lead to BYDV-PAV resistance.
Magnetite geochemistry as a proxy for metallogenic processes: A study on sulfide-mineralized mafic–ultramafic intrusions peripheral to the Kunene Complex in Angola and Namibia
Authors: Milani Lorenzo , Oosthuizen Lize , Owen-Smith Trishya M. , Bybee Grant M. , Hayes Ben , Lehmann Jérémie , Jelsma Hielke A.
Published: June 2024

Trace element concentrations in magnetite are dictated by the petrogenetic environment and by the physico-chemical conditions during magmatic, hydrothermal, or sedimentary processes. This makes magnetite chemistry a useful tool in the exploration of ore-forming processes. We describe magnetite compositions from Ni-Cu-(PGE)-sulfide mineralized rocks from seven mafic–ultramafic intrusions peripheral to the Mesoproterozoic AMCG (anorthosite-mangerite-charnockite-granite) suite of the Kunene Complex of Angola and Namibia to investigate metallogenic processes through the geochemical characterization of Fe-oxides, which were analyzed in-situ via Electron Probe Microanalysis (EPMA), and Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry (LA-ICP-MS). We identified magmatic magnetite, segregated from both a silicate liquid and an immiscible sulfide liquid. Elements like Cr, Co and V suggest that the sulfide-related magnetite segregated from a relatively primitive Fe-rich monosulfide solid solution (MSS). Secondary Cr-rich magnetite appears in intrusions with abundant chromite or Cr-spinel. Two types of hydrothermal magnetite were identified, related to the pervasive replacement of sulfides and a late-stage, low-T fluid circulation event. Magnetite replacing sulfides is associated with serpentinized ultramafic rocks and is preferentially observed in the intrusions with the highest base and precious metal tenors. The high concentration of Ni, Co, Cu, Pd, As and Sb in these grains is corroborated by the identification of micron-size PGE mineral inclusions. We infer that serpentinization during hydrothermal fluid circulation was accompanied by desulphurization of sulfides with metal remobilization and reconcentration to generate magnetite carrying Pd microinclusions. We suggest that the highly serpentinized ultramafic rocks in the Kunene Complex region may become a possible target for economic Ni-Cu-(PGE) mineralization.
Tieboutian clubs revisited
Authors: Heikkila Eric J. , Coutin Jordy
Published: June 2024

This paper examines the evolution of Tieboutian clubs over time and across metropolitan regions. We address this topic by examining a large set of socioeconomic characteristics of metropolitan regions to assess empirically whether and how those member attributes may figure into a Tiebout sorting process. The method entails factor analysis to reduce an initial set of forty-nine variables to a much smaller number of factors that represent groups of intercorrelated variables. An analysis of variance is then undertaken on the corresponding factor scores to assess whether census tracts within municipalities are more alike than those between municipalities. We do this for the Los Angeles metropolitan region using census data from 1970, 1990 and 2020, and we repeat the process for the twenty largest metropolitan regions (core-based statistical areas) in the USA for 2020. Several key results emerge from this analysis. While in most cases seven or eight factors emerge repeatedly, four are most persistent and ubiquitous; these pertain to economic class, race, age cohort and immigration status. These are, in effect, the most enduring fundamental aspects of the socioeconomic landscape in metropolitan regions in the USA. The final question addressed by our work links back to the original motivation, which is to assess the role of municipalities in the formation of these clubs. We do so for the twenty largest metropolitan regions in the USA. The results from our analyses of variance are compelling. With very few exceptions we find that census tracts with similar club characteristics have a strong tendency to be co-located within the same municipalities. This strong result holds regardless of which metropolitan region we examined, or which decade. This affirms that municipalities are indeed Tieboutian clubs.
The role of labor discrimination in spatial sorting: the USA as an example of ethnic groups staying apart
Authors: Díaz-Dapena Alberto , Pérez Villadóniga María José
Published: June 2024

Despite the vast research about discrimination, there is little evidence about how space interacts with it. Our main hypothesis is that a discriminated group could have incentives to stay together, even if the location is less dynamic—avoiding areas where firms do not usually hire workers of their group. A virtuous and/or vicious circle emerges for each group, even in the long run. Using USA as an example, this article introduces a theoretical economic model to explain the incentives of ethnic groups in terms of location. We extend the well-known model of discrimination with imperfect information to a spatial framework. The results seem to indicate that the initial population distribution and the barriers to agglomerate activity (transport costs), as well as the behavior of employees, are key elements to determine the equilibrium. As a general conclusion, discrimination processes could clearly modify the location pattern of the population. Hence, the discriminated group could suffer from lower incentives to move from non-agglomerated areas to dynamic areas. These processes could help to explain why some populations prefer to maintain their traditional location in poor areas even if there are places with higher wages or better quality of life.
Analysis of highly polar anionic pesticides in food of plant and animal origin by ion chromatography and tandem mass spectrometry with emphasis on addressing adverse effects caused by matrix co-extractives
Authors: Schäfer Ann-Kathrin , Vetter Walter , Anastassiades Michelangelo
Published: June 2024

Residues of various highly polar pesticides and their metabolites are commonly found in numerous food products. Some of these compounds, such as glyphosate, are not only used in large amounts in agriculture, but are also controversially discussed in public. Here, we present a method, employing ion chromatography (IC) coupled to tandem mass spectrometry (IC-MS/MS), for the analyses of glyphosate, aminomethyl phosphonic acid (AMPA), N-acetyl-glyphosate (NAGly), fosetyl, and 10 further highly polar pesticides and metabolites in various plant and animal matrices following a minimal sample preparation by means of the QuPPe method. Thorough investigations showed that an AS19 column enabled the analysis of all 14 compounds within 30 min. The best sensitivity could be obtained with the make-up solvent acetonitrile being admixed to the mobile phase at a 1:2 flow rate ratio. Matrix effects were thoroughly studied in terms of ion suppression and retention time shifts. Conductivity detection was used to monitor elution profiles of matrix co-extractives in comparison with matrix effect profiles obtained by continuous post-column infusion of a mix with 13 highly polar pesticides and metabolites. These tests indicated that a fivefold dilution of QuPPe extracts was suitable for the routine analysis of samples for MRL-conformity, as it considerably reduced matrix effects maintaining sufficient sensitivity and high recovery rates in eight different commodities. The suitability of the final method for its application in routine analysis was verified by the analysis of >130 samples containing incurred residues where the results were compared with two existing LC-MS/MS methods.

Graphical Abstract
Diffuse peritoneal dissemination of intracranial pure germinoma via ventriculoperitoneal shunt
Authors: Kurokawa Ryo , Amemiya Shiori , Kurokawa Mariko , Onoda Soma , Takami Hirokazu , Takayanagi Shunsaku , Ikemura Masako , Yoshikawa Gakushi , Abe Osamu
Published: June 2024

Germinomas frequently cause hydrocephalus, and ventriculoperitoneal shunts (VPS) have been commonly used for their management. Although VPS can potentially serve as a route for peritoneal dissemination of germinomas, the abdominal imaging characteristics of this rare yet important complication remain unknown. In this article, we report the computed tomography imaging findings of diffuse peritoneal dissemination of intracranial germinoma.
Development of an HSV-1 production process involving serum-reduced culturing and bead-to-bead transfer
Authors: Wang Helin , Hu Xiuhua , Zhang Mingfang , Yang Lin , Xu Yueying , Gu Xiaoxu , Jiang Junjun , Hu Weiwei
Published: June 2024

Herpes simplex virus type 1 (HSV-1) plays an important role in the field of gene therapy and viral vaccines, especially as an oncolytic virus. However, the mass production of HSV-1 viral vectors remains a challenge in the industry. In this study, a microcarrier-mediated serum-reduced medium culture was used to improve the bioprocess of HSV-1 production and increase HSV-1 yields. The composition of the culture media, which included a basal medium, serum concentration, and glutamine additive, was optimized. The process was successfully conducted in a 1 L bioreactor, and virus production was threefold greater than that of conventional processes with a 10% serum medium. The bead-to-bead transfer process was also developed to further increase scalability. In spinner flasks, the detachment rate increased from 49.4 to 80.6% when combined agitation was performed during digestion; the overall recovery proportion increased from 37.9 to 71.1% after the operational steps were optimized. Specifically, microcarrier loss was reduced during aspiration and transfer, and microcarriers and detached cells were separated with filters. Comparable cell growth was achieved with the baseline process using 2D culture as the inoculum by exchanging the subculture medium. To increase virus production after bead-to-bead transfer, critical parameters, including shear stress during digestion, TrypLE and EDTA concentrations in the subculture, and the CCI, were identified from 47 parameters via correlation analysis and principal component analysis. The optimized bead-to-bead transfer process achieved an average of 90.4% overall recovery and comparable virus production compared to that of the baseline process. This study is the first to report the optimization of HSV-1 production in Vero cells cultured on microcarriers in serum-reduced medium after bead-to-bead transfer.

Key points

• An HSV-1 production process was developed that involves culturing in serum-reduced medium, and this process achieved threefold greater virus production than that of traditional processes.

• An indirect bead-to-bead transfer process was developed with over 90% recovery yield in bioreactors.

• HSV-1 production after bead-to-bead transfer was optimized and was comparable to that achieved with 2D culture as inoculum.
Comparative transcriptomic and proteomic kinetic analysis of adeno-associated virus production systems
Authors: Lin Yu-Chieh , Lu Min , Cai Wen , Hu Wei-Shou
Published: June 2024

Recombinant adeno-associated virus (rAAV) is a major gene delivery vehicle. We have constructed a stable rAAV producer cell line by integrating essential rAAV genome, viral and helper genes into the genome of HEK293 cell under the control of inducible promoters. Upon induction, the cell line produces transducing rAAV. To gain insight into enhancing rAAV productivity and vector quality, we performed a comparative transcriptomic and proteomic analysis of our synthetic cell line GX2 and two wild-type AAV (wtAAV) production systems, one by virus co-infection and the other by multi-plasmid transfection. The three systems had different kinetics in viral component synthesis but generated comparable copies of AAV genomes; however, the capsid titer of GX2 was an order of magnitude lower compared to those two wtAAV systems, indicating that its capsid production may be insufficient. The genome packaging efficiency was also lower in GX2 despite it produced higher levels of Rep52 proteins than either wtAAV systems, suggesting that Rep52 protein expression may not limit genome packaging. In the two wtAAV systems, VP were the most abundant AAV proteins and their levels continued to increase, while GX2 had high level of wasteful cargo gene expression. Furthermore, upregulated inflammation, innate immune responses, and MAPK signaling, as well as downregulated mitochondrial functions, were commonly observed in either rAAV or wtAAV systems. Overall, this comparative multi-omics study provided rich insights into host cell and viral factors that are potential targets for genetic and process intervention to enhance the productivity of synthetic rAAV producer cell lines.

Key points

• wtAAV infection was more efficient in producing full viral particles than the synthetic cell GX2.

• Capsid protein synthesis, genome replication, and packaging may limit rAAV production in GX2.

• wtAAV infection and rAAV production in GX2 elicited similar host cell responses.
Exploring operational boundaries for acoustic concentration of cell suspensions
Authors: de Hemptinne Amaury , Gelin Pierre , Bihi Ilyesse , Kinet Romain , Thienpont Benoit , De Malsche Wim
Published: June 2024

The development of a standardized, generic method for concentrating suspensions in continuous flow is challenging. In this study, we developed and tested a device capable of concentrating suspensions with an already high cell concentration to meet diverse industrial requirements. To address typical multitasking needs, we concentrated suspensions with high solid content under a variety of conditions. Cells from Saccharomyces cerevisiae, Escherichia coli, and Chinese hamster ovary cells were effectively focused in the center of the main channel of a microfluidic device using acoustophoresis. The main channel bifurcates into three outlets, allowing cells to exit through the central outlet, while the liquid evenly exits through all outlets. Consequently, the treatment separates cells from two-thirds of the surrounding liquid. We investigated the complex interactions between parameters. Increasing the channel depth results in a decrease in process efficiency, attributed to a decline in acoustic energy density. The study also revealed that different cell strains exhibit distinct acoustic contrast factors, originating from differences in dimensions, compressibility, and density values. Finally, a combination of high solid content and flow rate leads to an increase in diffusion through a phenomenon known as shear-induced diffusion.

Key points

• Acoustic focusing in a microchannel was used to concentrate cell suspensions

• The parameters influencing focusing at high concentrations were studied

• Three different cell strains were successfully concentrated

Graphical abstract
[18F]FDG-PET/CT atypical response patterns to immunotherapy in non-small cell lung cancer patients: long term prognosis assessment and clinical management proposal
Authors: Masse Mathilde , Chardin David , Tricarico Pierre , Ferrari Victoria , Martin Nicolas , Otto Josiane , Darcourt Jacques , Comte Victor , Humbert Olivier
Published: June 2024

Aim

To determine the long-term prognosis of immune-related response profiles (pseudoprogression and dissociated response), not covered by conventional PERCIST criteria, in patients with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPIs).

Methods

109 patients were prospectively included and underwent [18F]FDG-PET/CT at baseline, after 7 weeks (PETinterim1), and 3 months (PETinterim2) of treatment. On PETinterim1, tumor response was assessed using standard PERCIST criteria. In the event of PERCIST progression at this time-point, the study design provided for continued immunotherapy for 6 more weeks. Additional response patterns were then considered on PETinterim2: pseudo-progression (PsPD, subsequent metabolic response); dissociated response (DR, coexistence of responding and non-responding lesions), and confirmed progressive metabolic disease (cPMD, subsequent homogeneous progression of lesions). Patients were followed up for at least 12 months.

Results

Median follow-up was 21 months. At PETinterim1, PERCIST progression was observed in 60% (66/109) of patients and ICPI was continued in 59/66. At the subsequent PETinterim2, 14% of patients showed PsPD, 11% DR, 35% cPMD, and 28% had a sustained metabolic response. Median overall survival (OS) and progression-free-survival (PFS) did not differ between PsPD and DR (27 vs 29 months, p = 1.0; 17 vs 12 months, p = 0.2, respectively). The OS and PFS of PsPD/DR patients were significantly better than those with cPMD (29 vs 9 months, p < 0.02; 16 vs 2 months, p < 0.001), but worse than those with sustained metabolic response (p < 0.001). This 3-group prognostic stratification enabled better identification of true progressors, outperforming the prognostic value of standard PERCIST criteria (p = 0.03).

Conclusion

[18F]FDG-PET/CT enables early assessment of response to immunotherapy. The new wsPERCIST (“wait and see”) PET criteria proposed, comprising immune-related atypical response patterns, can refine conventional prognostic stratification based on PERCIST criteria.

Trial registration

HDH F20230309081206. Registered 20 April 2023. Retrospectively registered.
Predictive value of C-X-C motif chemokine receptor 4-directed molecular imaging in patients with advanced adrenocortical carcinoma
Authors: Schloetelburg Wiebke , Hartrampf Philipp E. , Kosmala Aleksander , Serfling Sebastian E. , Dreher Niklas , Schirbel Andreas , Fassnacht Martin , Buck Andreas K. , Werner Rudolf A. , Hahner Stefanie
Published: June 2024

Background

In patients affected with adrenocortical carcinoma (ACC), C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in sites of disease in an ex-vivo setting. We aimed to determine the predictive value of CXCR4-targeting [68Ga]Ga-PentixaFor PET/CT for outcome when compared to clinical parameters.

Methods

We identified 41 metastasized ACC patients imaged with [68Ga]Ga-PentixaFor PET/CT. Scans were assessed visually and on a quantitative level by manually segmenting the tumor burden (providing tumor volume [TV], peak/mean/maximum standardized uptake values [SUV] and tumor chemokine receptor binding on the cell surface [TRB], defined as SUVmean multiplied by tumor volume). Clinical parameters included sex, previous therapies, age, Weiss-Score, and Ki67 index. Following imaging, overall survival (OS) was recorded.

Results

After [68Ga]Ga-PentixaFor PET/CT, median OS was 9 months (range, 1–96 months). On univariable analysis, only higher TRB (per 10 ml, HR 1.004, 95%CI: 1.0001–1.007, P = 0.005) and presence of CXCR4-positive peritoneal metastases (PM) were associated with shorter OS (HR 2.03, 95%CI: 1.03–4.02, P = 0.04). Presence of CXCR4-positive liver metastases (LM) trended towards significance (HR 1.85, 0.9–4.1, P = 0.11), while all other parameters failed to predict survival. On multivariable analysis, only TRB was an independent predictor for OS (HR 1.0, 95%CI: 1.00-1.001, P = 0.02). On Kaplan-Meier analysis, TRB above median (13.3 months vs. below median, 6.4 months) and presence of CXCR4-positive PM (6.4 months, vs. no PM, 11.4 months) were associated with shorter survival (P < 0.05, respectively). Presence of LM, however, was also linked to less favorable outcome (8.5 months vs. no LM, 18.1 months), without reaching significance (P = 0.07).

Conclusions

In advanced ACC, elevated tumor chemokine receptor binding on the tumor cell surface detected through [68Ga]Ga-PentixaFor PET/CT is an independent predictor for OS, while other imaging and clinical parameters failed to provide relevant prognostic information.
Interstate Air Pollution Governance in the United States: Exploring Clean Air Act Section 126
Authors: Underwood Alixandra , Marcantonio Richard , Wood Danielle , Crippa Paola
Published: June 2024

Air pollution is arguably the most pressing human health concern today, accounting for approximately 7–9 million premature deaths worldwide. In the United States, more than 40% of early deaths caused by air pollution are assessed to be caused by emissions produced by neighboring states. This article examines one of the governance mechanisms used by the U.S. to address this issue: section 126 of the Clean Air Act. Critical factors including case length, evidence used, and case outcome are compiled for the population of section 126 petitions submitted from 2000–2022. This evidence is assessed using comparative case analysis. The findings reinforce two issues with the petition process already identified in the literature–the use of cost as a proxy for significance and the excessive and unclear burden of proof placed on downwind states–adding texture to the latter issue by examining the modeling techniques used by downwind states. This analysis identifies lengthy response timelines as an additional issue and calls to attention the infrequency with which the EPA has formally accepted petitions. Collectively, these issues increase the cost, complexity, and unpredictability of filing a section 126 petition.
Machine Learning to Predict Prostate Artery Embolization Outcomes
Authors: Vigneswaran G. , Doshi N. , Maclean D. , Bryant T. , Harris M. , Hacking N. , Farrahi K. , Niranjan M. , Modi S.
Published: June 2024

Purpose

This study leverages pre-procedural data and machine learning (ML) techniques to predict outcomes at one year following prostate artery embolization (PAE).

Materials and Methods

This retrospective analysis combines data from the UK-ROPE registry and patients that underwent PAE at our institution between 2012 and 2023. Traditional ML approaches, including linear regression, lasso regression, ridge regression, decision trees and random forests, were used with leave-one-out cross-validation to predict international prostate symptom score (IPSS) at baseline and change at 1 year. Predictors included age, prostate volume, Qmax (maximum urinary flow rate), post-void residual volume, Abrams-Griffiths number (urodynamics score) and baseline IPSS (for change at 1 year). We also independently confirmed our findings using a separate dataset. An interactive digital user interface was developed to facilitate real-time outcome prediction.

Results

Complete data were available in 128 patients (66.7 ± 6.9 years). All models predicting IPSS demonstrated reasonable performance, with mean absolute error ranging between 4.9–7.3 for baseline IPSS and 5.2–8.2 for change in IPSS. These numbers represent the differences between the patient-reported and model-predicted IPSS scores. Interestingly, the model error in predicting baseline IPSS (based on objective measures alone) significantly correlated with the change in IPSS at 1-year post-PAE (R2 = 0.2, p < 0.001), forming the basis for our digital user interface.

Conclusion

This study uses ML methods to predict IPSS improvement at 1 year, integrated into a user-friendly interface for real-time prediction. This tool could be used to counsel patients prior to treatment.
The prognostic importance of traumatic axonal injury on early MRI: the Trondheim TAI-MRI grading and quantitative models
Authors: Moen Kent Gøran , Flusund Anne-Mari Holte , Moe Hans Kristian , Andelic Nada , Skandsen Toril , Håberg Asta , Kvistad Kjell Arne , Olsen Øystein , Saksvoll Elin Hildrum , Abel-Grüner Sebastian , Anke Audny , Follestad Turid , Vik Anne
Published: June 2024

Objectives

We analysed magnetic resonance imaging (MRI) findings after traumatic brain injury (TBI) aiming to improve the grading of traumatic axonal injury (TAI) to better reflect the outcome.

Methods

Four-hundred sixty-three patients (8–70 years) with mild (n = 158), moderate (n = 129), or severe (n = 176) TBI and early MRI were prospectively included. TAI presence, numbers, and volumes at predefined locations were registered on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging, and presence and numbers on T2*GRE/SWI. Presence and volumes of contusions were registered on FLAIR. We assessed the outcome with the Glasgow Outcome Scale Extended. Multivariable logistic and elastic-net regression analyses were performed.

Results

The presence of TAI differed between mild (6%), moderate (70%), and severe TBI (95%). In severe TBI, bilateral TAI in mesencephalon or thalami and bilateral TAI in pons predicted worse outcomes and were defined as the worst grades (4 and 5, respectively) in the Trondheim TAI-MRI grading. The Trondheim TAI-MRI grading performed better than the standard TAI grading in severe TBI (pseudo-R2 0.19 vs. 0.16). In moderate-severe TBI, quantitative models including both FLAIR volume of TAI and contusions performed best (pseudo-R2 0.19–0.21). In patients with mild TBI or Glasgow Coma Scale (GCS) score 13, models with the volume of contusions performed best (pseudo-R2 0.25–0.26).

Conclusions

We propose the Trondheim TAI-MRI grading (grades 1–5) with bilateral TAI in mesencephalon or thalami, and bilateral TAI in pons as the worst grades. The predictive value was highest for the quantitative models including FLAIR volume of TAI and contusions (GCS score <13) or FLAIR volume of contusions (GCS score ≥ 13), which emphasise artificial intelligence as a potentially important future tool.

Clinical relevance statement

The Trondheim TAI-MRI grading reflects patient outcomes better in severe TBI than today’s standard TAI grading and can be implemented after external validation. The prognostic importance of volumetric models is promising for future use of artificial intelligence technologies.

Key Points

Traumatic axonal injury (TAI) is an important injury type in all TBI severities. Studies demonstrating which MRI findings that can serve as future biomarkers are highly warranted.

This study proposes the most optimal MRI models for predicting patient outcome at 6 months after TBI; one updated pragmatic model and a volumetric model.

The Trondheim TAI-MRI grading, in severe TBI, reflects patient outcome better than today’s standard grading of TAI and the prognostic importance of volumetric models in all severities of TBI is promising for future use of AI.
The Hanging Chain Problem in the Sphere and in the Hyperbolic Plane
Authors: López Rafael
Published: June 2024

In this paper, the notion of the catenary curve in the sphere and in the hyperbolic plane is introduced. In both spaces, a catenary is defined as the shape of a hanging chain when its potential energy is determined by the distance to a given geodesic of the space. Several characterizations of the catenary are established in terms of the curvature of the curve and of the angle that its unit normal makes with a vector field of the ambient space. Furthermore, in the hyperbolic plane, we extend the concept of catenary substituting the reference geodesic by a horocycle or the hyperbolic distance by the horocycle distance.
A clock for all seasons
Authors: Helfrich-Förster Charlotte , Rieger Dirk
Published: June 2024

Circadian clocks play an essential role in adapting locomotor activity as well as physiological, and metabolic rhythms of organisms to the day-night cycles on Earth during the four seasons. In addition, they can serve as a time reference for measuring day length and adapt organisms in advance to annual changes in the environment, which can be particularly pronounced at higher latitudes. The physiological responses of organisms to day length are also known as photoperiodism. This special issue of the Journal of Comparative Physiology A aims to account for diurnal and photoperiodic adaptations by presenting a collection of ten review articles, five original research articles, and three perspective pieces. The contributions include historical accounts, circadian and photoperiodic clock models, epigenetic, molecular, and neuronal mechanisms of seasonal adaptations, latitudinal differences in photoperiodic responses and studies in the wild that address the challenges of global change.
Mitochondrial calcium in cardiac ischemia/reperfusion injury and cardioprotection
Authors: Bertero Edoardo , Popoiu Tudor-Alexandru , Maack Christoph
Published: June 2024

Mitochondrial calcium (Ca2+) signals play a central role in cardiac homeostasis and disease. In the healthy heart, mitochondrial Ca2+ levels modulate the rate of oxidative metabolism to match the rate of adenosine triphosphate consumption in the cytosol. During ischemia/reperfusion (I/R) injury, pathologically high levels of Ca2+ in the mitochondrial matrix trigger the opening of the mitochondrial permeability transition pore, which releases solutes and small proteins from the matrix, causing mitochondrial swelling and ultimately leading to cell death. Pharmacological and genetic approaches to tune mitochondrial Ca2+ handling by regulating the activity of the main Ca2+ influx and efflux pathways, i.e., the mitochondrial Ca2+ uniporter and sodium/Ca2+ exchanger, represent promising therapeutic strategies to protect the heart from I/R injury.
Annexin A11 aggregation in FTLD–TDP type C and related neurodegenerative disease proteinopathies
Authors: Robinson John L. , Suh EunRan , Xu Yan , Hurtig Howard I. , Elman Lauren , McMillan Corey T. , Irwin David J. , Porta Sílvia , Van Deerlin Vivianna M. , Lee Edward B.
Published: June 2024

TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD–TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD–TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD–TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3–6%) of sporadic and genetic forms of FTLD–TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD–TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.
Observational pilot study on the influence of an app-based self-management program on the quality of life of women with endometriosis
Authors: Rohloff Nadine , Rothenhöfer Markus , Götz Teresa , Schäfer Sebastian Daniel
Published: June 2024

Purpose

Endometriosis can significantly impair the quality of life of those affected. Multimodal self-help measures are recommended but often difficult to access. Smartphone apps have been shown to improve the quality of life for other conditions with chronic pain. The aim of this study was to examine whether there is evidence of beneficial effects of the smartphone app “Endo-App®” and whether a multicenter randomized controlled trial should be planned to substantiate these effects.

Methods

In a sample of N = 106 women affected by endometriosis the present study determined the influence of the use of Endo-App® on their quality of life. Among others, the validated questionnaire Endometriosis Health Profile from Oxford University was used for this purpose.

Results

The use of Endo-App® lead to a highly significant improvement in quality of life already after 2 weeks. A statistically significant change was found for nine out of ten measured variables of quality of life. A series of further analyses validated that the measured positive effects were not due to other confounding factors.

Conclusion

In summary, the results indicate that the quality of life of women with endometriosis improved by the digital self-management tool Endo-App®. More studies are needed to further explore the influence of the app on quality of life and as confirmatory evidence of beneficial effects. For this purpose, a randomized controlled trial should be conducted over a longer period of time.

Trial registration

This trial is registered at clinicaltrials.gov under the registration number NCT05528601 on August 18, 2022. It was retrospectively registered.
New valproate regulations, informed choice and seizure risk
Authors: Angus-Leppan Heather , Arkell Rachel , Watkins Lance , Heaney Dominic , Cooper Paul , Shankar Rohit
Published: June 2024

Valproate is the most effective medication for generalised epilepsies, and several specific epilepsy syndromes. For some people, it will be the only medication to establish seizure remission, and withdrawing it carries risks of seizure recurrence and Sudden Unexpected Death in Epilepsy (SUDEP). It is also of proven efficacy for bipolar disorder and migraine prevention. Guidelines based on observational and epidemiological studies stress that maternal valproate related teratogenicity and neurodevelopmental effects are significantly higher than for other antiseizure medications (ASMs). It should, therefore, only be used if other medications are ineffective and after balancing the teratogenicity risk. Regulatory restrictions have changed prescribing practices and reduced valproate use. The number of other medications that must be trialled in the different conditions for which valproate has effectiveness and the consequences of the lack of efficacy of those drugs leading to significant harm including death remains unexplored. Risk minimisation measures (RMMs) for valproate, chiefly Pregnancy Prevention practices (PPP), consider foetal risk and not risk to people living with epilepsy. In the United Kingdom (UK), limitations relating to valproate use in all people < 55 years commenced in January 2024. While the evidence in child-bearing women is not disputed, the data in males are based on animal models, case reports, and one commissioned, unpublished, non-peer reviewed report unavailable to the UK public, stakeholder charities or professionals. Evidence suggests that 30–40% of people switching from valproate have breakthrough seizures. Thus, an estimated 21,000–28000 people in the UK will imminently be exposed to the potential hazards of breakthrough seizures, including death. There is little government investment in monitoring the effects of these changes to valproate prescribing on patient health and quality of life. This review summarises the history of valproate regulation, evidence underpinning it and argues how the latest regulations in the UK do not align with the country’s medical regulatory bodies ethical principles nor with the Montgomery principles of informed patient choice and autonomy. It dissects how such regulations infringe Common Law principles, nor give due regard for patient outcomes beyond reproduction. The paper looks to provide recommendations to redress these concerns while appreciating the core need for such governance to emerge in the first place.
Changes in forced vital capacity over ≤ 13 years among patients with late-onset Pompe disease treated with alglucosidase alfa: new modeling of real-world data from the Pompe Registry
Authors: Berger Kenneth I. , Chien Yin-Hsiu , Dubrovsky Alberto , Kishnani Priya S. , Llerena Juan C. , Neilan Edward , Roberts Mark , Sheng Bun , Batista Julie L. , Periquet Magali , Wilson Kathryn M. , van der Ploeg Ans T.
Published: June 2024

Background

Chronic respiratory insufficiency from progressive muscle weakness causes morbidity and mortality in late-onset Pompe disease (LOPD). Previous Pompe Registry (NCT00231400) analyses for ≤ 5 years’ alglucosidase alfa treatment showed a single linear time trend of stable forced vital capacity (FVC) % predicted.

Methods

To assess longer term Pompe Registry data, piecewise linear mixed model regression analyses estimated FVC% predicted trajectories in invasive-ventilator-free patients with LOPD aged ≥ 5 years. We estimated annual FVC change 0–6 months, > 6 months–5 years, and > 5–13 years from treatment initiation, adjusting for baseline age, sex, and non-invasive ventilation.

Findings

Among 485 patients (4612 FVC measurements; 8.3 years median follow-up), median ages at symptom onset, diagnosis, and alglucosidase alfa initiation were 34.3, 41.1, and 44.9 years, respectively. FVC% increased during the first 6 months’ treatment (slope 1.83%/year; 95% confidence interval: 0.66, 3.01; P = 0.0023), then modestly declined −0.54%/year (−0.79, −0.30; P < 0.0001) during > 6 months–5 years, and −1.00%/year (−1.36, −0.63; P < 0.0001) during > 5–13 years. The latter two periods’ slopes were not significantly different from each other (Pdifference = 0.0654) and were less steep than published natural history slopes (−1% to −4.6%/year). Estimated individual slopes were ≥ 0%/year in 96.1%, 30.3%, and 13.2% of patients during the 0–6 month, > 6 month–5 year, and > 5–13 year periods, respectively.

Conclusion

These real-world data indicate an alglucosidase alfa benefit on FVC trajectory that persists at least 13 years compared with published natural history data. Nevertheless, unmet need remains since most individuals demonstrate lung function decline 5 years after initiating treatment. Whether altered FVC trajectory impacts respiratory failure incidence remains undetermined.

Trial registration

This study was registered (NCT00231400) on ClinicalTrials.gov on September 30, 2005, retrospectively registered.
Greater cortical thinning and microstructural integrity loss in myotonic dystrophy type 1 compared to myotonic dystrophy type 2
Authors: Krieger Britta , Schneider-Gold Christiane , Genç Erhan , Güntürkün Onur , Prehn Christian , Bellenberg Barbara , Lukas Carsten
Published: June 2024

Background

Myotonic dystrophy is a multisystem disorder characterized by widespread organic involvement including central nervous system symptoms. Although myotonic dystrophy disease types 1 (DM1) and 2 (DM2) cover a similar spectrum of symptoms, more pronounced clinical and brain alterations have been described in DM1. Here, we investigated brain volumetric and white matter alterations in both disease types and compared to healthy controls (HC).

Methods

MRI scans were obtained from 29 DM1, 27 DM2, and 56 HC. We assessed macro- and microstructural brain changes by surface-based analysis of cortical thickness of anatomical images and tract-based spatial statistics of fractional anisotropy (FA) obtained by diffusion-weighted imaging, respectively. Global MRI measures were related to clinical and neuropsychological scores to evaluate their clinical relevance.

Results

Cortical thickness was reduced in both patient groups compared to HC, showing similar patterns of regional distribution in DM1 and DM2 (occipital, temporal, frontal) but more pronounced cortical thinning for DM1. Similarly, FA values showed a widespread decrease in DM1 and DM2 compared to HC. Interestingly, FA was significantly lower in DM1 compared to DM2 within most parts of the brain.

Conclusion

Comparisons between DM1 and DM2 indicate a more pronounced cortical thinning of grey matter and a widespread reduction in microstructural integrity of white matter in DM1. Future studies are required to unravel the underlying and separating mechanisms for the disease courses of the two types and their neuropsychological symptoms.
Absence of orthopaedia homeobox protein (OTP) expression is associated with disease spread and adverse outcome in pulmonary carcinoid tumour patients
Authors: Niinimäki Jenni , Mononen Sanna , Kaprio Tuomas , Arola Johanna , Vesterinen Tiina
Published: June 2024

Pulmonary carcinoid (PC) tumours typically have a good prognosis, although metastases occur, and the disease may progress after a long period of time. Expression of orthopaedia homeobox protein (OTP) has been recognized as a possible independent prognostic marker in PCs. Immunohistochemical (IHC) OTP expression has been associated with better prognosis, but the staining has yet to be implemented in routine clinical diagnostics. In response to this, two new monoclonal OTP antibodies were recently developed.

This retrospective study included 164 PC patients operated on at Helsinki University Hospital between 1990 and 2020. Tissue microarray slides, prepared from formalin-fixed and paraffin-embedded primary tumour samples, were stained with OTP IHC using one polyclonal and two novel monoclonal antibodies.

Absence of OTP expression was associated with a shorter disease-specific survival (DSS) and disease progression (p < 0.001). Patients without OTP expression had a 5-year DSS of 73–79%, whereas 5-year DSS was 91–94% with OTP expression, depending on the primary antibody. In a univariable Cox regression model, absence of OTP expression was associated with adverse outcome along with atypical histological subtype, metastatic disease, Ki-67 proliferation index > 1%, and larger tumour size. In a multivariable Cox regression model, only absence of OTP expression and lymph node involvement at the time of diagnosis were associated with risk of worse prognosis. All three antibodies showed good concordance with each other.

Our findings support the role of OTP as an independent prognostic marker in PCs and applicability of IHC staining in routine clinical use with novel monoclonal antibodies.
Parameterized Complexity of Streaming Diameter and Connectivity Problems
Authors: Oostveen Jelle J. , van Leeuwen Erik Jan
Published: June 2024

We initiate the investigation of the parameterized complexity of Diameter and Connectivity in the streaming paradigm. On the positive end, we show that knowing a vertex cover of size k allows for algorithms in the Adjacency List (AL) streaming model whose number of passes is constant and memory is $$\mathcal {O}(\log n)$$

O
(
log
n
)

for any fixed k. Underlying these algorithms is a method to execute a breadth-first search in $$\mathcal {O}(k)$$

O
(
k
)

passes and $$\mathcal {O}(k \log n)$$

O
(
k
log
n
)

bits of memory. On the negative end, we show that many other parameters lead to lower bounds in the AL model, where $$\Omega (n/p)$$

Ω
(
n
/
p
)

bits of memory is needed for any p-pass algorithm even for constant parameter values. In particular, this holds for graphs with a known modulator (deletion set) of constant size to a graph that has no induced subgraph isomorphic to a fixed graph H, for most H. For some cases, we can also show one-pass, $$\Omega (n \log n)$$

Ω
(
n
log
n
)

bits of memory lower bounds. We also prove a much stronger $$\Omega (n^2/p)$$

Ω
(

n
2

/
p
)

lower bound for Diameter on bipartite graphs. Finally, using the insights we developed into streaming parameterized graph exploration algorithms, we show a new streaming kernelization algorithm for computing a vertex cover of size k. This yields a kernel of 2k vertices (with $$\mathcal {O}(k^2)$$

O
(

k
2

)

edges) produced as a stream in $$\text {poly}(k)$$

poly
(
k
)

passes and only $$\mathcal {O}(k \log n)$$

O
(
k
log
n
)

bits of memory.