bluuebunny/crossref_metadata_2025_split huggingface dataset:
Short-term safety results from compassionate use of risdiplam in patients with spinal muscular atrophy in Germany
Authors: Hahn Andreas , Günther René , Ludolph Albert , Schwartz Oliver , Trollmann Regina , Weydt Patrick , Weiler Markus , Neuland Kathrin , Schwaderer Martin Sebastian , Hagenacker Tim ,   the Risdiplam Compassionate Use Program Group
Published: July 2022

AbstractBackgroundThe oral, selectiveSMN2-splicing modifier risdiplam obtained European approval in March 2021 for the treatment of patients ≥ 2 months old with a clinical diagnosis of 5q-associated spinal muscular atrophy (SMA) 1/2/3 or with 1–4SMN2gene copies. For the preceding 12 months, this compassionate use program (CUP) made risdiplam available to patients with SMA1/2 in Germany who could not receive any approved SMA therapy.Patients and methodsPatients with SMA1/2, aged ≥ 2 months at enrollment, could be included if they were not eligible for, no longer responsive to, or not able to tolerate nusinersen or not able to receive onasemnogene abeparvovec. Oral risdiplam dosing ranged from 0.2 mg/kg to 5 mg depending on age and weight. All treatment decisions were made by the attending physicians, who were required to report all adverse events (AEs).ResultsBetween March 12, 2020 and March 30, 2021, 36 patients with SMA1 and 98 patients with SMA2 were enrolled, with 31 patients and 80 patients receiving ≥ 1 risdiplam dose, respectively. The median (range) age was 10.5 (3–52) years in the SMA1 cohort, and 26.5 (3–60) years in the SMA2 cohort. 22.2% of patients with SMA1 and 48.0% with SMA2 were treatment-naïve. Most patients were not eligible/could not continue to receive nusinersen due to scoliosis/safety risk (SMA1: 75.0%; SMA2: 96.9%), risks associated with sedation (77.8%; 63.3%), or loss of efficacy (30.6%; 12.2%). Safety data were generally in line with the safety profile of risdiplam in ongoing clinical studies. Gastrointestinal disorders were the most common AEs. For patients with SMA1, 30 AEs were reported in 13 cases with 2 serious AEs in 1 patient. For SMA2, 100 AEs were documented in 31 case reports, including 8 serious AEs in 2 patients.ConclusionsWe present the first real-world safety data of risdiplam in patients with SMA in Germany. Our observations indicated no new safety signals under real-world conditions. Real-world SMA1/2 populations comprise considerable numbers of patients who are not eligible for gene therapy and cannot tolerate or have failed nusinersen treatment. This medical need may be addressed by oral risdiplam.
RSPO1-mutated keratinocytes from palmoplantar keratoderma display impaired differentiation, alteration of cell–cell adhesion, EMT-like phenotype and invasiveness properties: implications for squamous cell carcinoma susceptibility in patients with 46XX disorder of sexual development
Authors: Dellambra Elena , Cordisco Sonia , Delle Monache Francesca , Bondanza Sergio , Teson Massimo , Nicodemi Ezio Maria , Didona Biagio , Condorelli Angelo Giuseppe , Camerino Giovanna , Castiglia Daniele , Guerra Liliana 
Published: July 2022

AbstractBackgroundSecreted R-spondin (RSPO) proteins play a key role in reproductive organ development, epithelial stem cell renewal and cancer induction by reinforcing canonical Wnt signaling. We have previously reported that palmoplantar keratoderma (PPK), predisposition to cutaneous squamous cell carcinoma (SCC) development and sex reversal segregate as autosomal recessive trait in patients carryingRSPO1-mutations.Although our previous findings suggested that RSPO1 secreted from fibroblasts regulates keratinocyte growth or differentiation, the role of this protein in the epidermis remains largely unexplored. Our study was aimed at expanding the phenotypic, molecular and functional characterization ofRSPO1-mutated skin and keratinocytes.ResultsCultured primary keratinocytes from PPK skin of aRSPO1-mutated XX-sex reversed patient displayed highly impaired differentiation and epithelial-mesenchymal transition (EMT)-like phenotype. Interestingly,RSPO1-mutated PPK skin expressed markers of increased proliferation, dedifferentiation and altered cell–cell adhesion. Furthermore, all these signs were more evident in SCC specimens of the patient. Cultured PPK patient’s keratinocytes exhibited increased expression of cell‒matrix adhesion proteins and extracellular matrix remodeling enzymes. Moreover, they showed invasiveness properties in an organotypic skin model in presence of PPK fibroblasts, which behave like cancer-associated fibroblasts. However, the co-culture with normal fibroblasts or treatment with the recombinant RSPO1 protein did not revert or reduce the EMT-like phenotype and invasion capability of PPK keratinocytes. Notably,RSPO1-mutated PPK fibroblasts induced a hyperproliferative and dedifferentiated phenotype of age-matched normal control plantar keratinocytes. Wnt signaling has a key role in both PPK promotion and SCC development. Accordingly, Wnt mediators were differentially expressed in both PPK keratinocytes and skin specimens ofRSPO1-mutated patient compared to control.ConclusionsAltogether our data indicate that the absence of RSPO1 in patients with 46XX disorder of sexual development affects the skin microenvironment and epidermal integrity, thus contributing to the risk of SCC tumorigenesis in palmoplantar regions exposed to major frictional stresses.
Implant migration and functional outcome of Reverse Shoulder Lateralized Glenosphere Line Extension System: a study protocol for a randomized controlled trial
Authors: Jensen Marie Louise , Olsen Bo S. , Nyring Marc R. K. , Yilmaz Müjgan , Petersen Michael M. , Flivik Gunnar , Rasmussen Jeppe V. 
Published: July 2022

Abstract
Background
Inferior scapular notching is a complication unique to reverse shoulder arthroplasty. The most efficient technique to avoid inferior scapular notching has been reported to be lateralization of the glenoid offset. This study aims to compare radiological and functional outcomes of the DELTA Xtend® Reverse Shoulder System Lateralized Glenosphere Line Extension (intervention group) with the Standard DELTA Xtend® Reverse Shoulder System (control group). We hypothesize that the lateralization improves the patient outcome by decreasing the risk of inferior scapular notching without increasing the risk of migration and loosening of glenoid component.

Methods
In this randomized controlled trial, all Danish citizens with rotator cuff arthropathy or degeneration of the glenohumeral joint with severe posterior wear and allocated for a reverse total shoulder arthroplasty at the department of orthopaedic surgery at Herlev and Gentofte Hospital, Copenhagen University Hospital, will be considered for participation. The exclusion criteria are as follows: below 50 years of age, cognitive or linguistic impairment, insufficient glenoid bone stock, previous fracture in the upper extremity and autoimmune-mediated inflammatory arthritis. There will be included a total of 122 patients of which 56 will participate in the radiostereometric analysis. This number of patients allows 20% to drop out. The co-primary outcomes are the pattern and magnitude of the migration of the glenoid component assessed by radiostereometric analysis and the Western Ontario Osteoarthritis of the Shoulder index. The secondary outcomes are inferior scapular notching, patient-reported and functional outcomes (Oxford shoulder score, Constant-Murley score and pain), side effects and complications, changes in bone mineral density and economy. The included patients will be examined before the surgery, within 1 week and 3, 6, 12 and 24 months after.

Discussion
No previous studies have compared the conventional reverse shoulder arthroplasty with the lateralized reverse shoulder arthroplasty in a randomized controlled trial regarding migration and functional outcome. Furthermore, radiostereometric analysis has not been used to evaluate the migration of reverse shoulder arthroplasty in a randomized controlled trial. This study intends to determine which treatment has the most optimal outcome for the benefit of future patients with an indication for reverse shoulder arthroplasty.

Trial registration
The study has been notified to Pactius and has approval number P-2021-231. Furthermore, the study will be registered on Clinicaltrials.gov before starting the inclusion.
Stromal vascular fraction-enriched fat grafting as treatment of adherent scars: study design of a non-randomized early phase trial
Authors: Vriend Linda , van Dongen Joris A. , Pijpe Anouk , Nieuwenhuis Marianne K. , Jongen Sandra J. M. , Harmsen Martin C. , van Zuijlen Paul P. M. , van der Lei Berend 
Published: July 2022

Abstract
Background
In the last decades, autologous fat grafting has been used to treat adherent dermal scars. The observed regenerative and scar-reducing properties have been mainly ascribed to the tissue-derived stromal vascular fraction (tSVF) in adipose tissue. Adipose tissue’s components augment local angiogenesis and mitosis in resident tissue cells. Moreover, it promotes collagen remodeling. We hypothesize that tSVF potentiates fat grafting-based treatment of adherent scars. Therefore, this study aims to investigate the effect of tSVF-enriched fat grafting on scar pliability over a 12-month period.

Methods and design
A clinical multicenter non-randomized early phase trial will be conducted in two dedicated Dutch Burn Centers (Red Cross Hospital, Beverwijk, and Martini Hospital, Groningen). After informed consent, 46 patients (≥18 years) with adherent scars caused by burns, necrotic fasciitis, or degloving injury who have an indication for fat grafting will receive a sub-cicatricic tSVF-enriched fat graft. The primary outcome is the change in scar pliability measured by the Cutometer between pre- and 12 months post-grafting. Secondary outcomes are scar pliability (after 3 months), scar erythema, and melanin measured by the DSM II Colormeter; scar quality assessed by the patient and observer scales of the Patient and Observer Scar Assessment Scale (POSAS) 2.0; and histological analysis of scar biopsies (voluntary) and tSVF quality and composition. This study has been approved by the Dutch Central Committee for Clinical Research (CCMO), NL72094.000.20.

Conclusion
This study will test the clinical efficacy of tSVF-enriched fat grafting to treat dermal scars while the underlying working mechanism will be probed into too.

Trial registration
Dutch Trial Register NL 8461. Registered on 16 March 2020
S1PR1 regulates NDV-induced IL-1β expression via NLRP3/caspase-1 inflammasome
Authors: Gao Pei , Zhang Shiyuan , Zhang Xinxin , Xu Chenggang , Chen Libin , Fan Lei , Ren Jinlian , Lin Qiuyan , Xiang Bin , Ren Tao 
Published: July 2022

AbstractNewcastle disease (ND) is an acute, febrile, and highly contagious disease caused by the Newcastle disease virus (NDV), an important pathogen harmful to domestic poultry. Virulent NDV strain infection induces IL-1β expression and along with strong inflammatory response, ultimately results in death. Inhibition or overexpression of S1PR1, an important target for inflammatory disease treatment, regulates IL-1β expression, suggesting that S1PR1 may alter the degree of the inflammatory response induced by NDV infection by regulating pro-inflammatory cytokine expression. However, the molecular mechanism by which S1PR1 regulates IL-1β expression remains unclear. Here, we explore the expression and tissue distribution of S1PR1 after NDV infection and found that S1PR1 expression increased in the lungs, bursa of Fabricius, and DF-1. IL-1β expression induced by NDV was increased following treatment of cells with the S1PR1-specific agonist, SEW2871. In contrast, IL-1β expression induced by NDV was decreased after cells were treated with the S1PR1 inhibitor W146, suggesting that S1PR1 promotes NDV-induced IL-1β expression. Further investigation demonstrated that NDV induced IL-1β expression through p38, JNK/MAPK, and NLRP3/caspase-1 signaling molecules and S1PR1 affected the expression of IL-1β by activating the NLRP3/caspase-1 inflammasome but had no significant effect on p38 and JNK/MAPK. Our study shows that NDV infection promotes S1PR1 expression and induces IL-1β expression through p38, JNK/MAPK, and NLRP3/caspase-1 inflammasomes and that S1PR1 regulates IL-1β expression mainly through the NLRP3/caspase-1 inflammasome.
Practical considerations for navigating the regulatory landscape of non-clinical studies for clinical translation of radiopharmaceuticals
Authors: Korde Aruna , Mikolajczak Renata , Kolenc Petra , Bouziotis Penelope , Westin Hadis , Lauritzen Mette , Koole Michel , Herth Matthias Manfred , Bardiès Manuel , Martins Andre F. , Paulo Antonio , Lyashchenko Serge K. , Todde Sergio , Nag Sangram , Lamprou Efthimis , Abrunhosa Antero , Giammarile Francesco , Decristoforo Clemens 
Published: July 2022

Abstract
Background
The development of radiopharmaceuticals requires extensive evaluation before they can be applied in a diagnostic or therapeutic setting in Nuclear Medicine. Chemical, radiochemical, and pharmaceutical parameters must be established and verified to ensure the quality of these novel products.

Main body
To provide supportive evidence for the expected human in vivo behaviour, particularly related to safety and efficacy, additional tests, often referred to as “non-clinical” or “preclinical” are mandatory. This document is an outcome of a Technical Meeting of the International Atomic Energy Agency. It summarises the considerations necessary for non-clinical studies to accommodate the regulatory requirements for clinical translation of radiopharmaceuticals. These considerations include non-clinical pharmacology, radiation exposure and effects, toxicological studies, pharmacokinetic modelling, and imaging studies. Additionally, standardisation of different specific clinical applications is discussed.

Conclusion
This document is intended as a guide for radiopharmaceutical scientists, Nuclear Medicine specialists, and regulatory professionals to bring innovative diagnostic and therapeutic radiopharmaceuticals into the clinical evaluation process in a safe and effective way.
Prioritizing indigenous health equity in health registers: an environmental scan of strategies for equitable ascertainment and quality data
Authors: Wright Karen , Dehar Aria , Stott N. Susan , Mackey Anna , Sorhage Alexandra , Tapera Rachel , Williams Sîan A. 
Published: July 2022

Abstract
Background
Cerebral palsy (CP) registers serve as instrumental tools to support development of care pathways, preventative strategies, and health gains. Such health gains, however, are not always universal, with Indigenous health inequities common. To support Indigenous health, health registers need complete, consistent, and high-quality data. The aim of this study was to identify perceived barriers to the ascertainment of Indigenous peoples on health registers and to collate strategies supporting comprehensive ascertainment and achievement of high-quality Indigenous data.

Methods
Environmental scanning methods were utilized within a Kaupapa Māori theoretical framework, which aims to produce research that is transformational and supportive of Indigenous health gain. Knowledge and insights were obtained from CP registers in countries with Indigenous populations and complemented by information from health registers in Aotearoa New Zealand (NZ). Data collection methods included an online survey and scan of organizational websites. Data extraction focused on general information about the register, barriers to ascertainment, and strategies to support ascertainment and high data quality.

Results
52 registers were identified, 20 completed the survey and 19 included in the study (CP registers, n = 10, NZ health registers, n = 9). Web scan data were included for the other 32 registers (CP registers, n = 21, NZ health registers, n = 11). Indigenous health equity was identified in the visions and aims of only two health registers. Ethnicity data collection was identified in nearly three quarters of survey respondents and a limited number of organizational websites. Over half of survey respondents described system, health provider/service, or workforce barriers to ascertainment. Strategies were categorized into collaboration, health provider/service, workforce, and systems-levels. Indigenous-specific strategies were limited and focused on personal behaviour and access to registration.

Conclusions
CP and other health registers can have a significant role in identifying and addressing Indigenous health inequities. However, this is not currently an overt priority for many registers in this study and few registers describe ascertainment and data quality strategies specific to Indigenous peoples. Significant opportunity exists for health registers to be accountable and to implement approaches to support Indigenous health equity, address structural determinants of inequities, and achieve health gain for all.
Multi-detector CT chest: can it omit the further need for contrast enhnaced spectral mammography in breast cancer patients candidate for CT staging?
Authors: Rahman Rasha Wessam Abdel , Al-Dhurani Salwa Yahya Ahmed , Radwan Amira Hamed , Mohamed Ahmed Abdellatif , Kamal Eman Faker 
Published: July 2022

Abstract
Background
During multi-detector computed tomography (MDCT) of the chest, incidental breast lesions (IBLs) are occasionally encountered. Mammography remains the gold standard for the early detection of breast cancer. However, limitations exist in patients with dense breasts. Contrast spectral mammography (CESM) is widely available compared to MRI; it increases the sensitivity for breast cancer detection without decreasing the specificity.

Results
The study is a prospective study that included 113 female breast cancer patients for CT staging. One hundred and six of the patients had unilateral carcinoma and 7 of them had bilateral cancer with a total of 120 breasts evaluated. The CT findings were correlated with CESM findings regarding the multiplicity and bilaterality of the disease. The sensitivity, specificity, PPV, NPV, and accuracy of the CT in the detection of multiplicity were 97.44%, 100%, 100%, 95.45%, and 98.33%, respectively, and the sensitivity, specificity, PPV, NPV, and accuracy of the CT in the detection of bilateral disease were 68.18%, 97.96%, 88.24%, 93.20%, and 92.50%, respectively.

Conclusions
Breast cancer patients for MDCT chest as a part of their metastatic workup can omit the further need for CESM.
Not Just an Anchor: The Human Filum Terminale Contains Stretch Sensitive and Nociceptive Nerve Endings and Responds to Electrical Stimulation With Paraspinal Muscle Activation
Authors: Klinge Petra M. , McElroy Abigail , Leary Owen P. , Donahue John E. , Mumford Andrew , Brinker Thomas , Gokaslan Ziya L. 
Published: July 2022

BACKGROUND:
Neural components of the fibrous filum terminale (FT) are well known but are considered as embryonic remnants without functionality.

OBJECTIVE:
To investigate the ultrastructure of human FT specimens for sensory nerve endings and record paraspinal muscle activity on electrostimulation of the FT.

METHODS:
We prospectively investigated a cohort of 53 patients who underwent excision of the FT for the treatment of tethered cord syndrome. Surgical FT specimens were investigated by light and transmission electron microscopy. Intraoperative electrophysiological routine monitoring was extended by recording paraspinal muscles above and below the laminotomy level.

RESULTS:
Light microscopy revealed tiny peripheral nerves piercing the pia mater of the FT and entering its fibrous core. Transmission electron microscopy unveiled within the fibrous core of the FT myelinated nerve structures in 8 of the 53 patients and unmyelinated ones in 10 of the 53 patients. Both nerve endings encapsulated in fibrous tissue or unencapsulated nonmyelinated Schwann cell nerve bundles, that is, Remak cells, were found. Those nerve endings resembled mechanoreceptor and nociceptive receptor structures found in human skin, muscle tendons, and skeletal ligaments. Specifically, we found Ruffini mechanoreceptors and in addition nerve endings which resembled nociceptive glioneural structures of the skin. Bipolar electrostimulation of the FT was associated with paraspinal muscle activity above and below the spinal segment at which the FT was stimulated.

CONCLUSION:
Morphological and electrophysiological results indicate the presence of functional sensory nerve endings in the FT. Like other spine ligaments, the FT may serve as a proprioceptive element but may also contribute to back pain in spine disorders.
Model Study on the Catalytic Cycle of Glutathione Peroxidase Utilizing Selenocysteine-Containing Tripeptides: Elucidation of the Protective Bypass Mechanism Involving Selenocysteine Selenenic Acids
Authors: Masuda Ryosuke , Kuwano Satoru , Sase Shohei , Bortoli Marco , Madabeni Andrea , Orian Laura , Goto Kei 
Published: July 2022

Abstract
Although much attention has been paid to chemical elucidation of the catalytic cycle of glutathione peroxidase (GPx), it has been hampered by instability of selenocysteine selenenic acid (Sec–SeOH) intermediates. In this study, not only chemical processes of the canonical catalytic cycle but also those involved in the bypass mechanism, including the intramolecular cyclization of a Sec–SeOH to the corresponding five-membered ring selenenyl amide were demonstrated experimentally by utilizing selenopeptide model systems in which reactive intermediates can be stabilized by a nano-sized molecular cradle. The resulting cyclic selenenyl amide exhibited higher durability under oxidative conditions than in the state of a Sec–SeOH, corroborating its role as the protective form of GPx. The cyclization of Sec–SeOHs of the Sec-Gly-Thr and Sec-Gly-Lys models, which mimic the catalytic site of isozymes GPx1 and GPx4, respectively, was found to proceed at lower temperature than in the Sec-Gly-Gly model, which corresponds to the generalized form of the tripeptides in the catalytic site of GPx. The role of the hydrogen-bond accepting moieties in the cyclization process was elucidated by DFT calculation. It was indicated that, if the selenocysteine centers are incorporated in appropriate microenvironments, the bypass mechanism can function efficiently.
Rede tecnopolítica e territórios nas Olimpíadas no Rio
Authors: Egler Tamara Tania Cohen , Azevedo de Oliveira Fabiana Mabel , Da Silva Heitor Ney Mathias 
Published: July 2022

Esse artigo tem por objeto de investigação demonstrar como redes tecnopolíticas transforam o território, para isso o objeto de investigação está construído na articulação de agentes que formam uma rede tecnopolítica para a concepção, construção e realização dos ogos olímpicos na cidade do Rio de Janeiro, em 2016. Para tanto se interroga: Que territórios foram produzidos pela rede focada nos Jogos Olímpicos do Rio de Janeiro? Quem os produziu? E de que forma? Essas perguntas, que movem a nossa reflexão, têm por objetivo analisar como a inovação tecnológica a articulação de diferentes atores e a a fluidez de narrativas, pode se constituir em importante estratégia de ação na política urbana. Essa pesquisa nos habilita a demonstrar a hipótese queconsidera que essa rede tecnopolítica não só redefine os atores que participam da política urbana, como também transforma o poder sobre o território e as condições de apropriação do espaço. Estamos diante de atores, nacionais e internacionais, que se associaram na transversalidade dos campos, se comunicaram por inovação tecnológica e transformaram as condições de existência social na cidade do Rio de Janeiro em benefício de suas corporações.
Estratégias de desenvolvimento a partir do mar
Authors: Santos Thauan , Hasenclever Lia , Mendes Heitor Soares 
Published: July 2022

Resumo expandido da proposta de dossiê temático, intitulada "estratégias de desenvolvimento a partir do mar", organizada pelos professores Thauan Santos, Lia Hasenclever e Heitor Mendes.