bluuebunny/crossref_metadata_2025 huggingface dataset:
Alzheimer's disease drug development pipeline: 2022
Authors: Cummings Jeffrey , Lee Garam , Nahed Pouyan , Kambar Mina Esmail Zadeh Nojoo , Zhong Kate , Fonseca Jorge , Taghva Kazem
Published: May 2022

Introduction

Alzheimer's disease (AD) represents a global health crisis. Treatments are needed to prevent, delay the onset, slow the progression, improve cognition, and reduce behavioral disturbances of AD. We review the current clinical trials and drugs in development for the treatment of AD.

Methods

We searched the governmental website clinicaltrials.gov where are all clinical trials conducted in the United States must be registered. We used artificial intelligence (AI) and machine learning (ML) approaches to ensure comprehensive detection and characterization of trials and drugs in development. We use the Common Alzheimer's Disease Research Ontology (CADRO) to classify drug targets and mechanisms of action of drugs in the pipeline.

Results

As of January 25, 2022 (index date for this study) there were 143 agents in 172 clinical trials for AD. The pipeline included 31 agents in 47 trials in Phase 3, 82 agents in 94 trials in Phase 2, and 30 agents in 31 trials in Phase 1. Disease‐modifying therapies represent 83.2% of the total number of agents in trials; symptomatic cognitive enhancing treatments represent 9.8% of agents in trials; and drugs for the treatment of neuropsychiatric symptoms comprise 6.9%. There is a diverse array of drug targets represented by agents in trials including nearly all CADRO categories. Thirty‐seven percent of the candidate agents in the pipeline are repurposed drugs approved for other indications. A total of 50,575 participants are needed to fulfill recruitment requirements for all currently active clinical trials.

Discussion

The AD drug development pipeline has agents representing a substantial array of treatment mechanisms and targets. Advances in drug design, outcome measures, use of biomarkers, and trial conduct promise to accelerate the delivery of new and better treatments for patients with AD.

Highlights

There are 143 drugs in the current Alzheimer's disease (AD) drug development pipeline.

Disease‐modifying therapies represent 83.2% of the candidate treatments.

Current trials require 50,575 participants who will donate 3,878,843 participant‐weeks to clinical trials.

The biopharmaceutical industry sponsors 50% of all clinical trials including 68% of Phase 3 trials.

Sixty‐three percent of Phase 3 trials and 46% of Phase 2 trials include non–North American clinical trial site locations indicating the global ecosystem required for AD drug development.
Canine mast cell tumours part I: Clinical and survival outcomes
Authors: Tamlin Vanessa S. , Bottema Cynthia D. K. , Woolford Lucy , Dobson Elizabeth C. , Kessell Allan E. , Peaston Anne E.
Published: May 2022

Background

Dogs have a species‐specific susceptibility for developing mast cell tumours (MCTs). Mutations in the KIT proto‐oncogene (KIT) are known to contribute to the neoplastic biology of mast cells. In dogs, the most common KIT mutation is an internal tandem duplication (ITD) in exon 11 which has been considered a useful prognostic supplement to traditional histopathological tumour grading.

Objective

The aim of this retrospective study was to explore the importance of KIT exon 11 ITD mutation status and known clinical and pathological indices in predicting prognosis in a cohort of Australian dogs diagnosed with MCT.

Methods

Clinical parameters, survival data, and KIT mutation status were collected and assessed for 220 dogs with cutaneous or subcutaneous MCT (n = 189 and n = 31, respectively).

Results

In at least one of the multivariable models, tumour grade (cutaneous Kiupel low or high grade) or tumour subcutaneous location, multiple concurrent MCTs, metastasis at the time of surgery, and senior age were statistically significant in predicting the outcome (MCT‐related death and/or second MCT diagnosis) at 6‐ or 12‐month post‐tumour excision. KIT exon 11 ITD mutation status was not a significant predictor in any of the final multivariable models and was strongly correlated with high histological grade (p < 0.001).

Conclusion

In this sample of dogs, tumour histological grading remained the single most powerful prognostic indicator for MCT outcome. However, concurrent evaluation of multiple prognostically significant parameters provides information of potential value to inform therapeutic management for each patient.
Features of ophthalmic, magnetic resonance imaging, and histopathology of a feline case of idiopathic sclerosing orbital pseudotumor
Authors: Lee Hao , Wu Chih‐Ching , Liao Pei‐Wen , Michael Chang Kunbee , Wei Li‐Ning , Wu Yi‐Ying , Chan Man‐Ha , Chiang Yi‐Shan , Pang Victor Fei , Lin Chung‐Tien
Published: May 2022

In the present report, we describe a case of sclerosing orbital pseudotumor in an 11‐year‐old castrated male American Shorthair cat. Ophthalmic exam showed lagophthalmos, retracted right upper eyelid, and resistant to retropulsion in his right eye. Under magnetic resonance imaging (MRI) scans, increased volume of the extraocular muscles (EOMs) of the right eye was prominent. Immunosuppressive dosage of prednisolone partially ameliorated the clinical signs, but some clinical signs were still gradually progressive or persistent. In the second MRI scan, decreased diameter of the thickened right extraocular muscles was found. After the third MRI scan, enucleation of the right eye was performed due to substantial adverse effects of systemic steroid therapy. Histopathological examination revealed no evidence of neoplastic transformation nor infection. Feline restrictive orbital myofibroblastic sarcoma (FROMS) was therefore excluded, suggesting unknown causes of extensive fibrotic changes in the right orbit of the affected cat.
Anatomical study of the scleral ring and eyeball of the long‐eared owl (Asio otus) with anatomical methods and diagnostic imaging techniques
Authors: Zehtabvar Omid , Masoudifard Majid , Ekim Okan , Ghorbani Faezeh , Davudypoor Somaye , Memarian Iman , Zarghami Dastjerdi Paniz
Published: May 2022

Background

The scleral ring in birds consists of ossicles that are fixed as small plates by cartilage joints and have no articulation to other parts of the skeleton.

Objective

Due to inadequate examination of the scleral ring anatomy and its specific form in owls, this study aimed to investigate the exact structure of the scleral ring and some morphometric characteristics of the eyeball in a long‐eared owl (Asio otus).

Methods

The eyes of 20 alive and 10 dead male and female owls were examined. In addition to common anatomical methods, computed tomography scans and radiographic and ultrasonographic imaging techniques were used in this study.

Results

The structure consisted of 15 ossicles. In the ventral part of the ring, these tubercles were observed in the scleral rings of all owls; in each ring, there were four bones with these tubercles. Additionally, there was no significant difference between the left and right eye parameters. Most ocular parameters in female owls were larger than those in males, but in the case of some parameters, such as optic nerve length and optic nerve sheath diameter, this difference was not observed.

Conclusions

According to this study, the scleral ring in the Asio otus has anterior and posterior parts, and the lens is in the immediate vicinity of the anterior part. The right and left scleral rings and eyeballs are bilaterally symmetrical in terms of the shape, size, and number of ossicles that form the ring.
Sustainable Energy Access for Sustainable Communities: Introduction by a Social Scientist
Authors: Obrecht Andreas J.
Published: May 2022

Three pillars are essential to building a sustainable future for current and next generations: sustainable energy access, inclusive knowledge and equal opportunities in education, peacebuilding, and democratisation. These pillars interact like communicating vessels; they can neither be conceived nor achieved in isolation from one another. Sustainable energy access relies on access to broad and decentralised knowledge and to innovation in technologies, which is the pursuit of higher education. Community-based implementation of the sustainable energy principles is only possible if the stakeholders own these principles and thus create the basis for participatory, transparent, democratic, and above all, peaceful conditions for action. Peaceful contexts are necessary for communities to achieve the socio-ecological transformation that is necessary to mitigate climate change and to build models of a sustainable coexistence that preserves our common good, which is the environment.
Management of Intermittent Solar and Wind Energy Resources: Storage and Grid Stabilization
Authors: Nkounga W. M. , Ndiaye M. F. , Ndiaye M. L.
Published: May 2022

The chapter documents options for management of the intermittency of solar and wind energy resources, with the aim of supporting transition to energy sustainability with these resources. It explores different techniques for creating storage in high power and high energy systems. We review indicators to support the decision on the selection of these storage options combined or not to grid management strategies. Our results show that flywheel is more appropriate in short-term high power storage given its low investment cost and its power density per cubic metre. For long-term energy storage, still considering the investment cost and power density per cubic metre, hydrogen, and hydraulic pumping are the best options. The smart management of storage options can significantly reduce the impact of solar and wind resources intermittency on the stability of the grid.
Cookinations: Mechanisms to Decouple Wood Production and Food Preparation in Sub-Urban Areas
Authors: Sow S.
Published: May 2022

In Senegal, the share of households that cook using primarily biomass fuels accounts for over 70%. Although the use of these fuels is more frequent in rural areas, there are still households in sub-urban areas that rely on charcoal. Beyond the promotion of subsidized LPG, domestic biogas and improved cookstoves are tested in some rural and sub-urban areas of the country. The results of the experiences compiled in this chapter show that these mechanisms are effective in decoupling biomass use and food preparation in sub-urban areas. Improved cookstoves can contribute to reducing biomass use by up to 45%. Domestic biogas digesters can replace biomass fuels for cooking in rural communities.
SRF depletion in early life contributes to social interaction deficits in the adulthood
Authors: Roszkowska Matylda , Krysiak Anna , Majchrowicz Lena , Nader Karolina , Beroun Anna , Michaluk Piotr , Pekala Martyna , Jaworski Jacek , Kondrakiewicz Ludwika , Puścian Alicja , Knapska Ewelina , Kaczmarek Leszek , Kalita Katarzyna
Published: May 2022

Alterations in social behavior are core symptoms of major developmental neuropsychiatric diseases such as autism spectrum disorders or schizophrenia. Hence, understanding their molecular and cellular underpinnings constitutes the major research task. Dysregulation of the global gene expression program in the developing brain leads to modifications in a number of neuronal connections, synaptic strength and shape, causing unbalanced neuronal plasticity, which may be important substrate in the pathogenesis of neurodevelopmental disorders, contributing to their clinical outcome. Serum response factor (SRF) is a major transcription factor in the brain. The behavioral influence of SRF deletion during neuronal differentiation and maturation has never been studied because previous attempts to knock-out the gene caused premature death. Herein, we generated mice that lacked SRF from early postnatal development to precisely investigate the role of SRF starting in the specific time window before maturation of excitatory synapses that are located on dendritic spine occurs. We show that the time-controlled loss of SRF in neurons alters specific aspects of social behaviors in SRF knock-out mice, and causes deficits in developmental spine maturation at both the structural and functional levels, including downregulated expression of the AMPARs subunits GluA1 and GluA2, and increases the percentage of filopodial/immature dendritic spines. In aggregate, our study uncovers the consequences of postnatal SRF elimination for spine maturation and social interactions revealing novel mechanisms underlying developmental neuropsychiatric diseases.
Toric Sasaki–Einstein metrics with conical singularities
Authors: de Borbon Martin , Legendre Eveline
Published: May 2022

We show that any toric Kähler cone with smooth compact cross-section admits a family of Calabi–Yau cone metrics with conical singularities along its toric divisors. The family is parametrized by the Reeb cone and the angles are given explicitly in terms of the Reeb vector field. The result is optimal, in the sense that any toric Calabi–Yau cone metric with conical singularities along the toric divisor (and smooth elsewhere) belongs to this family. We also provide examples and interpret our results in terms of Sasaki–Einstein metrics.
Zusammenhänge zwischen psychischen Erkrankungen und Wohnungslosigkeit: Ergebnisse einer Sekundärdatenanalyse in einem Berliner Gesundheitszentrum für Obdachlose
Authors: Knörle Uwe , Gutwinski Stefan , Willich Stefan N. , Berghöfer Anne
Published: May 2022

Hintergrund

Wohnungslosigkeit ist Ausdruck und Folge einer komplexen Problemlage, die die medizinischen und sozialen Versorgungssysteme in Deutschland vor große Herausforderungen stellt. Etwa 3 Viertel der wohnungslosen Menschen leiden an psychischen Erkrankungen. Ziel dieser Studie war es, Assoziationen zwischen psychischen Erkrankungen und Wohnungslosigkeit zu untersuchen.

Material und Methoden

Es wurde eine Sekundärdatenanalyse von Patient*innendokumentationen eines Berliner Gesundheitszentrums für Obdachlose durchgeführt. In die explorative Studie eingeschlossen wurden Daten von 112 wohnungslosen Patient*innen, die dort zwischen den Jahren 2006 und 2020 versorgt wurden.

Ergebnisse

Bei 84,9 % der Patient*innen lagen psychische Erkrankungen bereits vor dem Beginn der Wohnungslosigkeit vor. Assoziiert mit einem frühen Beginn der Wohnungslosigkeit waren die Faktoren niedrige Schulbildung sowie Drogenabusus. Eine lange Dauer der Wohnungslosigkeit war mit den Faktoren Alkoholabusus sowie Haftaufenthalte assoziiert. Jede erneute Episode der Straßenobdachlosigkeit war mit einer durchschnittlichen Verlängerung der Dauer der Wohnungslosigkeit um 7,9 Monate assoziiert.

Diskussion

Da psychische Erkrankungen wichtige Einflussfaktoren für die Entstehung und Aufrechterhaltung von Wohnungslosigkeit sind, sollten vermehrt präventive Strategien sowie spezialisierte Angebote für diese vulnerable Gruppe geschaffen werden. Insbesondere wiederkehrende Episoden der Straßenobdachlosigkeit sollten so weit wie möglich verhindert werden. Der Zusammenhang zwischen Inhaftierungen und Wohnungslosigkeit legt nahe, dass eine intensivere Begleitung bei der Wiedereingliederung nach Haftentlassung erforderlich ist.
Acute clinical evaluation for syndesmosis injury has high diagnostic value
Authors: Baltes Thomas P. A. , Al Sayrafi Omar , Arnáiz Javier , Al-Naimi Maryam R. , Geertsema Celeste , Geertsema Liesel , Holtzhausen Louis , D’Hooghe Pieter , Kerkhoffs Gino M. M. J. , Tol Johannes L.
Published: May 2022

Purpose

To determine the diagnostic value of injury history, physical examination, six syndesmosis tests and overall clinical suspicion for syndesmosis injury.

Methods

All athletes (> 18 yrs) with an acute ankle injury presenting within 7 days post-injury were assessed for eligibility. Acute ankle injuries were excluded if imaging studies demonstrated a frank fracture or 3 T MRI could not be acquired within 10 days post-injury. Standardized injury history was recorded, and physical examination was performed by an Orthopaedic Surgeon or Sports Medicine Physician. Overall clinical suspicion was documented prior to MRI. Multivariate logistic regression was used to determine the association between independent predictors and syndesmosis injury.

Results

Between September 2016 and July 2019, a total of 150 acute ankle injuries were included. The median time from injury to acute clinical evaluation was 2 days (IQR 2). Prior to clinical evaluation, the median patient reported Visual Analog Scale for pain was 8/10 (IQR 2). Syndesmosis injury was present in 26 acute ankle injuries. An eversion mechanism of injury had a positive LR 3.47 (CI 95% 1.55–7.77). The squeeze tests had a positive LR of 2.20 (CI 95% 1.29–3.77) and a negative LR of 0.68 (CI 95% 0.48–0.98). Overall clinical suspicion had a sensitivity of 73% (CI 95% 52–88) and negative predictive value of 89% (CI 95% 78–95). Multivariate regression analyses demonstrated significant association for eversion mechanism of injury (OR 4.99; CI 95% 1.56–16.01) and a positive squeeze test (OR 3.25; CI 95% 1.24–8.51).

Conclusions

In an acute clinical setting with patients reporting high levels of ankle pain, a negative overall clinical suspicion reduces the probability of syndesmosis injury. Eversion mechanism of injury and a positive squeeze test are associated with higher odds of syndesmosis injury.

Level of evidence

Level III.
Direct conversion of latitude and height from one ellipsoid to another
Authors: Smith Walter H. F.
Published: May 2022

I suggest a method for converting geodetic height and latitude from one oblate ellipsoid of revolution to another having the same center and symmetry axis. Unlike other approaches, the method here does not obtain height and latitude from Earth-centered, Earth-fixed (ECEF) Cartesian coordinates; this feature allows height conversion with high accuracy even in cases where the data format limits the precision of the latitude data. Height and latitude conversions can be expressed as a Fourier series in even multiples of latitude, with height changes having only cosines and latitude changes having only sines. The absolute difference of the flattenings of the two ellipsoids furnishes a simple upper bound on the maximum absolute latitude change. Conversions between the TOPEX and WGS84 ellipsoids, a practical necessity for the inter-mission comparison of satellite laser and radar altimeter data, illustrate the findings. Because the differences in the flattenings and semi-major axes of these ellipsoids are small, truncating the Fourier series after the term in twice the latitude gives an approximate conversion with an error less than 9 $$\times $$
×
10–12 radians of latitude and about 6 $$\times $$
×
10–6 m of height.
Effectiveness and safety of gonadotropins used in female infertility: a population-based study in the Lazio region, Italy
Authors: Rosa Alessandro Cesare , Pacchiarotti Arianna , Addis Antonio , Ciardulli Andrea , Belleudi Valeria , Davoli Marina , Kirchmayer Ursula
Published: May 2022

Purpose

Infertility is a topic of growing interest, and female infertility is often treated with gonadotropins. Evidence regarding comparative safety and efficacy of different gonadotropin formulations is available from clinical studies, while real-world data are missing. The present study aims to investigate effectiveness and safety of treatment with different gonadotropin formulations in women undergoing medically assisted procreation treatments in Latium, a region in central Italy, through a real-world data approach.

Methods

A retrospective population-based cohort study in women between the ages of 18 and 45 years who were prescribed with at least one gonadotropin between 2007 and 2019 was conducted. Women were enrolled from the regional drug dispense registry, and data on their clinical history, exposure to therapeutic cycles (based on recombinant “REC” or extractives “EXT” gonadotropin, or combined protocol “CMD” (REC + EXT)), and maternal/infantile outcomes were linked from the regional healthcare administrative databases. Multivariate logistic regression models were applied to estimate the association between exposure and outcomes.

Results

Overall, 90,292 therapeutic cycles prescribed to 35,899 women were linked to pregnancies. Overall, 15.8% of cycles successfully led to pregnancy. Compared to extractives, recombinant and combined treatments showed a stronger association with conception rate (RRREC adj = 1.06, 95% CI: 1.01–1.12; RRCBD adj = 1.17, 95% CI: 1.11–1.24). Maternal outcomes occurred in less than 5% of deliveries, and no significant differences between treatments were observed (REC vs EXT, pre-eclampsia: RR adj = 1.24, 95% CI: 0.86–1.79, ovarian hyperstimulation syndrome: RR adj = 1.25, 95% CI: 0.59–2.65, gestational diabetes: RR adj = 1.06, 95% CI: 0.84–1.35). Regarding infantile outcomes, similar results were obtained for different gonadotropin formulations (REC vs EXT: low birth weight: RR adj = 0.98, 95% CI: 0.83–1.26, multiple births: RR adj = 1.06, 95% CI: 0.92–1.23, preterm birth: RR adj = 1.03, 95% CI: 0.92–1.26).

Conclusions

Efficacy and safety profiles of REC proved to be similar to those of EXT. Regarding the efficacy in terms of conception rate and birth rate, protocols using the combined approach performed slightly better. Outcomes related to maternal and infantile safety were generally very rare, and safety features were overlapping between gonadotropin formulations.
Fibrin-targeting molecular MRI in inflammatory CNS disorders
Authors: Lohmeier Johannes , Silva Rafaela V. , Tietze Anna , Taupitz Matthias , Kaneko Takaaki , Prüss Harald , Paul Friedemann , Infante-Duarte Carmen , Hamm Bernd , Caravan Peter , Makowski Marcus R.
Published: May 2022

Background

Fibrin deposition is a fundamental pathophysiological event in the inflammatory component of various CNS disorders, such as multiple sclerosis (MS) and Alzheimer’s disease. Beyond its traditional role in coagulation, fibrin elicits immunoinflammatory changes with oxidative stress response and activation of CNS-resident/peripheral immune cells contributing to CNS injury.

Purpose

To investigate if CNS fibrin deposition can be determined using molecular MRI, and to assess its capacity as a non-invasive imaging biomarker that corresponds to inflammatory response and barrier impairment.

Materials and methods

Specificity and efficacy of a peptide-conjugated Gd-based molecular MRI probe (EP2104-R) to visualise and quantify CNS fibrin deposition were evaluated. Probe efficacy to specifically target CNS fibrin deposition in murine adoptive-transfer experimental autoimmune encephalomyelitis (EAE), a pre-clinical model for MS (n = 12), was assessed. Findings were validated using immunohistochemistry and laser ablation inductively coupled plasma mass spectrometry. Deposition of fibrin in neuroinflammatory conditions was investigated and its diagnostic capacity for disease staging and monitoring as well as quantification of immunoinflammatory response was determined. Results were compared using t-tests (two groups) or one-way ANOVA with multiple comparisons test. Linear regression was used to model the relationship between variables.

Results

For the first time (to our knowledge), CNS fibrin deposition was visualised and quantified in vivo using molecular imaging. Signal enhancement was apparent in EAE lesions even 12-h after administration of EP2104-R due to targeted binding (M ± SD, 1.07 ± 0.10 (baseline) vs. 0.73 ± 0.09 (EP2104-R), p = .008), which could be inhibited with an MRI-silent analogue (M ± SD, 0.60 ± 0.14 (EP2104-R) vs. 0.96 ± 0.13 (EP2104-La), p = .006). CNS fibrin deposition corresponded to immunoinflammatory activity (R2 = 0.85, p < .001) and disability (R2 = 0.81, p < .001) in a model for MS, which suggests a clinical role for staging and monitoring. Additionally, EP2104-R showed substantially higher SNR (M ± SD, 6.6 ± 1 (EP2104-R) vs. 2.7 ± 0.4 (gadobutrol), p = .004) than clinically used contrast media, which increases sensitivity for lesion detection.

Conclusions

Molecular imaging of CNS fibrin deposition provides an imaging biomarker for inflammatory CNS pathology, which corresponds to pathophysiological ECM remodelling and disease activity, and yields high signal-to-noise ratio, which can improve diagnostic neuroimaging across several neurological diseases with variable degrees of barrier impairment.
The Role of Different Types of Actors In The Future of Sustainable Agriculture In a Dutch Peri-urban Area
Authors: Schulp Catharina J. E. , Komossa Franziska , Scherer Laura , van der Zanden Emma H. , Debolini Marta , Piorr Annette
Published: May 2022

Peri-urban areas support a broad range of multifunctional demands for public goods. In northwest Europe, peri-urban areas tend to overlap with intensive agricultural land, resulting in conflicts between agricultural use and the public good demands of residents. Sustainable intensification (SI) of agriculture might help reconcile agricultural and well-being goals, but it is unclear how the mix of actors in a peri-urban setting can trigger or restrain SI. In a Dutch case study, we explored how SI of agriculture can contribute to making peri-urban areas more sustainable, and which actors are key enabling factors for implementing SI. We used interviews, surveys, workshops, and empirical analysis to obtain insight into the stakeholder’s vision of a sustainable future for the case study area, the farming system and actor network. We integrated these insights in a Bayesian Belief Network, where we linked the actor network to implementation of three SI measures (farm-level efficiency measures, small landscape elements, and direct sales), and used sensitivity analysis to model effects of support for implementation by different groups of actors. The case study has a dense stakeholder network, where, dependent on the SI measure, farmers are triggered by all actors to implement SI, or have a stronger role in uptake themselves. The sensitivity analysis suggested that the future preferred by the stakeholders requires broad support of all actors involved, with local actors without a formal role being essential for uptake. Overall, trade-offs among public goods are almost inevitable when taking up SI measures.
Evaluation of Neoadjuvant Chemoradiotherapy Followed by Surgery for Borderline Resectable Esophageal Squamous Cell Carcinoma
Authors: Hirohata Ryosuke , Hamai Yoichi , Hihara Jun , Emi Manabu , Kurokawa Tomoaki , Yoshikawa Toru , Ohsawa Manato , Kitasaki Nao , Okada Morihito
Published: May 2022

Background

It is occasionally difficult to diagnose cT3 or cT4b using imaging examinations for esophageal cancer. The optimal treatment strategy for borderline resectable esophageal squamous cell carcinoma (BR‐ESCC) is unclear.

Methods

We included 131 patients with cT3 ESCC who received neoadjuvant chemoradiotherapy (NCRT) followed by surgery. The patients were classified as having definitive cT3 (D‐cT3) or borderline resectable cT3 (BR‐cT3), based on presence of undeniable adjacent organ invasion on pretreatment CT. Surgical outcomes and prognoses were compared among patients with D‐cT3 and BR‐cT3 tumors, and the risk factors for non‐R0 resection were assessed.

Results

Ninety and 41 patients were classified as D‐cT3 and BR‐cT3, respectively. Although BR‐cT3 had a significantly higher non‐R0 resection rate than D‐cT3 (D‐cT3 3.7%; BR‐cT3 14.6%), BR‐cT3 was not correlated with shorter overall survival (OS) (D‐cT3 5‐year OS, 50.8%; BR‐cT3 5‐year OS 38.4%; p = 0.234). Conversely, non‐R0 resection was significantly associated with poor OS (R0 resection 5‐year OS 48.8%; non‐R0 resection 5‐year OS 22.2%; p = 0.031). Cox regression analysis of OS demonstrated that BR‐cT3 was not a prognostic factor. In the analysis of risk factors for non‐R0 resection, BR‐cT3 (p = 0.027), suspected invasion of the trachea or bronchus (p = 0.046), and high SUVmax of the primary lesion after NCRT (p = 0.002) were risk factors.

Conclusions

NCRT followed by surgery achieved a relatively high R0 resection rate and an almost equal overall survival rate for BR‐cT3 compared with D‐cT3 ESCC. Thus, NCRT followed by surgery is an effective treatment strategy for patients with BR‐cT3 ESCC.
Forensic age assessment by 3.0 T MRI of the wrist: adaption of the Vieth classification
Authors: Ottow C. , Schmidt S. , Heindel W. , Pfeiffer H. , Buerke B. , Schmeling A. , Vieth V.
Published: May 2022

Objectives

In order to find a reliable method to correctly assess majority in both sexes by MRI, a study was conducted to evaluate the applicability of the recently presented Vieth classification in wrist MRI, after it had originally been proposed for knee MRI.

Methods

After receiving a positive vote by the ethics committee, the left-hand wrists of 347 male and 348 female volunteers of German nationality in the age bracket 12–24 years were scanned. Before conducting the prospective, cross-sectional examinations, an informed consent was obtained from each volunteer. A 3.0 T MRI scanner was used, acquiring a T1 turbo spin-echo sequence (TSE) and a T2 TSE sequence with fat suppression by spectral presaturation with inversion recovery (SPIR). The images were assessed by applying the Vieth classification. Minimum, maximum, mean ± standard deviation, and median with lower and upper quartiles were defined. Intra- and interobserver agreements were determined by calculating the kappa coefficients. Differences between the sexes were analyzed using the Mann-Whitney U test.

Results

By applying the unmodified Vieth classification with corresponding schematics, it was possible to assess majority in both sexes via the epiphyseal-diaphyseal fusion of the distal radius and in males also via the epiphyseal-diaphyseal fusion of the distal ulna. The Mann-Whitney U test implied significant sex-related differences for all stages. For both epiphyses, the intra- and interobserver agreement levels were very good (κ > 0.8).

Conclusion

If confirmed by further studies, it would be possible to determine the completion of the 18th year of life in both sexes by 3.0 T MRI of the wrist and using the Vieth classification.

Key Points

• The Vieth classification allows determining majority in males and females alike based on the distal radius’ epiphysis by 3.0 T MRI of the wrist.

• The Vieth classification also allows determining majority in males based on the distal ulna’s epiphysis by 3.0 T MRI of the wrist, but not in females.

• The presented data can be deemed referential within certain discussed boundaries.
Safety and Clinical Benefits of Laryngeal Closure in Patients with Amyotrophic Lateral Sclerosis
Authors: Yokoi Sayaka , Nishio Naoki , Maruo Takashi , Hiramatsu Mariko , Mukoyama Nobuaki , Tsuzuki Hidenori , Wada Akihisa , Atsuta Naoki , Ito Daisuke , Tsuboi Takashi , Sobue Gen , Katsuno Masahisa , Fujimoto Yasushi , Sone Michihiko
Published: May 2022

This study evaluated the safety of laryngeal closure and post-surgical changes in swallowing function of patients with amyotrophic lateral sclerosis (ALS) and proposed an appropriate surgical strategy for patients with ALS. Clinical and surgical data of 26 consecutive patients with ALS who underwent laryngeal closure at Nagoya University Hospital in Japan between 2003 and 2020 were retrospectively analyzed. Changes in swallowing functions were evaluated before and approximately 1 month post-surgery using Neuromuscular Disease Swallowing Status Scale (NdSSS), and Functional Oral Intake Scale (FOIS). The median operation time was 126 min (range, 51–163 min), and the median intraoperative blood loss was 20 mL (range, 0–88 mL). Among the 26 ALS patients who underwent laryngeal closure, grade 1 (mild) complications occurred in three patients (12%); however, no severe complications were observed. After surgery, 25 patients (96%) maintained the swallowing function and only one patient (4%) had deteriorating NdSSS and FOIS scores. No patients were referred to our hospital due to severe aspiration pneumonia after the surgery. Two patients did not require a feeding tube after the surgery and returned to oral intake. Laryngeal closure may be a safe surgical procedure for preventing chronic aspiration and may also maintain swallowing function of patients with ALS. Further multicenter prospective studies using the gold standard videofluoroscopic swallowing examination are required to support our findings.
Risk factors for metastasis and survival of patients with T1 gastric neuroendocrine carcinoma treated with endoscopic therapy versus surgical resection
Authors: Ye Hua , Yuan Yuan , Chen Ping , Zheng Qi
Published: May 2022

Background

Gastrectomy with lymphadenectomy is recommended for early gastric Neuroendocrine carcinoma (G-NEC). We attempted to determine the prevalence and risk factors of metastasis of T1 G-NEC and compare the long-term survival of patients after receiving endoscopic therapy (ET) and radical surgery.

Methods

In this study, 205 patients in total with T1 G-NEC were collected from the Surveillance Epidemiology and End Result database. Independent predictors of metastasis were identified by Logistic regression analysis, followed by the calculation of both cancer-specific survival (CSS) and overall survival (OS).

Results

Twenty-five patients (12.2%) were burdened with metastasis at initial diagnosis, with a prevalence of 5.2% (3/58) in mucosa lesions and 16.2% (16/99) in submucosa lesions (P = 0.045). No metastasis was detected in lesions with mucosa involvement and tumors ≦ 20 mm (0%, 0/49). The most significant risk factor for metastasis was tumors > 20 mm [odds ratio (OR) 18.64; 95% confidence interval (CI) 4.01–86.68; P < 0.001]. For patients with T1N0M0 G-NEC who received ET or surgery, the 10-year OS was similar between the mucosa extension and submucosa extension groups, which was 91.56% in ET group vs 87.50% in surgery group (P = 0.62) and 57.33% vs 77.83% (P = 0.11), respectively. In addition, the 10-year CSS was also similar between the mucosa extension and submucosa extension groups with 97.30% in ET vs 100% in surgery (P = 0.51) and 97.62% vs 86.49% (P = 0.65).

Conclusions

In G-NEC, tumors > 20 mm were considered as the most significant risk factor for metastasis. ET seemed adequate for the lesions with mucosa involvement and size ≦ 2 cm.
Analysis of the risk factors for early tether breakage following vertebral body tethering in adolescent idiopathic scoliosis
Authors: Baroncini A. , Trobisch P. , Eschweiler J. , Migliorini F.
Published: May 2022

Introduction

Tether breakage is a common mechanical complication after VBT. When this occurs shortly after surgery, patients may be at higher risk for loss of correction. Aim of this study was to analyze demographic and radiographic parameters that may potentially be risk factors for early tether breakage, as no data are yet available on this topic.

Materials and methods

All skeletally immature patients who underwent VBT and for whom a 1-year follow-up was available were included in the study. Demographic, intraoperative and coronal and sagittal parameters from the preoperative and 1st standing X-rays were collected. Patients were divided in two groups according to the presence or absence of a breakage and the outcomes of interest were compared.

Results

Data from 105 patients were available (age 14.2 ± 1.5, 153 curves). Lumbar curves showed a higher risk of breakage than thoracic ones (71% vs. 29%, P < 0.0001). Overall, preoperative risk factors were a high curve magnitude (MD, mean difference − 4.1°, P = 0.03) and a limited flexibility (MD 8.9%, P = 0.006); postoperative risk factors were a large residual curve (MD − 6.4°, P = 0.0005) and a limited correction (MD 8.4%, P = 0.0005). The same risk factors were identified in thoracic curves, while in lumbar instrumentation only a higher preoperative Cobb angle represented a risk factor for breakage. Age and skeletal maturity did not represent risk factors.

Conclusion

The main preoperative risk factors for early tether breakage after VBT are a high curve magnitude and a limited flexibility. A limited curve correction also represents a risk factor for this complication.
Dalbergiones lower the inflammatory response in oral cells in vitro
Authors: Shao Feng , Panahipour Layla , Omerbasic Anes , Tang Fangrui , Gruber Reinhard
Published: May 2022

Objectives

Periodontitis is a global health burden that underlines the demand for anti-inflammatory treatment. Dalbergia melanoxylon being a rich source of flavonoids has been widely used in traditional medicine but the potential anti-inflammatory activity of its dalbergiones remains to be shown.

Material and methods

We have isolated 3′-hydroxy-4,4′-dimethoxydalbergione, 4-methoxydalbergione, and 4′-hydroxy-4-methoxydalbergione from Dalbergia melanoxylon and tested their potential anti-inflammatory activity.

Results

All dalbergiones are potent inhibitors of an LPS-induced inflammatory response of RAW 264.7 macrophages. This is specified by IL1β and IL6 production, and the p65 nuclear translocation. Consistently, in primary macrophages, the dalbergiones caused an M1-to-M2 polarization switch indicated by the decreased ration of IL1β and IL6 versus arginase 1 and YM1 expression. To implement oral cells, we have used gingival fibroblasts exposed to IL1β and TNFα. Consistently, all dalbergiones reduced the expression of IL6 and IL8 as well as the nuclear translocation of p65.

Conclusion

These findings increase the accumulating knowledge on dalbergiones and extend it towards its capacity to lower the inflammatory response of oral cells.

Clinical relevance

These findings are another piece of evidence that supports the use of herbal medicine to potentially lower inflammatory events related to dentistry.
A remote sensing-based classification approach for river mouths of the Amazon-influenced Guianas coast
Authors: Gardel Antoine , Anthony Edward J. , Santos Valdenira F. , Huybrechts Nicolas , Lesourd Sandric , Sottolichio Aldo , Maury Tanguy
Published: May 2022

The mouths of the rivers on the 1500-km-long Guianas coast, South America, are strongly influenced by large mud banks migrating alongshore from the Amazon River. To probe this influence, a river-mouth morphological classification scheme was carried out from satellite images, complemented by data from rare previous studies of estuarine hydrodynamics. The classification highlights a variety of morphological and dynamic river-mouth types that are further influenced by both fluvial water discharge and fluvial catchment rock type. Three basic types are identified: (1) river mouths diverted westward by capes and spits built from multi-decadal to multi-millennial accumulation of mud supplied by the Amazon; among these, mouths close to the Amazon are fixed by bedrock surrounded by mud; (2) small river mouths in French Guiana fixed by outcrops of Precambrian rocks that form headlands devoid of Amazon mud; and (3) large river mouths characterized by high water discharge that imparts an orientation normal to the coast; the largest two belonging to this type (the Essequibo in Guyana and the Maroni on the border between French Guiana and Suriname) exhibit infilled mouths that are transitioning towards deltas. These river mouths show a tropical seasonal estuarine circulation regime strongly influenced by Amazon mud. The influence of mud from the distant Amazon constitutes a unique aspect of the river mouths on the Guianas coast. Field and modelling studies in the future will be needed in order to achieve better characterization of the influence of Amazon mud on the estuarine circulation systems and of the distribution of sediment types within these river mouths, including sand supplied by the rivers.
Increasing the Efficacy of Treatment for Socially Anxious Youth Through Theoretically Derived Improvements: A Pilot Study
Authors: Leigh Lynda H. , Doyle Frances L. , Hudson Jennifer L.
Published: May 2022

Cognitive behavioural therapy is the first line of treatment for social anxiety disorder; however, children with social anxiety disorder do not respond as well to generic cognitive behavioural therapy programs, compared to children with other anxiety disorders. The aim of the study was to provide a preliminary examination of the efficacy and applicability of a new disorder specific intervention for children with social anxiety disorder. Five children aged 7–13 years, with a primary or secondary DSM-5 diagnosis of social anxiety disorder were provided with an adapted version of the Cool Kids anxiety program. Three out of the five children were in remission from social anxiety disorder at the end of the intervention and at 3-month follow-up. Statistically significant improvements were also noted in overall anxiety symptoms and functioning. Preliminary evidence was found for the efficacy of a social anxiety version of the Cool Kids program.
Modeling Dinophysis in Western Andalucía using an autoregressive hidden Markov model
Authors: Aron Jordan , Albert Paul S. , Gribble Matthew O.
Published: May 2022

Dinophysis spp. can produce diarrhetic shellfish toxins (DST) including okadaic acid and dinophysistoxins, and some strains can also produce non-diarrheic pectenotoxins. Although DSTs are of human health concern and have motivated environmental monitoring programs in many locations, these monitoring programs often have temporal data gaps (e.g., days without measurements). This paper presents a model for the historical time-series, on a daily basis, of DST-producing toxigenic Dinophysis in 8 monitored locations in western Andalucía over 2015–2020, incorporating measurements of algae counts and DST levels. We fitted a bivariate hidden Markov Model (HMM) incorporating an autoregressive correlation among the observed DST measurements to account for environmental persistence of DST. We then reconstruct the maximum-likelihood profile of algae presence in the water column at daily intervals using the Viterbi algorithm. Using historical monitoring data from Andalucía, the model estimated that potentially toxigenic Dinophysis algae is present at greater than or equal to 250 cells/L between< 1% and>10% of the year depending on the site and year. The historical time-series reconstruction enabled by this method may facilitate future investigations into temporal dynamics of toxigenic Dinophysis blooms.
Breadth of study at secondary school and the attainment and progression of university graduates in Scotland, 1960–2002
Authors: Paterson Lindsay
Published: May 2022

The relationship between the breadth of the curriculum which university students followed at secondary school and their degree attainment or their entry to employment is studied using a series of surveys of graduates from Scottish universities between 1960 and 2002. The relationship of the school curriculum to the later experience of students who entered university has not been extensively studied. Scotland is a useful case study for this purpose because breadth of study at school was a core feature of school-leaving assessment from the origins of modern secondary schooling in the early twentieth century until the end of the century. Breadth of learning was also a principle of the dominant university tradition in Scotland from the mid-nineteenth century onwards. The conclusion of the analysis is that breadth was associated with propensity to enter professions rather than managerial occupations, and to avoiding low-status occupations. But also, for students with relatively moderate or low attainment from school, breadth was associated with a lower chance of gaining the highest attainment at university.
Aponeurosis discission, a low-detergent method for tissue-engineered acellular ligament scaffolds
Authors: Zhou Sheng-yuan , Yuan Bo , Huang Wen-mao , Chen Xiong-sheng , Jia Lian-shun
Published: May 2022

Detergent treatment is the most commonly used method for the decellularization of ligaments and tendon grafts. However, it is well recognized that detergent treatment can also adversely affect the extracellular matrix. This study found that discission into the aponeurosis layer of the patellar tendon (PT) before decellularization is conducive to extracting cells from the PT using a low quantity of detergent in a short time period. The acellular aponeurosis discission ligament (AADL) retains its native collagen fibril structure and mechanical properties. Moreover, the PT retained cell and tissue compatibility in vitro and in vivo. After implantation into a defective allogeneic PT, we found that the AADL healed well in the host, and its collagen structure exhibited gradual improvement 12 months after implantation with satisfactory reconstruction.

Impact

The aponeurosis of tendons/ligaments is the main barrier to achieving complete decellularization, and it thus prevents complete recellularization for applications in tissue engineering. Aponeurosis can obstruct the removal of cell components. We found that excising the aponeurosis before decellularization allows for the removal of cellular components with a reduced amount of detergent, thus improving the biological properties of the acellular ligament. To the best of our knowledge, no similar studies have been performed.
Contrasting Explanations for Understanding and Regularizing Model Adaptations
Authors: Artelt André , Hinder Fabian , Vaquet Valerie , Feldhans Robert , Hammer Barbara
Published: May 2022

Many of today’s decision making systems deployed in the real world are not static—they are changing and adapting over time, a phenomenon known as model adaptation takes place. Because of their wide reaching influence and potentially serious consequences, the need for transparency and interpretability of AI-based decision making systems is widely accepted and thus have been worked on extensively—e.g. a very prominent class of explanations are contrasting explanations which try to mimic human explanations. However, usually, explanation methods assume a static system that has to be explained. Explaining non-static systems is still an open research question, which poses the challenge how to explain model differences, adaptations and changes. In this contribution, we propose and (empirically) evaluate a general framework for explaining model adaptations and differences by contrasting explanations. We also propose a method for automatically finding regions in data space that are affected by a given model adaptation—i.e. regions where the internal reasoning of the other (e.g. adapted) model changed—and thus should be explained. Finally, we also propose a regularization for model adaptations to ensure that the internal reasoning of the adapted model does not change in an unwanted way.
Interaction between soil and fertiliser nitrogen drives plant nitrogen uptake and nitrous oxide (N2O) emissions in tropical sugarcane systems
Authors: Takeda Naoya , Friedl Johannes , Kirkby Robert , Rowlings David , De Rosa Daniele , Scheer Clemens , Grace Peter
Published: May 2022

Aims

High nitrogen (N) fertiliser inputs in intensive sugarcane systems drive productivity but also significant emissions of nitrous oxide (N2O), a potent greenhouse gas. Fertiliser and soil N availability for both plant N uptake and N2O emissions across different N rates remain unknown, hindering efficient N management. This study investigated the contribution of fertiliser and soil N and their interaction to plant N uptake and N2O emissions in two intensively managed tropical sugarcane systems.

Methods

High temporal resolution N2O measurements were combined with 15N recoveries across four N fertiliser rates, (100, 150, 200 and 250 kg N ha− 1) in soil, plant and N2O emissions.

Results

Cumulative N2O emissions ranged from 0.3 to 4.1 kg N ha− 1, corresponding to emission factors ranging from 0.7 to 2.4%. Native soil N accounted for > 60% of cumulative N2O emissions and total plant N uptake. Fertiliser N addition increased N2O emissions from native soil N compared to the unfertilised control, highlighting the interaction between fertiliser and soil N, which determined the overall magnitude but also the response of total N2O emissions to N rates dependent on the site conditions. Overall fertiliser 15N loss responded exponentially to N rates with 50% of applied N fertiliser permanently lost even at the recommended N rate.

Conclusions

The interaction between fertiliser and soil N and its contribution to N uptake and N2O emissions demonstrate the importance of integrating soil fertility management with N fertiliser rate recommendations for sugarcane systems to maintain crop productivity and reduce environmental impacts.