bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating the fiscal impact of rare diseases using a public economic framework: a case study applied to hereditary transthyretin-mediated (hATTR) amyloidosis
Authors: Connolly Mark P. , Panda Saswat , Patris Julien , Hazenberg Bouke P. C. 
Published: September 2019

Abstract

Background
A wide range of rare diseases can have fiscal impacts on government finances that extend beyond expected healthcare costs. Conditions preventing people from achieving national lifetime work averages will influence lifetime taxes paid and increase the likelihood of dependence on public income support. Consequently, interventions that influence projected lifetime work activity, morbidity and mortality can have positive and negative fiscal consequences for government. The aim of this study was to apply a public economic framework to a rare disease that takes into consideration a broad range of costs that are relevant to government in relation to transfers received and taxes paid. As a case study we constructed a simulation model to calculate the fiscal life course of an individual with hereditary transthyretin-mediated (hATTR) amyloidosis in The Netherlands. In this lethal disease different progressive disease scenarios occur, including polyneuropathy and/or cardiomyopathy.

Results
Due to progressive disability, health care resource use, and early death, hATTR amyloidosis with polyneuropathy receives more transfers from government compared to the general population. In a scenario where a patient is diagnoses with hATTR at age 45, an individual pays €180,812 less in lifetime taxes and receives incrementally €111,695 in transfers from the government, compared to a person without hATTR. Patients suffering from cardiomyopathy die after median 4 years. The health costs of this scenario are therefore lower than that of the other polyneuropathy-based scenarios.

Conclusions
The fiscal analysis illustrates how health conditions influence not only health costs, but also the cross-sectorial public economic burden attributed to lost tax revenues and public disability allowances. Due to the progressive nature of hATTR amyloidosis used in this study, public costs including disability increase as the disease progresses with reduced lifetime taxes paid. The results indicate that halting disease progression early in the disease course would generate fiscal benefits beyond health benefits for patients. This analysis highlights the fiscal consequences of diseases and the need for broader perspectives applied to evaluate health conditions. Conventional cost-effectiveness framework used by many health technology assessment agencies have well-documented limitations in the field of rare diseases and fiscal modeling should be a complementary approach to consider.
C-banding and AgNOR-staining were still effective complementary methods to indentify chromosomal heteromorphisms and some structural abnormalities in prenatal diagnosis
Authors: Zhu Jian Jiang , Qi Hong , Cai Li Rong , Wen Xiao Hui , Zeng Wen , Tang Guo Dong , Luo Yao , Meng Ran , Mao Xue Qun , Zhang Shao Qin 
Published: September 2019

Abstract

Background
In prenatal diagnosis, CMA has begun to emerge as a favorable alternative to karyotype analysis, but it could not identify balanced translocations, triploidies, inversion and heteromorphisms. Therefore, conventional cytogenetic and specific staining methods still play an important role in the work-up of chromosome anomaly. This study investigated the application of C-banding and AgNOR-staining techniques in prenatal diagnosis of chromosomal heteromorphisms and some structure abnormalities.

Results
Among the 2970 samples, the incidence of chromosomal heteromorphisms was 8.79% (261/2970). The most frequent was found to be chromosome Y (2.93%, 87/2970), followed by chromosome 1 (1.65 %, 49/2970), 9 (1.52 %, 45/2970), 22 (0.77 %, 23/2970) and 15 (0.64 %, 19/2970). We compared the incidence of chromosomal heteromorphisms between recurrent spontaneous abortion (RSA) group and control group. The frequency of autosomal hetermorphisms in RSA group was 7.63% higher than that in control group (5.78%), while the frequency of Y chromosomal heteromorphisms was 4.76% lower than that in control group (5.71%). Here we summarized 4 representative cases, inv (1) (p12q24), psu dic (4;17) (p16.3;p13.3), r(X)(p11; q21) and an isodicentric bisatellited chromosome to illustrate the application of C-banding or AgNOR-staining, CMA or NGS was performed to detect CNVs if necessary.

Conclusions
This study indicated that C-banding and AgNOR-staining were still effective complementary methods to identify chromosomal heteromorphisms and marker chromosomes or some structural rearrangements involving the centromere or acrocentric chromosomes. Our results suggested that there was no evidence for an association between chromosomal heteromorphisms and infertility or recurrent spontaneous abortions. Undoubtedly, sometimes we needed to combine the results of CMA or CNV-seq to comprehensively reflect the structure and aberration of chromosome segments. Thus, accurate karyotype reports and genetic counseling could be provided.
Graphene oxide arms oncolytic measles virus for improved effectiveness of cancer therapy
Authors: Xia Mao , Luo Dongjun , Dong Jie , Zheng Meihong , Meng Gang , Wu Junhua , Wei Jiwu 
Published: September 2019

Abstract

Background
Replication-competent oncolytic viruses (OVs) have been proven to be a potent anticancer weapon for clinical therapy. The preexisting neutralizing antibody in patients is a big challenge for oncolytic efficacy of OVs. Graphene oxide sheets (GOS) possess excellent biological compatibility and are easy to decorate for targeted delivery.

Methods
We generated PEI-GOS-PEG-FA (Polyethyleneimine-Graphene oxide sheets-Polyethylene glycol-Folic acid). After intravenous injection, the distribution of PEI-GOS-PEG-FA in tumor-bearing mice was visualized by the IVIS Lumina XR system. Then, the oncolytic measles virus (MV-Edm) was coated with PEI-GOS-PEG-FA to form a viral-GOS complex (GOS/MV-Edm). The oncolytic effects of GOS/MV-Edm were investigated both in vitro and in vivo.

Results
GOS/MV-Edm exhibited higher infectivity and enhanced oncolysis. In tumor-bearing mice, GOS/MV-Edm had significantly elevated viral replication within the tumor mass, and achieved an improved antitumor effect. Then, we confirmed that GOS/MV-Edm entered cancer cells via the folate receptor instead of CD46, a natural cognate receptor of MV-Edm. GOS/MV-Edm remained the infectivity in murine cells that lack CD46. Finally, we found that GOS/MV-Edm was effectively protected from neutralization in the presence of antiserum both in vitro and in vivo. In passively antiserum immunized tumor-bearing mice, the survival was remarkably improved with intravenous injection of GOS/MV-Edm.

Conclusion
Our findings demonstrate that GOS/MV-Edm displays significantly elevated viral replication within the tumor mass, leading to an improved antitumor effect in solid tumor mouse model. Our study provided a novel strategy to arm OVs for more efficient cancer therapy. That may become a promising therapeutic strategy for cancer patients.
UFM1 suppresses invasive activities of gastric cancer cells by attenuating the expression of PDK1 through PI3K/AKT signaling
Authors: Lin Jian-Xian , Xie Xin-Sheng , Weng Xiong-Feng , Qiu Sheng-Liang , Yoon Changhwan , Lian Ning-Zi , Xie Jian-Wei , Wang Jia-Bin , Lu Jun , Chen Qi-Yue , Cao Long-Long , Lin Mi , Tu Ru-Hong , Yang Ying-Hong , Huang Chang-Ming , Zheng Chao-Hui , Li Ping 
Published: September 2019

Abstract
Background
UFM1 has been found to be involved in the regulation of tumor development. This study aims to clarify the role and potential molecular mechanisms of UFM1 in the invasion and metastasis of gastric cancer.

Methods
Expression of UFM1 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was analyzed by Western blotting, immunohistochemistry, and realtime PCR. Its correlation with the clinicopathological characteristics and prognosis of gastric cancer patients was analyzed. The effects of UFM1 on the invasion and migration of gastric cancer cells were determined by the wound and trans-well assays, and the effect of UFM1 on subcutaneous tumor formation was verified in nude mice. The potential downstream targets of UFM1 and related molecular mechanisms were clarified by the human protein kinase assay and co-immunoprecipitation technique.

Results
Compared with the corresponding adjacent tissues, the transcription level and protein expression level of UFM1 in gastric cancer tissues were significantly downregulated (P < 0.05). The 5-year survival rate of gastric cancer patients with low UFM1 expression was significantly lower than the patients with high UFM1 expression (42.1% vs 63.0%, P < 0.05). The invasion and migration abilities of gastric cancer cells with stable UFM1 overexpression were significantly decreased, and the gastric cancer cells with UFM1 stable knockdown showed the opposite results; similar results were also obtained in the nude mouse model. Further studies have revealed that UFM1 could increase the ubiquitination level of PDK1 and decrease the expression of PDK1 at protein level, thereby inhibiting the phosphorylation level of AKT at Ser473. Additionally, the effect of UFM1 on gastric cancer cell function is dependent on the expression of PDK1. The expression level of UFM1 can improve the poor prognosis of PDK1 in patients with gastric cancer.

Conclusion
UFM1 suppresses the invasion and metastasis of gastric cancer by increasing the ubiquitination of PDK1 through negatively regulating PI3K/AKT signaling.
The management of unanticipated difficult airways in children of all age groups in anaesthetic practice - the position paper of an expert panel
Authors: Walas Wojciech , Aleksandrowicz Dawid , Kornacka Maria , Gaszyński Tomasz , Helwich Ewa , Migdał Marek , Piotrowski Andrzej , Siejka Grażyna , Szczapa Tomasz , Bartkowska-Śniatkowska Alicja , Halaba Zenon P. 
Published: September 2019

Abstract
Children form a specific group of patients, as there are significant differences between children and adults in both anatomy and physiology. Difficult airway may be unanticipated or anticipated. Difficulties encountered during intubation may cause hypoxia, hypoxic brain injury and, in extreme situations, may result in the patient’s death. There are few paediatric difficult-airway guidelines available in the current literature, and some of these have significant limitations. This position paper, intended for unanticipated difficult airway, was elaborated by the panel of specialists representing the Polish Society of Anaesthesiology and Intensive Care as well as the Polish Neonatal Society. It covers both elective intubation and emergency situations in children in all age groups. An integral part of the paper is an algorithm. The paper describes in detail all stages of the algorithm considering some modification in specific age groups, i.e. neonates.
Familial Mediterranean Fever: an unusual cause of liver disease
Authors: Maggio Maria Cristina , Castiglia Maria , Corsello Giovanni 
Published: September 2019

Abstract

Background
Familial Mediterranean Fever is an autoinflammatory disease typically expressed with recurrent attacks of fever, serositis, aphthous stomatitis, rash. Only a few reports describe the association with hepatic involvement.

Case presentation
We describe the clinical case of a child affected, since the age of 1 year, by recurrent fever, aphthous stomatitis, rash, arthralgia, associated with abdominal pain, vomiting, lymphadenopathy. The diagnosis of Familial Mediterranean Fever was confirmed by the genetic study of MEFV gene; the homozygous mutation M694 V in exon was documented. A partial control of attacks was obtained with colchicine. The child continued to manifest only recurrent episodes of abdominal pain without fever, however serum amyloid A persisted high, in association with enhanced levels of CRP, AST and ALT (1.5 x n.v.). The dosage of colchicine was increased step by step and the patient achieved a better control of symptoms and biochemical parameters. However, the patient frequently needed an increase in the dose of colchicine, suggesting the possible usefulness of anti-interleukin-1 beta treatment.

Conclusions
The unusual presentation of Familial Mediterranean Fever with liver disease suggests the role of inflammasome in hepatic inflammation. Colchicine controls systemic inflammation in most of the patients; however, subclinical inflammation can persist in some of them and can manifest with increased levels of CRP, ESR, serum amyloid A also in attack-free intervals.
Li-Fraumeni syndrome: not a straightforward diagnosis anymore—the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis
Authors: Batalini Felipe , Peacock Ellie G. , Stobie Lindsey , Robertson Alison , Garber Judy , Weitzel Jeffrey N. , Tung Nadine M. 
Published: September 2019

Abstract
The introduction of next-generation sequencing has resulted in testing multiple genes simultaneously to identify inherited pathogenic variants (PVs) in cancer susceptibility genes. PVs with low minor allele frequencies (MAFs) (< 25–35%) are highlighted on germline genetic test reports. In this review, we focus on the challenges of interpreting PVs with low MAF in breast cancer patients undergoing germline testing and the implications for management.
The clinical implications of a germline PV are substantial. For PV carriers in high-penetrance genes like BRCA1, BRCA2, and TP53, prophylactic mastectomy is often recommended and radiation therapy avoided when possible for those with Li-Fraumeni syndrome (LFS). For germline PV carriers in more moderate-risk genes such as PALB2, ATM, and CHEK2, annual breast MRI is recommended and prophylactic mastectomies considered for those with significant family histories. Detection of PVs in cancer susceptibility genes can also lead to recommendations for other prophylactic surgeries (e.g., salpingo-oophorectomy) and increased surveillance for other cancers. Therefore, recognizing when a PV is somatic rather than germline and distinguishing somatic mosaicism from clonal hematopoiesis (CH) is essential. Mutational events that occur at a post-zygotic stage are somatic and will only be present in tissues derived from the mutated cell, characterizing classic mosaicism. Clonal hematopoiesis is a form of mosaicism restricted to the hematopoietic compartment.
Among the genes in multi-gene panels used for germline testing of breast cancer patients, the detection of a PV with low MAF occurs most often in TP53, though has been reported in other breast cancer susceptibility genes. Distinguishing a germline TP53 PV (LFS) from a somatic PV (TP53 mosaicism or CH) has enormous implications for breast cancer patients and their relatives.
We review how to evaluate a PV with low MAF. The identification of the PV in another tissue confirms mosaicism. Older age, exposure to chemotherapy, radiation, and tobacco are known risk factors for CH, as is the absence of a LFS-related cancer in the setting of a TP53 PV with low MAF. The ability to recognize and understand the implications of somatic PVs, including somatic mosaicism and CH, enables optimal personalized care of breast cancer patients.
Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial
Authors: Adamo Barbara , Bellet Meritxell , Paré Laia , Pascual Tomás , Vidal Maria , Pérez Fidalgo José A. , Blanch Salvador , Martinez Noelia , Murillo Laura , Gómez-Pardo Patricia , López-González Ana , Amillano Kepa , Canes Jordi , Galván Patricia , González-Farré Blanca , González Xavier , Villagrasa Patricia , Ciruelos Eva , Prat Aleix 
Published: September 2019

AbstractBackgroundThe biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed.MethodsPostmenopausal women with untreated stage I–III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures.ResultsSixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1–2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (− 73.2%) was superior to both monotherapy arms combined (− 49.9%;p = 0.001) and mVNB (− 19.1%;p < 0.001). The anti-proliferative effect of LTZ+mVNB (− 73.2%) was numerically higher compared to LTZ (− 65.7%) but did not reach statistical significance (p = 0.328). LTZ+mVNB induced high expression of immune-related genes and gene signatures, including CD8 T cell signature and PDL1 gene and low expression of ER-regulated genes (e.g., progesterone receptor) and cell cycle-related and DNA repair genes. In tumors with ≤ 10% sTILs at baseline, a statistically significant increase in sTILs was observed following LTZ (paired analysisp = 0.049) and LTZ+mVNB (p = 0.012). Grade 3 adverse events occurred in 3.4% of the cases.ConclusionsShort-term mVNB is well-tolerated and presents anti-proliferative activity alone and in combination with LTZ. The high expression of immune-related biological processes and sTILs observed with the combination opens the possibility of studying this combination with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted.Trial registrationNCT02802748, registered 16 June 2016.
The impact of surgeon and patient treatment preferences in an orthopaedic trauma surgery trial
Authors: Keding Ada , Handoll Helen , Brealey Stephen , Jefferson Laura , Hewitt Catherine , Corbacho Belen , Torgerson David , Rangan Amar 
Published: September 2019

Abstract

Background
Surgeon and patient treatment preferences are important threats to the internal and external validity of surgical trials such as PROFHER, which compared surgical versus non-surgical treatment for displaced fractures of the proximal humerus in adults. We explored the treatment preferences expressed by surgeons and patients in the trial and how these impacted on patient selection, trial conduct and patient outcome.

Methods
A series of exploratory secondary analyses of the PROFHER trial data were undertaken. We reviewed the extent of surgeon and patient treatment preferences (surgery or not surgery) at screening (n = 1250) as well as prior preference (including no preference) of randomised patients (n = 250), and assessed their impact on recruitment and adherence to follow-up and rehabilitation. Changes in treatment after 2 years’ follow-up were explored. Patient preference and characteristics associated with trial inclusion or treatment preference (t test, chi-squared test, Wilcoxon rank-sum test) were included as treatment interaction terms in the primary trial analysis of shoulder functioning (Oxford Shoulder Score, OSS).

Results
Surgeons excluded 17% of otherwise eligible patients based on lack of equipoise; these patients had less complex fractures (p < 0.001) and tended to be older (p = 0.062). Surgeons were more likely to recommend surgery for patients under 65 years of age (p = 0.059) and who had injured their right shoulder (p = 0.052). Over half of eligible patients (56%) did not consent to take part in the trial; these patients tended to be older (p = 0.022), with a preference for not surgery (74%; which was associated with older age, p = 0.039). There were no differential treatment effects (p value of interaction) for shoulder functioning (OSS) based on subgroups of patient preference (p = 0.751), age group (p = 0.264), fracture type (p = 0.954) and shoulder dominance (p = 0.850). Patients who were randomised to their preferred treatment had better follow-up rates (94 vs 84% at 2 years) and treatment adherence (90 vs 83% reported completing home exercises). Patients who were not randomised to their preferred treatment were more likely to change their treatment preference at 24 months (60 vs 26%).

Conclusions
The robustness of the PROFHER trial findings was confirmed against possible bias introduced by surgeon and patient preferences. The importance of collecting preference data is highlighted.

Trial registration
ISRCTN50850043. Registered on 25 March 2008.
Collaborative care model for treatment of persistent symptoms after concussion among youth (CARE4PCS-II): Study protocol for a randomized, controlled trial
Authors: McCarty Carolyn A. , Zatzick Douglas , Hoopes Teah , Payne Katelyn , Parrish Rebecca , Rivara Frederick P. 
Published: September 2019

Abstract

Background
Currently, there is limited evidence to guide intervention and service delivery coordination for youth who suffer a concussion and subsequently experience persistent post-concussive symptoms (PCS) (Lumba-Brown et al. JAMA Pediatr 172(11):e182853, 2018; Lumba-Brown A et al. JAMA Pediatr 172(11):e182847, 2018). We have developed a collaborative care intervention with embedded cognitive-behavioral therapy, care management, and stepped-up psychotropic medication consultation to address persistent PCS and related psychological comorbidities. The CARE4PCS-II study was designed to assess whether adolescents with persistent symptoms after sports-related concussion will demonstrate better outcomes when receiving this collaborative care intervention compared to a usual care (control) condition.

Methods/design
This investigation is a randomized comparative effectiveness trial to receive intervention (collaborative care) or control (usual care). Two hundred sports-injured male and female adolescents aged 11–18 years with three or more post-concussive symptoms that persist for at least 1 month but less than 9 months after injury will be recruited and randomized into the study. The trial focuses on the effects of the intervention on post-concussive, depressive, and anxiety symptoms measured 3, 6, and 12 months after baseline.

Discussion
The CARE4PCS II study is a large comparative effectiveness trial targeting symptomatic improvements in sports injured adolescents after concussion. The study is unique in its adaptation of the collaborative care model to a broad spectrum of primary care, sports medicine, and school settings. The investigation incorporates novel elements such as the delivery of CBT through HIPAA complaint video conferenceing technology and has excellent widespread dissemination potential should effectiveness be demonstrated.

Trial registration
ClinicalTrials.gov, NCT03034720. Registered on January 27, 2017.