bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical Safety Assessment and Toxicokinetics of Apitegromab, an Antibody Targeting Proforms of Myostatin for the Treatment of Muscle-Atrophying Disease
Authors: Welsh Brian T. , Cote Shaun M. , Meshulam Deborah , Jackson Justin , Pal Ajai , Lansita Janice , Kalra Ashish 
Published: July 2021

Myostatin is a negative regulator of skeletal muscle and has become a therapeutic target for muscle atrophying disorders. Although previous inhibitors of myostatin offered promising preclinical data, these therapies demonstrated a lack of specificity toward myostatin signaling and have shown limited success in the clinic. Apitegromab is a fully human, monoclonal antibody that binds to human promyostatin and latent myostatin with a high degree of specificity, without binding mature myostatin and other closely related growth factors. To support the clinical development of apitegromab, we present data from a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species. In vitro studies confirmed the ability of apitegromab to inhibit the activation of promyostatin. Toxicology studies in monkeys for 4 weeks and in adult rats for up to 26 weeks showed that weekly intravenous administration of apitegromab achieved sustained serum exposure and target engagement and was well-tolerated, with no treatment-related adverse findings at the highest doses tested of up to 100 mg/kg and 300 mg/kg in monkeys and rats, respectively. Additionally, results from an 8-week juvenile rat study showed no adverse effects on any endpoint, including neurodevelopmental, motor, and reproductive outcomes at 300 mg/kg administered weekly IV. In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that apitegromab is a selective inhibitor of proforms of myostatin that does not exhibit toxicities observed with other myostatin pathway inhibitors. These data support the conduct of ongoing clinical studies of apitegromab in adult and pediatric patients with spinal muscular atrophy (SMA).
Versatility of the Posterior Interosseous Artery Flap: Emphasis on Powering Up the Toe Transfer
Authors: Lee GiJun , Kim BumSik , Jeon Neunghan , Yoon JungSoo , Hong Ki Yong , Lim SooA , Eo SuRak 
Published: July 2021

Background: Reverse-flow posterior interosseous artery (rPIA) flap is an excellent tool for restoration of defects in the hand and upper extremity, sparing the main arteries to the hand. Its reliability has been well established. Materials and Methods: Fifty-one cases of rPIA flap involving 49 patients were retrospectively reviewed. The inclusion criteria were age, sex, etiology, size and location of the defect, flap size, number of perforators included, pedicle length, flap inset, donor site coverage, complications, and ancillary procedures. Results: This study included 44 men and 5 women, ranging in age between 10 and 73 years. The subjects had soft tissue defects of the hand and upper extremity mainly due to traumatic injuries, including scar contractures of the first web space in 18 cases, thumb amputations in 6 cases, and congenital defects in 1 case. Among the 51 rPIA flap elevations, 3 cases involved flap failure due to the absence of proper pedicle. A fasciocutaneous pattern was observed in 45 cases and a myocutaneous pattern in 3 cases. In 5 cases of unplantable thumb amputations, the rPIA flap was performed for arterial inflow to the secondary toe-to-thumb transfer. Venous congestion of varying degrees was noted in 7 cases involving partial necrosis in 2 cases. During the mean 17 months of follow-up, patients were generally satisfied with the final outcomes. Conclusion: The rPIA flap can be used not only for soft tissue coverage of the hand and upper extremity but also as a recipient arterial pedicle for a secondary toe-to thumb transfer.
Immediate Pain Relief at Time of Corticosteroid Injection for Idiopathic Adhesive Capsulitis as a Predictor of Eventual Outcomes
Authors: Lesevic Milos , Awowale John T. , Moran Thomas E. , Diduch David R. , Brockmeier Stephen F. , Werner Brian C. 
Published: July 2021

Background: Corticosteroid injection and physical therapy remain the mainstay of treatment for idiopathic adhesive capsulitis of the shoulder; however, a certain percentage of patients will not improve using these interventions and will require manipulation under anesthesia (MUA) and/or lysis of adhesions (LOA). Purpose: To evaluate whether the immediate pain reduction after fluoroscopic-guided, mixed anesthetic-corticosteroid injection for idiopathic adhesive capsulitis is related to the eventual need for LOA/MUA or a repeat glenohumeral steroid injection. Study Design: Case-control study; Level of evidence, 3. Methods: This single-institution study involved patients undergoing fluoroscopic glenohumeral corticosteroid injection for a diagnosis of idiopathic adhesive capsulitis between 2010 and 2017. Included were patients with a minimum of 1-year postinjection follow-up and visual analog scale (VAS) pain scores from immediately before and after the injection. The primary analysis was the relationship between patients with an immediate change in VAS score after injection and those who underwent LOA/MUA. A repeat glenohumeral injection was also evaluated as an outcome. Receiver operator characteristic curves and a multivariate binomial logistic regression analysis were performed. Results: Overall, 739 shoulders in 728 patients (mean age, 52.6 years; 68% women) were included, of which 38 (5.1%) underwent LOA/MUA and 209 (28%) underwent repeat injections. The immediate change in the VAS score was not significantly associated with the eventual need for LOA/MUA. Preinjection VAS and immediate postinjection VAS scores were not significant predictors of eventual LOA/MUA or subsequent injection. For all 3 predictors, the area under the receiver operator characteristic curve classified them as extremely poor discriminators. Conclusion: The immediate pain response to a fluoroscopic-guided glenohumeral injection for idiopathic shoulder adhesive capsulitis was not predictive of the eventual need for LOA/MUA or subsequent injection. Patients can be counseled that even if their initial pain response to an injection is poor, they still have an excellent chance of avoiding surgery, as the overall rate of LOA/MUA was low (5.1%).
Pulmonary metastasectomy in renal cell carcinoma: Predictive and prognostic elements from paired histopathological analysis of primary tumors and respective metastases
Authors: Bersanelli Melissa , Buti Sebastiano , Gnetti Letizia , Varotti Elena , Carbognani Paolo , Rusca Michele , Leonardi Francesco , Campanini Nicoletta , Ziglioli Francesco , Dadomo Clara Indira , Pilato Francesco Paolo , Ventura Luigi , Braggio Cesare , Bocchialini Giovanni , Cortellini Alessio , Brunelli Matteo , Rapacchi Elena , Camisa Roberta , Caruso Giuseppe , Silini Enrico Maria , Maestroni Umberto , Ampollini Luca 
Published: July 2021

Objective: To identify histopathological and immunophenotypical features with potential predictive or prognostic value in patients undergoing pulmonary metastasectomy from renal cell carcinoma (RCC). Methods: We retrospectively collected all consecutive patients undergoing pulmonary metastasectomy from RCC after prior nephrectomy. Paired samples of primary tumors and corresponding pulmonary metastases were analyzed, revising histopathological features and testing C-MET, mTOR, and PD-L1 by immunohistochemistry. Results: A total of 25 patients were included. Median overall survival (mOS) from metastasectomy was 5.5 years (95% CI = 1.9–9.1). The laterality of metastases had a significant predictive value, with median relapse-free survival (mRFS) from metastasectomy not reached (NR) at mean follow-up (FU) of 60.8 months for left lung involvement, mRFS of 52.9 months (95% CI = 0–145.5) for the right lung and 6.4 months (95% CI = 1.7–11) for bilateral metastases ( p = 0.028). Primary RCC with positive expression of mTOR had higher mOS after metastasectomy than negative cases ( p < 0.001), NR at mean FU of 4.3 years versus mOS of 2 years (95% CI = 0.7–3.3), respectively. PD-L1 positivity on intra-tumor (TILs) and peri-tumor (RILs) infiltrating lymphocytes of metastases was related to higher OS, NR versus 2 years (95% CI = 1.2–2.7, p = 0.003), and NR versus 1.4 years (95% CI = 0.2–2.6, p = 0.012), respectively. The shorter was the surgical interval, the more probably the metastases had high c-MET expression (>70%) ( p = 0.007) and PD-L1 expression >10% on TILs ( p = 0.024). Conclusions: mTOR positivity on primary RCC could be a favorable prognostic factor to select patients for pulmonary metastasectomy. The positive impact of PD-L1 expression on immune cells is opposite to the well-known negative prognostic value of PD-L1 on tumor cells in RCC.
Analysis of the chemical composition and phase structure of ‘Ru-type ware’ bodies under the influence of firing temperature
Authors: Wu Bo , Zhao Weijuan 
Published: July 2021

AbstractThe Qingliang Temple kiln located in Baofeng County, Henan Province, China, is the discovery site of Ru Kuan porcelain, which is one of the five famous porcelain types of the Song dynasty in China. The ‘Ru-type ware’ and unglazed firing bodies were unearthed from the Qingliang Temple kiln in 2014, and the excavation site was very close to the central firing area of Ru Kuan porcelain. In this paper, the chemical composition, firing temperature and phase structure of the Ru-type ware and unglazed firing bodies from the Qingliang Temple kiln were analysed systematically using energy-dispersive X-ray fluorescence spectrometry, high-temperature thermal expansion and X-ray diffraction. The raw-material sources of the Ru-type ware bodies with various glaze colours are consistent but differ significantly from those of the unglazed firing bodies. The firing temperatures of the Ru-type ware and unglazed firing bodies are 1150–1200°C and 950°C, respectively, which are considered underfired. Mullite, α-quartz, β-cristobalite and α-Fe2O3 are the main constituents of the Ru-type ware bodies, whereas α-quartz and anatase were identified in the unglazed firing bodies. The Ru-type ware is related to the Ru Kuan ware in terms of firing techniques and official use.
Relationship between clone metrics and clinical outcome in clonal cytopenia
Authors: Gallì Anna , Todisco Gabriele , Catamo Eulalia , Sala Cinzia , Elena Chiara , Pozzi Sara , Bono Elisa , Ferretti Virginia Valeria , Rizzo Ettore , Molteni Elisabetta , Zibellini Silvia , Sarchi Martina , Boveri Emanuela , Ferrari Jacqueline , Fiorelli Nicolas , Camaschella Clara , Gasparini Paolo , Toniolo Daniela , Cazzola Mario , Malcovati Luca 
Published: July 2021

Abstract
Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that is associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n = 355) or with unexplained anemia (n = 177), and 592 patients with overt MN. Ninety-two of 311 (30%) patients with ICUS carried a somatic genetic lesion that signaled CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of nonanemic and anemic community-dwelling individuals, respectively. Different mutation patterns and variant allele frequencies (VAFs) (clone metrics parameters) were observed in the conditions studied. Recurrent mutation patterns exhibited different VAFs associated with marrow dysplasia (0.17-0.48), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified 2 major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR, 1.8). In patients with CCUS, the 2 clusters had different risk of progression to MN (HR, 2.7). Within the MN-like cluster, distinct subsets with different risk of progression to MN were identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical for informing clinical decision-making in patients with clonal cytopenia.
Lizards and snakes from the earliest Miocene of Saint-Gérand-le-Puy, France: an anatomical and histological approach of some of the oldest Neogene squamates from Europe
Authors: Georgalis Georgios L. , Scheyer Torsten M. 
Published: July 2021

Abstract
Background
The earliest Miocene (Aquitanian) represents a crucial time interval in the evolution of European squamates (i.e., lizards and snakes), witnessing a high diversity of taxa, including an array of extinct forms but also representatives of extant genera. We here conduct a taxonomical survey along with a histological/microanatomical approach on new squamate remains from the earliest Miocene of Saint-Gérand-le-Puy, France, an area that has been well known for its fossil discoveries since the nineteenth century.

Results
We document new occurrences of taxa, among which, the lacertid Janosikia and the anguid Ophisaurus holeci, were previously unknown from France. We provide a detailed description of the anatomical structures of the various cranial and postcranial remains of lizards and snakes from Saint-Gérand-le-Puy. By applying micro-CT scanning in the most complete cranial elements of our sample, we decipher previously unknown microanatomical features. We report in detail the subsurface distribution and 3D connectivity of vascular channels in the anguid parietal. The fine meshwork of channels and cavities or sinuses in the parietal of Ophisaurus could indicate some thermoregulatory function, as it has recently been demonstrated for other vertebrate groups, providing implications for the palaeophysiology of this earliest Miocene anguine lizard.

Conclusions
A combination of anatomical and micro-anatomical/histological approach, aided by micro-CT scanning, enabled the documentation of these new earliest Miocene squamate remains. A distinct geographic expansion is provided for the extinct anguine Ophisaurus holeci and the lacertid Janosikia (the closest relative of the extant insular Gallotia from the Canary Islands).
Long-term monitoring of a brown trout (Salmo trutta) population reveals kin-associated migration patterns and contributions by resident trout to the anadromous run
Authors: Duval Eloïse , Skaala Øystein , Quintela María , Dahle Geir , Delaval Aurélien , Wennevik Vidar , Glover Kevin A. , Hansen Michael M. 
Published: July 2021

AbstractBackgroundIn species showing partial migration, as is the case for many salmonid fishes, it is important to assess how anthropogenic pressure experienced by migrating individuals affects the total population. We focused on brown trout (Salmo trutta) from the Guddal River in the Norwegian Hardanger Fjord system, which encompasses both resident and anadromous individuals. Aquaculture has led to increased anthropogenic pressure on brown trout during the marine phase in this region. Fish traps in the Guddal River allow for sampling all ascending anadromous spawners and descending smolts. We analyzed microsatellite DNA markers from all individuals ascending in 2006–2016, along with all emigrating smolts in 2017. We investigated (1) if there was evidence for declines in census numbers and effective population size during that period, (2) if there was association between kinship and migration timing in smolts and anadromous adults, and (3) to what extent resident trout were parents of outmigrating smolts.ResultsCensus counts of anadromous spawners showed no evidence for a decline from 2006 to 2016, but were lower than in 2000–2005. Estimates of effective population size also showed no trends of declines during the study period. Sibship reconstruction of the 2017 smolt run showed significant association between kinship and migration timing, and a similar association was indicated in anadromous spawners. Parentage assignment of 2017 smolts with ascending anadromous trout as candidate parents, and assuming that unknown parents represented resident trout, showed that 70% of smolts had at least one resident parent and 24% had two resident parents.ConclusionsThe results bear evidence of a population that after an initial decline has stabilized at a lower number of anadromous spawners. The significant association between kinship and migration timing in smolts suggests that specific episodes of elevated mortality in the sea could disproportionally affect some families and reduce overall effective population size. Finally, the results based on parentage assignment demonstrate a strong buffering effect of resident trout in case of elevated marine mortality affecting anadromous trout, but also highlight that increased mortality of anadromous trout, most of which are females, may lower overall production in the system.
Validation of a novel associative transcriptomics pipeline in Brassica oleracea: identifying candidates for vernalisation response
Authors: Woodhouse Shannon , He Zhesi , Woolfenden Hugh , Steuernagel Burkhard , Haerty Wilfried , Bancroft Ian , Irwin Judith A. , Morris Richard J. , Wells Rachel 
Published: July 2021

Abstract
Background
Associative transcriptomics has been used extensively in Brassica napus to enable the rapid identification of markers correlated with traits of interest. However, within the important vegetable crop species, Brassica oleracea, the use of associative transcriptomics has been limited due to a lack of fixed genetic resources and the difficulties in generating material due to self-incompatibility. Within Brassica vegetables, the harvestable product can be vegetative or floral tissues and therefore synchronisation of the floral transition is an important goal for growers and breeders. Vernalisation is known to be a key determinant of the floral transition, yet how different vernalisation treatments influence flowering in B. oleracea is not well understood.

Results
Here, we present results from phenotyping a diverse set of 69 B. oleracea accessions for heading and flowering traits under different environmental conditions. We developed a new associative transcriptomics pipeline, and inferred and validated a population structure, for the phenotyped accessions. A genome-wide association study identified miR172D as a candidate for the vernalisation response. Gene expression marker association identified variation in expression of BoFLC.C2 as a further candidate for vernalisation response.

Conclusions
This study describes a new pipeline for performing associative transcriptomics studies in B. oleracea. Using flowering time as an example trait, it provides insights into the genetic basis of vernalisation response in B. oleracea through associative transcriptomics and confirms its characterisation as a complex G x E trait. Candidate leads were identified in miR172D and BoFLC.C2. These results could facilitate marker-based breeding efforts to produce B. oleracea lines with more synchronous heading dates, potentially leading to improved yields.
Predictive value of creatine kinase MB for contrast-induced acute kidney injury among myocardial infarction patients
Authors: Wei Wen , Zhang Lingyu , Zhang Yunhan , Tang Ronghui , Zhao Miao , Huang Zhidong , Liu Jin , Xu Danyuan , He Yibo , Wang Bo , Huang Haozhang , Li Qiang , Lin Mengfei , Liu Yong , Chen Kaihong , Chen Shiqun 
Published: July 2021

Abstract
Background
Predictive value of creatine kinase MB (CK-MB) for contrast-induced acute kidney injury (CI-AKI) among myocardial infarction (MI) patients has rarely been reported. We aim to evaluate the predictive value of CK-MB for CI-AKI among MI patients.

Methods
Totally, 1131 MI patients were included from the REduction of rIsk for Contrast-Induced Nephropathy (REICIN) study. The peak CK-MB before coronary angiography (CAG) was chosen. The study population was divided into two groups by log-transformed CK-MB cut-off point. The association between CK-MB and CI-AKI was tested by multivariable logistic regression. CK-MB was integrated with Age, creatinine and ejection fraction (ACEF) score and Mehran risk score (MRS) to evaluate the additive value of CK-MB. The integrated models were validated internally by the bootstrap method and externally by the PREdictive Value of COntrast voluMe to creatinine Clearance Ratio (PRECOMIN) study data set.

Results
Overall, 62(5.48%) patients developed CI-AKI, patients with CK-MB point > 4.7 displayed a higher incidence of CI-AKI than those without (11.9% vs. 4.0%, p < 0.001). CK-MB point > 4.7 was independently associated with CI-AKI (adjusted OR: 3.40, 95% CI: 1.93–5.98, p < 0.001). The additions of CK-MB to ACEF score, Mehran score A and Mehran score B resulted in increases in C-statistics, which ranged from 0.680 to 0.733 (p = 0.046), 0.694 to 0.727 (p = 0.091), 0.704 to 0.734 (p = 0.102), respectively. Internal validation also showed increases in C-statistics, and external validation performed well in discrimination and calibration.

Conclusions
Preprocedural peak CK-MB was a predictor of CI-AKI among MI patients.
Return on investment of internet delivered exposure therapy for irritable bowel syndrome: a randomized controlled trial
Authors: Wallén Hugo , Lindfors Perjohan , Andersson Erik , Hedman-Lagerlöf Erik , Hesser Hugo , Lindefors Nils , Svanborg Cecilia , Ljótsson Brjánn 
Published: July 2021

Abstract
Background
Irritable bowel syndrome (IBS) is a debilitating and costly disorder. Cognitive behavior therapy (CBT) is effective in the treatment of IBS, both when delivered over the internet and in face-to-face settings. CBT consists of different components and little is known about their relative importance. We have in an earlier study showed that inclusion of exposure in the CBT for IBS makes it even more effective. In the present study we wanted to evaluate the economic effects for society of inclusion vs exclusion of exposure in an internet delivered CBT for IBS.

Methods
We used data from a previous study with 309 participants with IBS. Participants were randomized to internet delivered CBT with (ICBT) or without exposure (ICBT-WE). We compared direct and indirect costs at baseline, after treatment, and 6 months after treatment (primary endpoint; 6MFU). Data was also collected on symptom severity and time spent by therapists and participants. The relative Incremental Cost Effectiveness Ratio (ICER) was calculated for the two treatment conditions and the return on investment (ROI).

Results
Results showed that ICBT cost $213.5 (20%) more than ICBT-WE per participant. However, ICBT was associated with larger reductions regarding both costs and symptoms than ICBT-WE at 6MFU. The ICER was − 301.69, meaning that for every point improvement on the Gastrointestinal Symptom Rating Scale—IBS version in ICBT, societal costs would be reduced with approximately $300. At a willingness to pay for a case of clinically significant improvement in IBS symptoms of $0, there was an 84% probability of cost-effectiveness. ROI analysis showed that for every $1 invested in ICBT rather than ICBT-WE, the return would be $5.64 six months after treatment. Analyses of post-treatment data showed a similar pattern although cost-savings were smaller.

Conclusions
Including exposure in Cognitive Behavior Treatment for IBS is more cost-effective from a societal perspective than not including it, even though it may demand more therapist and patient time in the short term.

Trial registration
This study is reported in accordance with the CONSORT statement for non-pharmacological trials [1]. Clinicaltrials.gov registration ID: NCT01529567 (14/02/2013).