bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Japanese single-center experience of the efficacy and safety of asfotase alfa in pediatric-onset hypophosphatasia
Authors: Sugiyama Yohei , Watanabe Taijiro , Tajika Makiko , Matsuhashi Tetsuro , Shimura Masaru , Fushimi Takuya , Ichimoto Keiko , Matsunaga Ayako , Ebihara Tomohiro , Tsuruoka Tomoko , Akiyama Tomoyuki , Murayama Kei 
Published: February 2022

Abstract
Background
Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific alkaline phosphatase. The severity of HPP is widely diverse from the perinatal form to the adult mild form. The former represents the most severe form and was earlier associated with high mortality due to pneumonia which was caused by severe hypomineralization of the bones—such as chest deformity and fractured ribs—and muscle weakness. Enzyme replacement therapy using asfotase alfa (AA) was approved in 2015 in Japan for treating patients with HPP and has improved their pulmonary function and life prognosis. There are several practical and ethical challenges related to using orphan drugs for a rare disorder in a publicly funded healthcare system. Sharing experiences about their application is essential towards formulating guidelines to assist clinicians with decisions about their initiation and withdrawal. We report the details of AA experience in ten cases of pediatric-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 [7.6–12.5] years; 60% male). This is a study of a single-center cohort describing the clinical course of patients with HPP, mainly consisting of the mild childhood form of HPP, treated with AA in Japan.

Results
One case of perinatal form of HPP, two cases of benign prenatal form, and seven cases of childhood form were observed. The most common symptom at onset was pain. All patients had low serum alkaline phosphatase levels as compared to the age-matched reference range before the commencement of AA. All HPP patients seem to have responded to AA treatment, as evidenced by pain alleviation, increased height standard deviation, improvement in respiratory condition and 6-min walk test result improvement, disappearance of kidney calcification, alleviation of fatigue, and/or increases in bone mineralization. There were no serious adverse events, but all patients had an injection site reaction and skin changes at the injection sites. Genetic analysis showed that eight out of ten patients had compound heterozygosity.

Conclusions
AA may be effective in patients with mild to severe pediatric-onset forms of HPP.
Healthcare resource utilization, total costs, and comorbidities among patients with myotonic dystrophy using U.S. insurance claims data from 2012 to 2019
Authors: Howe Sarah J. , Lapidus David , Hull Michael , Yeaw Jason , Stevenson Tanya , Sampson Jacinda B. 
Published: February 2022

Abstract
Background
Myotonic dystrophy (DM) is a rare, inherited disorder with multi-systemic effects that impact the skeletal muscles, eyes, heart, skin and gastrointestinal, endocrine, respiratory, and central nervous systems. DM is divided into two subtypes: DM1 can present from early childhood through adulthood and also has a congenital form (cDM) while DM2 typically manifests during mid-adulthood. Both forms are progressive with no approved treatments, and unmet need for disease-modifying therapies remains high. This study interrogated health insurance claims data to explore the clinical experience, healthcare resource utilization (HCRU), and all-cause costs for DM.

Results
A total of 8541 patients with DM and 242 patients with cDM and their matched controls were selected from a database of over 200 million claimants. HCRU and all-cause costs, including pharmacy, outpatient, and inpatient services, were analyzed across four years in 12-month follow-up periods. Mean all-cause costs per DM patient were high in each of the four periods (range $14,640–$16,704) and showed a steady increase from 13 to 23 months on, while the control group mean costs declined from $9671 in the first 12 months after the index event, to approach the US population average ($5193) over time. For cDM, the highest mean costs were in the first 12-months ($66,496 vs. $2818 for controls), and remained high (above $17,944) across all subsequent periods, while control mean costs approached $0. For DM and cDM, HCRU was higher compared to controls across all study periods and all-cause healthcare costs were mostly driven by inpatient and outpatient encounters. Analysis of all diagnosis codes over the study period (comorbidities) demonstrated an elevated comorbidity profile consistent with the clinical profile of DM.

Conclusions
This study is among the first to utilize claims data to increase understanding of the clinical experience and health economic outcomes associated with DM. The markedly elevated HCRU patterns and comorbidity profile presented here add to the broad body of scientific and clinical knowledge on DM. These insights can inform clinical care and support the development of disease modifying and/or symptom-targeting therapies that address the multi-systemic, progressive nature of DM.
Wilson disease in Northern Portugal: a long-term follow-up study
Authors: Garrido Isabel , Marques Margarida , Liberal Rodrigo , Cardoso Hélder , Lopes Susana , Macedo Guilherme 
Published: February 2022

Abstract
Introduction
Wilson disease is an autosomal recessive disease of liver copper metabolism with predominant hepatic and neurological manifestations. Long-term data on the clinical follow-up and treatment efficacy are limited due to the low frequency of the disease. We evaluated a large cohort of Wilson disease patients from Northern Portugal during a 20-year follow-up period.

Methods
Twenty-four patients, diagnosed from 1975 to 2020 in a tertiary care center in Portugal, were retrospectively evaluated according to their clinical presentation, therapies and outcomes.

Results
Most of the patients were males (54%), with a median age at diagnosis of 19 years old (interquartile range 15–25). The main manifestations of Wilson disease were hepatic (71%) and neurological (25%). Family history was positive in 5 (21%) patients. Four patients (17%) presented with acute liver failure and fifteen (63%) individuals had cirrhosis at diagnosis. Penicillamine therapy was used by 11 (46%) patients, while trientine and zinc were given to 8 (33%) and 1 (4%) patient, respectively. Ten (42%) individuals underwent liver transplantation. The majority of patients (83%) had stable disease or improved outcomes during follow-up.

Conclusion
This is the largest cohort of adult patients with Wilson disease reported in Northern Portugal. We show that Wilson disease has favorable outcomes with long overall survival, assuming adherence to therapy and lack of other insults to their liver.
SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma
Authors: Salaroglio Iris Chiara , Belisario Dimas Carolina , Bironzo Paolo , Ananthanarayanan Preeta , Ricci Luisa , Digiovanni Sabrina , Fontana Simona , Napoli Francesca , Sandri Alberto , Facolmatà Chiara , Libener Roberta , Comunanza Valentina , Grosso Federica , Gazzano Elena , Leo Francesco , Taulli Riccardo , Bussolino Federico , Righi Luisella , Papotti Mauro Giulio , Novello Silvia , Scagliotti Giorgio Vittorio , Riganti Chiara , Kopecka Joanna 
Published: February 2022

Abstract
Background
The combination of pemetrexed and cisplatin remains the reference first-line systemic therapy for malignant pleural mesothelioma (MPM). Its activity is moderate because of tumor aggressiveness, immune-suppressive environment and resistance to chemotherapy-induced immunogenic cell death (ICD). Preliminary and limited findings suggest that MPM cells have deregulated ubiquitination and proteasome activities, although proteasome inhibitors achieved disappointing clinical results.

Methods
Here, we investigated the role of the E3-ubiquitin ligase SKP/Cullin/F-box (SCF) complex in cell cycle progression, endoplasmic reticulum (ER)/proteostatic stress and ICD in MPM, and the therapeutic potential of the neddylation/SCF complex inhibitor MLN4924/Pevonedistat.

Results
In patient-derived MPM cultures and syngenic murine models, MLN4924 and cisplatin showed anti-tumor effects, regardless of MPM histotype and BAP1 mutational status, increasing DNA damage, inducing S- and G2/M-cell cycle arrest, and apoptosis. Mechanistically, by interfering with the neddylation of cullin-1 and ubiquitin-conjugating enzyme UBE2M, MLN4924 blocks the SCF complex activity and triggers an ER stress-dependent ICD, which activated anti-MPM CD8+T-lymphocytes. The SKP2 component of SCF complex was identified as the main driver of sensitivity to MLN4924 and resistance to cisplatin. These findings were confirmed in a retrospective MPM patient series, where SKP2 high levels were associated with a worse response to platinum-based therapy and inferior survival.

Conclusions
We suggest that the combination of neddylation inhibitors and cisplatin could be worth of further investigation in the clinical setting for MPM unresponsive to cisplatin. We also propose SKP2 as a new stratification marker to determine the sensitivity to cisplatin and drugs interfering with ubiquitination/proteasome systems in MPM.
Assessing lead time bias due to mammography screening on estimates of loss in life expectancy
Authors: Syriopoulou Elisavet , Gasparini Alessandro , Humphreys Keith , Andersson Therese M.-L. 
Published: February 2022

Abstract
Background
An increasingly popular measure for summarising cancer prognosis is the loss in life expectancy (LLE), i.e. the reduction in life expectancy following a cancer diagnosis. The proportion of life lost (PLL) can also be derived, improving comparability across age groups as LLE is highly age-dependent. LLE and PLL are often used to assess the impact of cancer over the remaining lifespan and across groups (e.g. socioeconomic groups). However, in the presence of screening, it is unclear whether part of the differences across population groups could be attributed to lead time bias. Lead time is the extra time added due to early diagnosis, that is, the time from tumour detection through screening to the time that cancer would have been diagnosed symptomatically. It leads to artificially inflated survival estimates even when there are no real survival improvements.

Methods
In this paper, we used a simulation-based approach to assess the impact of lead time due to mammography screening on the estimation of LLE and PLL in breast cancer patients. A natural history model developed in a Swedish setting was used to simulate the growth of breast cancer tumours and age at symptomatic detection. Then, a screening programme similar to current guidelines in Sweden was imposed, with individuals aged 40–74 invited to participate every second year; different scenarios were considered for screening sensitivity and attendance. To isolate the lead time bias of screening, we assumed that screening does not affect the actual time of death. Finally, estimates of LLE and PLL were obtained in the absence and presence of screening, and their difference was used to derive the lead time bias.

Results
The largest absolute bias for LLE was 0.61 years for a high screening sensitivity scenario and assuming perfect screening attendance. The absolute bias was reduced to 0.46 years when the perfect attendance assumption was relaxed to allow for imperfect attendance across screening visits. Bias was also present for the PLL estimates.

Conclusions
The results of the analysis suggested that lead time bias influences LLE and PLL metrics, thus requiring special consideration when interpreting comparisons across calendar time or population groups.
Meta-analysis defines predominant shared microbial responses in various diseases and a specific inflammatory bowel disease signal
Authors: Abbas-Egbariya Haya , Haberman Yael , Braun Tzipi , Hadar Rotem , Denson Lee , Gal-Mor Ohad , Amir Amnon 
Published: February 2022

Abstract
Background
Gut microbial alteration is implicated in inflammatory bowel disease but is noted in other diseases. Systematic comparison to define similarities and specificities is hampered since most studies focus on a single disease.

Results
We develop a pipeline to compare between disease cohorts starting from the raw V4 16S amplicon sequence variants. Including 12,838 subjects, from 59 disease cohorts, we demonstrate a predominant shared signature across diseases, indicating a common bacterial response to different diseases. We show that classifiers trained on one disease cohort predict relatively well other diseases due to this shared signal, and hence, caution should be taken when using such classifiers in real-world scenarios, where diseases are intermixed. Based on this common signature across a large array of diseases, we develop a universal dysbiosis index that successfully differentiates between cases and controls across various diseases and can be used for prioritizing fecal donors and samples with lower disease probability. Finally, we identify a set of IBD-specific bacteria, which can direct mechanistic studies and design of IBD-specific microbial interventions.

Conclusions
A robust non-specific general response of the gut microbiome is detected in a large array of diseases. Disease classifiers may confuse between different diseases due to this shared microbial response. Our universal dysbiosis index can be used as a tool to prioritize fecal samples and donors. Finally, the IBD-specific taxa may indicate a more direct association to gut inflammation and disease pathogenesis, and those can be further used as biomarkers and as future targets for interventions.
Neighbourhood characteristics related to mental health service use among adults with diabetes: a population-based cohort study in New Brunswick, Canada
Authors: Gupta Neeru , Crouse Dan Lawson , Foroughi Ismael 
Published: February 2022

Abstract
Objective
It has been postulated that social and economic inequalities may shape the distributions of comorbid diabetes and mental illness. This observational cohort study using linked population-based administrative and geospatial datasets aimed to describe associations between neighbourhood socioenvironments and disorder-specific mental health service use among adults with diabetes in the province of New Brunswick, Canada.

Results
A baseline cohort of 66,275 persons aged 19 and over living with diabetes was identified. One-quarter (26.3%) had used healthcare services for mood and anxiety disorders at least once during the six-year follow-up period 2012/2013–2017/2018. Based on Cox proportional hazards models, the risk of mental health service contacts was significantly higher among those residing in the most materially deprived neighbourhoods [HR: 1.07 (95% CI: 1.01–1.14)] compared to those in the least so, and those in areas characterized with the highest residential instability [HR: 1.13 (95% CI: 1.05–1.22)] compared to those in areas with the lowest instability. Among adults with incident diabetes (N = 4410), age and sex but not neighbourhood factors were related to differential help-seeking behaviours for mental health problems. These findings underscored the gap between theoretical postulations and population-based observations in delineating the syndemics of neighbourhood socioenvironments and mental health outcomes in populations with high diabetes prevalence.
Competition age: does it matter for swimmers?
Authors: Born Dennis-Peter , Stäcker Ina , Romann Michael , Stöggl Thomas 
Published: February 2022

Abstract
Objective
To establish reference data on required competition age regarding performance levels for both sexes, all swimming strokes, and race distances and to determine the effect of competition age on swimming performance in the context of other common age metrics. In total, 36,687,573 race times of 588,938 swimmers (age 14.2 ± 6.3 years) were analyzed. FINA (Fédération Internationale de Natation) points were calculated to compare race times between swimming strokes and race distances. The sum of all years of race participation determined competition age.

Results
Across all events, swimmers reach top-elite level, i.e. > 900 FINA points, after approximately 8 years of competition participation. Multiple-linear regression analysis explained up to 40% of variance in the performance level and competition age showed a stable effect on all race distances for both sexes (β = 0.19 to 0.33). Increased race distance from 50 to 1500 m, decreased effects of chronological age (β = 0.48 to − 0.13) and increased relative age effects (β = 0.02 to 0.11). Reference data from the present study should be used to establish guidelines and set realistic goals for years of competition participation required to reach certain performance levels. Future studies need to analyze effects of transitions between various swimming strokes and race distances on peak performance.
Two neuroanatomical subtypes of males with autism spectrum disorder revealed using semi-supervised machine learning
Authors: Liu Guanlu , Shi Liting , Qiu Jianfeng , Lu Weizhao 
Published: February 2022

Abstract
Background
Clinical and etiological varieties remain major obstacles to decompose heterogeneity in autism spectrum disorders (ASD). Recently, neuroimaging raised new hope to identify neurosubtypes of ASD for further understanding the biological mechanisms behind the disorder.

Methods
In this study, brain structural MRI data and clinical measures of 221 male subjects with ASD and 257 healthy controls were selected from 7 independent sites from the Autism Brain Image Data Exchange database (ABIDE). Heterogeneity through discriminative analysis (HYDRA), a recently-proposed semi-supervised clustering method was utilized to divide individuals with ASD into several neurosubtypes by regional volumetric measures of gray matter, white matter, and cerebrospinal fluid. Voxel-wise volume, clinical measures, dynamic resting-state functional magnetic resonance imaging (R-fMRI) measures among different neurosubtypes of ASD were explored. In addition, support vector machine (SVM) model was applied to test whether the neurosubtyping of ASD could improve diagnostic accuracy of ASD.

Results
Two neurosubtypes of ASD with different voxel-wise volumetric patterns were revealed. The full-scale intelligence quotient (IQ), verbal IQ, Autism Diagnostic Observation Schedule (ADOS) total scores and ADOS severity scores were significantly different between the two neurosubtypes, the total intracranial volume was correlated with performance IQ in Subtype 1 and was correlated with ADOS communication score and ADOS social score in Subtype 2. Compared with Subtype 2, Subtype 1 showed lower dynamic R-fMRI measures, lower dynamic functional architecture stability, higher mean and lower standard deviation (SD) of concordance among dynamic R-fMRI measures in cerebellum. In addition, classification accuracies between ASD neurosubtypes and healthy controls were significantly improved compared with classification accuracy between entire ASD group and healthy controls.

Limitations
The present study excluded female subjects and left-handed subjects, which limited the ability to investigate the associations between these factors and the heterogeneity of ASD.

Conclusions
The two distinct neuroanatomical subtypes of ASD validated by other data modalities not only adds reliability of the result, but also bridges from brain phenomenology to clinical behavior. The current neurosubtypes of ASD could facilitate understanding the neuropathology of this disorder and could be potentially used to improve clinical decision-making process and optimize treatment.
Important role of the SDF-1/CXCR4 axis in the homing of systemically transplanted human amnion-derived mesenchymal stem cells (hAD-MSCs) to ovaries in rats with chemotherapy-induced premature ovarian insufficiency (POI)
Authors: Ling Li , Hou Jiying , Liu Dandan , Tang Dongyuan , Zhang Yanqin , Zeng Qianru , Pan Heng , Fan Ling 
Published: February 2022

Abstract
Background
Chemotherapy can induce premature ovarian insufficiency (POI). POI causes multiple sequelae and is currently incurable. As shown in our previous studies, systemically transplanted human amnion-derived mesenchymal stem cells (hAD-MSCs) home to ovaries with chemotherapy-induced POI and subsequently reduce ovarian injury and improve ovarian function in rats with POI. However, the cellular mechanisms that direct the migration and homing of hAD-MSCs to ovaries with chemotherapy-induced POI are incompletely understood. This study investigated the role of the SDF-1/CXCR4 axis in the migration and homing of systemically transplanted hAD-MSCs to ovaries with chemotherapy-induced POI and its relevant downstream signalling pathways.

Methods
CXCR4 expression in hAD-MSCs was assessed using Western blotting and immunofluorescence staining. hAD-MSC migration was tested using Transwell migration assays. SDF-1 levels were detected using ELISA. Seventy-two female SD rats were randomly divided into the control, POI, hAD-MSCs and hAD-MSCs + AMD3100 groups. Cyclophosphamide was used to establish rat POI models. For inhibitor treatment, hAD-MSCs were pretreated with AMD3100 before transplantation. PKH26-labeled hAD-MSCs were injected into the tail vein of POI rats 24 h after chemotherapy. After hAD-MSC transplantation, the homing of hAD-MSCs to ovaries and ovarian function and pathological changes were examined. We further investigated the molecular mechanisms by detecting the PI3K/Akt and ERK1/2 signalling pathways.

Results
hAD-MSCs expressed CXCR4. SDF-1 induced hAD-MSC migration in vitro. SDF-1 levels in ovaries and serum were significantly increased in rats with chemotherapy-induced POI, and ovaries with POI induced the homing of hAD-MSCs expressing CXCR4. Blocking the SDF-1/CXCR4 axis with AMD3100 significantly reduced the number of hAD-MSCs homing to ovaries with POI and further reduced their efficacy in POI treatment. The binding of SDF-1 to CXCR4 activated the PI3K/Akt signalling pathway, and LY294002 significantly inhibited hAD-MSC migration induced by SDF-1 in vitro. Moreover, inhibition of the PI3K/Akt signalling pathway significantly reduced the number of systemically transplanted hAD-MSCs homing to chemotherapy-induced ovaries in rats with POI.

Conclusions
SDF-1/CXCR4 axis partially mediates the migration and homing of systemically transplanted hAD-MSCs to the ovaries of rats with chemotherapy-induced POI, and the PI3K/Akt signalling pathway might be involved in the migration and homing of hAD-MSCs mediated by the SDF-1/CXCR4 axis.