bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of the Availability of Novel Drugs on Overall Survival of Multiple Myeloma Patients: A Real-World Study
Authors: Arcuri Leonardo Javier , Silva Cinthya Correa , Ovigli Danielle , Helman Ricardo , Kerbauy Mariana , Hamerschlak Nelson 
Published: November 2020

Introduction: Multiple myeloma is an incurable hematologic malignancy. However, many novel drugs (lenalidomide, carfilzomib, daratumumab, elotuzumab and ixazomib) have recently been approved in Brazil for this disease. Proving that the availability of these drugs increases survival is not straightforward, since pivotal trials with these drugs were designed to show benefit in progression-free survival and not in overall survival.
Hypothesis: We have hypothesized that the availability of novel drugs would reduce the risk of death.
Methods: This is a real-world, unicenter analysis that included patients with multiple myeloma treated between 1993 and 2017. The availability of novel drugs (lenalidomide, carfilzomib, daratumumab, elotuzumab and ixazomib) was treated as a time-dependent covariate and analyzed by Cox model. The analysis was controlled for the International Staging System (ISS) and for age.
Results: With a median follow-up of 6 years, we included 151 patients with multiple myeloma. Fourty percent had ISS-I, 34% ISS-II and 26% ISS-III. Mean age was 60.5 y/o (SD: 12.2). There has been 51 deaths, and 5-y overall survival was 90% for ISS-I, 80% for ISS-II and 54% for ISS-III (p=0.0004). In multivariable analysis, age (HR=1.06, p&lt;0.0001) and ISS-III (HR=4.51, p&lt;0.0001) were risk factors for death, while the availability of two or more novel drugs was protective (HR=0.31, p=0.006). The availability of a single novel drug was also protective (HR=0.58), although it did not reach statistical significance (p=0.13). Adjusted Simon-Makuch survival plot is in figure 1 (adjusted for ISS III and 60 y/o).
Discussion:
Our results show that the availability of two or more novel drugs increases overall survival in multiple myeloma. This is an important finding, since the pivotal trials were designed to show advantages in progression-free survival and, once achieved, the experimental drug was offered to the control group, hampering overall survival analyses. Overall survival benefit, therefore, are more likely to be seen in real-world studies. We included the availability of novel drugs as a time-dependent, and the interpretation of our results is that patients alive when two novel drugs became available had benefit in overall survival. Our study has two weaknesses. Two or more novel drugs were more likely to be available for patients from a more recent time. This difference could be due to changes in supportive care, but there has been no major change in supportive care for multiple myeloma patients. Another weakness is that patient alive in the more recent years may have not received novel drug-based treatment. Considering that multiple myeloma is an incurable disease, this is unlikely for the majority of patients. In conclusion, the availability of two or more novel drugs for multiple myeloma improves survival.
Figure

Disclosures
No relevant conflicts of interest to declare.
Phase Ib Trial with Dose Expansion of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Rituximab and Lenalidomide in Patients with Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL) and Refractory/Recurrent Secondary Central Nervous System Lymphoma (SCNSL)
Authors: Grommes Christian , Piotrowski Anna , Pentsova Elena , Nolan Craig , Francis Jasmine , DeAngelis Lisa , Schaff Lauren , Mellinghoff Ingo K 
Published: November 2020

BACKGROUND: Primary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Outcome and treatment options for patients with recurrent/refractory (r/r) disease are poor. We have observed promising efficacy of single-agent ibrutinib in r/r PCNSL and secondary CNS lymphoma (SCNSL). We hypothesize that combing ibrutinib with the immunomodulatory imide lenalidomide and theanti-CD20 antibody rituximab would be adding clinical efficacy. In this phase 1b trial, we investigate the toxicity of ibrutinib in combination with rituximab and lenalidomide in r/r PCNSL/SCNSL.
METHODS: Eligible patients had r/r PCNSL/SCNSL or newly diagnosed SCNSL, age≥18, ECOG≤2, normal end-organ function, and with any number and type of prior therapies. Enrollment followed the 3+3 design. Ibrutinib was dosed at 560mg daily (dose level 1) and 840mg (level 2, 3, 4); lenalidomide was dosed at 10mg daily (day 1-21) (level 1, 2), 15mg daily (day 1-21) (level 3) and 20mg daily (day 1-21) (level 4); rituximab was dosed at 500mg/m2 (all dose levels). Rituximab was given for 6 cycles, lenalidomide for 12 cycles, and ibrutinib ongoing.
RESULTS: Fifteen patients have been enrolled; 3 at dose level 1-3 and 6 at level 4. Median age was 69 years (range 56-82); 4 were women. Median ECOG was 1 (0: 5, 1: 7, 2: 3). Eleven had r/r PCNSL. Eleven had recurrent parenchymal disease; two had additional cerebrospinal fluid (CSF) involvement; two had both. Nine patients had recurrent and 6 refractory disease. No DLT occurred. One grade 4 lymphopenia was observed. The following grade 3 events occurred: rash (in 3 patients); lymphopenia (in 2); AST, ALT, lung infection, and elevated aPTT (in 1). The most common adverse events were thrombocytopenia, lymphopenia, and rash. No Aspergillosis infection was observed. After a median follow-up of 6.9 months, 14/15 were evaluated for response with 13/15 (73%) showing a response: 4 CR, 7 PR, and 2 SD, 1 PD. Median PFS was 3.03 months; not yet reached for Dose level 4 (only 1/6 has developed progression with a median follow up of 5 months).
CONCLUSION: Patients with CNS lymphoma tolerate the combination of rituximab, lenalidomide and ibrutinib well. No dose limiting toxicities were observed. No Aspergillosis infection occurred with this combination regimen. Continued enrollment is ongoing.

Disclosures
Grommes: BTG: Consultancy; Ono: Consultancy; Kite: Consultancy. Schaff:Debiopharm: Consultancy.
Loss of FXR Signaling Promotes Chronic Liver Injury in Sickle Cell Disease
Authors: Vats Ravi , Novelli Enrico M , Gladwin Mark T , Sundd Prithu , Pradhan Tirthadipa 
Published: November 2020

Hepatic crisis is an emergent complication affecting sickle cell disease (SCD) patients, however, the molecular mechanism of sickle cell hepatobiliary crisis remains poorly understood. We have used intravital imaging to show that sinusoidal ischemia occurs in the liver of transgenic-humanized SCD mice under basal condition. SCD mice manifested progressive hepatomegaly, liver injury and hyperbilirubinemia. RNA-sequence analysis identified dysregulation of genes encoding proteins responsible for fibrosis, bile acid synthesis, and bile transport in the SCD mice liver. Live injury was the result of NF-κB-dependent inhibition of FXR signaling and its downstream targets in hepatocytes, leading to loss of canalicular bile transport and bile metabolism. Blocking NF-κB activation rescued FXR-signaling, ameliorated liver injury and resolved sinusoidal ischemia in SCD mice. Moreover, administration of FXR agonist (GW4064) also ameliorated liver injury seen in SCD mice. These findings are the first to identify that FXR-dependent impaired bile secretion promotes intrahepatic bile accumulation, which contributes to hepatobiliary injury of SCD. Improved understanding of these pathways could potentially benefit the development of new therapies to treat sickle cell hepatic crisis.

Disclosures
No relevant conflicts of interest to declare.
Towards a better understanding of the low recall of insertion variants with short-read based variant callers
Authors: Delage Wesley J. , Thevenon Julien , Lemaitre Claire 
Published: November 2020

Abstract

Background
Since 2009, numerous tools have been developed to detect structural variants using short read technologies. Insertions >50 bp are one of the hardest type to discover and are drastically underrepresented in gold standard variant callsets. The advent of long read technologies has completely changed the situation. In 2019, two independent cross technologies studies have published the most complete variant callsets with sequence resolved insertions in human individuals. Among the reported insertions, only 17 to 28% could be discovered with short-read based tools.

Results
In this work, we performed an in-depth analysis of these unprecedented insertion callsets in order to investigate the causes of such failures. We have first established a precise classification of insertion variants according to four layers of characterization: the nature and size of the inserted sequence, the genomic context of the insertion site and the breakpoint junction complexity. Because these levels are intertwined, we then used simulations to characterize the impact of each complexity factor on the recall of several structural variant callers. We showed that most reported insertions exhibited characteristics that may interfere with their discovery: 63% were tandem repeat expansions, 38% contained homology larger than 10 bp within their breakpoint junctions and 70% were located in simple repeats. Consequently, the recall of short-read based variant callers was significantly lower for such insertions (6% for tandem repeats vs 56% for mobile element insertions). Simulations showed that the most impacting factor was the insertion type rather than the genomic context, with various difficulties being handled differently among the tested structural variant callers, and they highlighted the lack of sequence resolution for most insertion calls.

Conclusions
Our results explain the low recall by pointing out several difficulty factors among the observed insertion features and provide avenues for improving SV caller algorithms and their combinations.
Exercise interveNtion outdoor proJect in the cOmmunitY for older people – results from the ENJOY Seniors Exercise Park project translation research in the community
Authors: Levinger Pazit , Panisset Maya , Dunn Jeremy , Haines Terry , Dow Briony , Batchelor Frances , Biddle Stuart , Duque Gustavo , Hill Keith D. 
Published: November 2020

Abstract

Background
Many research studies evaluate physical activity interventions for older people in the community, however relatively few successfully promote maintenance of physical activity beyond the completion of the intervention. This study aimed to implement and evaluate the effects of sustained engagement in physical activity on mental, social and physical health outcomes through the use of the Seniors Exercise Park physical activity program for older people (the ENJOY project).

Method
People aged ≥60 years underwent a 12-week structured supervised physical activity program using outdoor exercise park equipment followed by 6 months unstructured independent use of the exercise park. Participants were assessed at baseline, 3 months and 9 months and completed a test battery evaluating physical activity, physical function and health related quality of life measures. Repeated measures ANOVA was used to compare differences between baseline, 3 and 9 months.

Results
Of the 95 participants, 80 (84.2%) completed the 3 months supervised program, and 58 (61%) completed the 9 month assessment (the latter impacted by COVID-19 restrictions). A significant increase in physical activity level was demonstrated following the 12 weeks intervention (p < 0.01). Significant improvements were also demonstrated in all physical function measures (p < 0.01), self-rated quality of life (p < 0.05), wellbeing (p < 0.01), fear of falls (p < 0.01), falls risk (p < 0.01), depressive symptoms (p = 0.01) and loneliness (p = 0.03) at 3 months. At the 9 months follow up, significant improvements from baseline were demonstrated in the frequency, duration and total of physical activity level (p < 0.05), and all physical function measures (p < 0.05), with no decline in these measures from 3 to 9 months. At 9 months, significant changes were observed in the health related quality of life mobility and self care domains with reductions in both fear of falls and falls risk (p < 0.05).

Conclusion
The Seniors Exercise Park may be an effective modality for improving and sustaining older people’s physical function and wellbeing and can be an important public health infrastructure investment in promoting physical activity for older people. Future work should focus on wider implementation of the program and on scaling up this initiative to achieve public health benefit for the community.

Trial registration
Trial registration number ACTRN12618001727235, Date of registration 19th October 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375979
Gender differences of depression and anxiety among social media users during the COVID-19 outbreak in China:a cross-sectional study
Authors: Hou Fengsu , Bi Fengying , Jiao Rong , Luo Dan , Song Kangxing 
Published: November 2020

Abstract

Background
Studies have shown that the outbreak of infectious diseases would result in mental health problems. Females are in greater risk for psychological problems than males. The present study investigated gender differences of depression and anxiety and explored associated factors during the COVID-19 epidemic among Chinese social media users.

Methods
We recruited 3088 participants through social media cross China. Participants completed sociodemographic and the COVID-19 epidemic related questions, the 2-item Patient Health Questionnaire (PHQ-2), and the 2-item Generalized Anxiety Disorder Scale (GAD-2), the Chinese version of the 10-item Connor-Davidson Resilience Scale. We applied Chi-square test and ANOVA for data description and linear regression analysis for exploring factors associated with depression and anxiety.

Results
Of 3063 participants eligible for analysis, the total prevalence of depression and anxiety was 14.14 and 13.25%. Females were experiencing more severe stress and anxiety symptoms, while males showed better resilience to stress. The severity of depression symptoms would decrease with the increase of age resilience, and it would increase if being unemployed, feeling less adapted, being more stressed. The severity of anxiety symptoms would decrease with higher education and better resilience, and it would increase if being female, spending over 60 min on COVID-19 related information, less adapted, and being more stressed.

Conclusion
The findings show the increased prevalence of depression and anxiety in Chinese population during the COVID-19 epidemic, and females are experiencing more severe anxiety symptoms than males. As social media is the current main resource of information related to COVID-19, interventions should be implemented to help users to limit the time they spend on social media and to get key information related to the epidemic from authoritative and authentic resource to avoid infodemic and prevent mental health problems.
Mental state of central sterile supply department staff during COVID-19 epidemic and CART analysis
Authors: Pan Wei , Hu Juan , Yi Liangying 
Published: November 2020

Abstract

Background
During the COVID-19 epidemic, the central sterile supply department (CSSD) staff handled many devices, implements and non-disposable protective articles used by suspected or confirmed COVID-19 patients. As a result, the CSSD staff may have experienced psychological stress, however, the mental state of the CSSD staff during the COVID-19 epidemic has been rarely studied. We aim to investigate the mental state of the CSSD staff and relevant influencing factors experienced during the COVID-19 epidemic.

Methods
The survey utilising a general information questionnaire, Chinese perceived stress scale (CPSS), self-rating anxiety scale (SAS), and Connor-Davidson resilience scale (CD-RISC) was conducted with 423 CSSD staff members from 35 hospitals in Sichuan Province, China. Data was analysed in SPSS24.0. Classification and regression tree (CART) was utilised to analyse variables and find variation between groups. A chi-square test was performed on enumeration data, and t-test and analysis of variance were performed on measurement data.

Results
The CSSD staff’s SAS score was 37.39 ± 8.458, their CPSS score was 19.21 ± 7.265, and their CD-RISC score was 64.26 ± 15.129 (Tenacity factor score: 31.70 ± 8.066, Strength factor score: 21.60 ± 5.066, Optimism factor scores: 10.96 ± 3.189). The CPSS score was positively correlated with the SAS score (r = 0.66; P < 0.01), the CPSS score was negatively correlated with the CD-RISC score (r = − 0.617, P < 0.01), and the SAS score was negatively correlated with the CD-RISC score (r = − 0.477, P < 0.01). The job position, age, and political status of the CSSD staff were the main factors affecting their mental state; for example, the CPSS score and SAS score of the CSSD nurses were significantly different from those of the CSSD logistic staff (P < 0.01).

Conclusion
During the epidemic, the CSSD staff’s psychological resilience was at a low level; the anxiety level of the CSSD nurses was higher than that of the CSSD logistic staff. Therefore, more attention should be given to the mental health of the CSSD staff, including taking protective measures regarding the risk factors to ensure they can maintain a healthy mental state.
Ringworm in calves: risk factors, improved molecular diagnosis, and therapeutic efficacy of an Aloe vera gel extract
Authors: Tartor Yasmine H. , El-Neshwy Wafaa M. , Merwad Abdallah M. A. , Abo El-Maati Mohamed F. , Mohamed Rehab E. , Dahshan Hesham M. , Mahmoud Hala I. 
Published: November 2020

Abstract

Background
Dermatophytosis in calves is a major public and veterinary health concern worldwide because of its zoonotic potential and associated economic losses in cattle farms. However, this condition has lacked adequate attention; thus, to develop effective control measures, we determined ringworm prevalence, risk factors, and the direct-sample nested PCR diagnostic indices compared with the conventional methods of dermatophytes identification. Moreover, the phenolic composition of an Aloe vera gel extract (AGE) and its in vitro and in vivo antidermatophytic activity were evaluated and compared with those of antifungal drugs.

Results
Of the 760 calves examined, 55.79% (424/760) showed ringworm lesions; 84.91% (360/424) were positive for fungal elements in direct-microscopy, and 79.72% (338/424) were positive in culture. Trichophyton verrucosum was the most frequently identified dermatophyte (90.24%). The risk of dermatophytosis was higher in 4–6-month-old vs. 1-month-old calves (60% vs. 41%), and in summer and winter compared with spring and autumn seasons (66 and 54% vs. 48%). Poor hygienic conditions, intensive breeding systems, animal raising for meat production, parasitic infestation, crossbreeding, and newly purchased animals were statistically significant risk factors for dermatophytosis. One-step PCR targeting the conserved regions of the 18S and 28S genes achieved unequivocal identification of T. verrucosum and T. mentagrophytes in hair samples. Nested-PCR exhibited an excellent performance in all tested diagnostic indices and increased the species-specific detection of dermatophytes by 20% compared with culture. Terbinafine and miconazole were the most active antifungal agents for dermatophytes. Gallic acid, caffeic acid, chlorogenic acid, cinnamic acid, aloe-Emodin, quercetin, and rutin were the major phenolic compounds of AGE, as assessed using high-performance liquid chromatography (HPLC). These compounds increased and synergized the antidermatophytic activity of AGE. The treated groups showed significantly lower clinical scores vs. the control group (P < 0.05). The calves were successfully treated with topical AGE (500 ppm), resulting in clinical and mycological cure within 14–28 days of the experiment; however, the recovery was achieved earlier in the topical miconazole 2% and AGE plus oral terbinafine groups.

Conclusions
The nested PCR assay provided a rapid diagnostic tool for dermatophytosis and complemented the conventional methods for initiating targeted treatments for ringworm in calves. The recognized antidermatophytic potential of AGE is an advantageous addition to the therapeutic outcomes of commercial drugs.
Fatal systemic toxoplasmosis in a 3-month-old young tibetan goat (Capra hircus)
Authors: Pavone Silvia , Crotti Silvia , Cruciani Deborah , D’Avino Nicoletta , Zema Jacopo , Morelli Simone , Gobbi Marco , Madeo Laura 
Published: November 2020

AbstractBackgroundToxoplasmosis is one of the most common parasitic infections in both humans and animals. It is a frequent cause of abortion and stillbirth in intermediate hosts, especially sheep and goats but rarely causes fatal clinical form in adult animals.Case presentationIn contrast, the study reports an unusual fatal case of toxoplasmosis in a young goat naturally infected with type II strain ofToxoplasma gondii. A three-month-old female goat was presented with dyspnea and died few days later. Grossly, lungs were firm, edematous and mottled with disseminated whitish areas. Generalized lymphadenopathy was found. The histopathological examination showed necrotic interstitial bronchopneumonia and necrotizing lymphadenitis with intralesional free and clustered within macrophages tachyzoites ofT. gondii. DNA extracted from lungs and lymph nodes was positive forT. gondiiby a fast qPCR. PCR-RFLP analysis and sequencing of GRA6 gene showed that the isolated strains belonged to type II genotype.ConclusionsThis is an unusual report of acute systemic toxoplasmosis caused by the type II strain ofT. gondiiwith a fatal outcome in a young goat.
Biogenesis and functions of circular RNAs and their role in diseases of the female reproductive system
Authors: Ma Yalan , Xu Ying , Zhang Jingshun , Zheng Lianwen 
Published: November 2020

Abstract
A member of the newly discovered RNA family, circular RNA (circRNA) is considered as the intermediate product of by-product splicing or abnormal RNA splicing. With the development of RNA sequencing, circRNA has recently drawn research interest. CircRNA exhibits stability, species conservatism, and tissue cell specificity. It acts as a miRNA sponge in the circRNA-microRNA (miRNA-mRNA axis, which can regulate gene transcription and protein translation. Studies have confirmed that circRNA is ubiquitous in eukaryotic cells, which play an important role in the regulation of human gene expression and participate in the occurrence and development of various human diseases. CircRNA may be closely related to the occurrence and development of female reproductive system diseases. By analyzing the biological functions and mechanism of circRNA, we find that circRNA has certain development prospects as biomarkers of the female reproductive system diseases. The production and degradation of circRNA, biological functions, and their association with the occurrence of diseases of female reproductive system are reviewed in this article.