bluuebunny/crossref_metadata_2025_split huggingface dataset:
Postmarketing safety of orphan drugs: a longitudinal analysis of the US Food and Drug Administration database between 1999 and 2018
Authors: Fan Min , Chan Adrienne Y. L. , Yan Vincent K. C. , Tong Xinning , Lau Lauren K. W. , Wan Eric Y. F. , Tam Eliza Y. T. , Ip Patrick , Lum Terry Y. , Wong Ian C. K. , Li X. 
Published: January 2022

Abstract
Background
Information about the specific regulatory environment of orphan drugs is scarce and inconsistent. Uncertainties surrounding the postmarketing long-term safety of orphan drugs remain. This study aimed to evaluate the labelling changes of orphan drugs and to identify postmarketing safety-associated approval factors.

Methods
This retrospective cohort study includes all drugs with orphan drug designation approved by the Center for Drug Evaluation and Research of the US Food and Drug Administration between 1999 and 2018. Main outcomes are safety-related labelling changes up to 31 December 2019. We defined any safety-related labelling changes as postmarketing safety events (PMSE). Safety-related withdrawals, suspensions, and boxed warnings were further categorised as severe postmarketing safety events (SPSE). Outcome measurements include frequencies of PMSE, SPSE, and association between approval factors and the occurrence of safety events.

Results
Amongst the 214 drugs identified with orphan drug designation (25.7% biologics), 83.6% were approved through at least one expedited programme, and 29.4% were approved with boxed warnings. During a median follow-up of 6.74 years since approval, 69.2% and 14.5% of the analysed orphan drugs had PMSE and SPSE, respectively. Safety-related withdrawal (0%, 0/214), suspended marketing (0.46%, 1/214) and new boxed warnings are uncommon (3.7%, 8/214). The safety-related labelling changes were more frequent in the drugs approved with boxed warnings [Incidence rate ratio (IRR): 1.95 (1.02–3.73)] and approved for long-term use [IRR: 2.76 (1.52–5.00)].

Conclusions and Relevance
In this long-term postmarketing analysis, approximately 70% of FDA-approved orphan drugs had safety-related labelling changes although severe safety events were rare. While maintaining early access to orphan drugs, the drug regulatory body has taken timely regulatory action with postmarketing surveillance to ensure patient safety.
Usefulness of random-start progestin-primed ovarian stimulation for fertility preservation
Authors: Huang Haipeng , Itaya Yukiko , Samejima Kouki , Ichinose Shunichiro , Narita Tatsuya , Matsunaga Shigetaka , Saitoh Masahiro , Takai Yasushi 
Published: January 2022

Abstract
Background
Progestin-primed ovarian stimulation (PPOS) has been used in infertility cases in recent years, and several reports have stated that it has oocyte collection results similar to those of gonadotropin-releasing hormone antagonist (GnRH-ant) protocol. For emergency fertility preservation, random-start ovarian stimulation is usually recommended. Therefore we compared the clinical outcomes of random-start PPOS with those of conventional random-start GnRH-ant protocols in fertility-preserving cases.

Methods
We retrospectively examined 86 cycles of oocyte collection, of which 56 were random-start GnRH-ant and 30 were random-start PPOS for fertility preservation at our hospital between January 2016 and April 2021. The primary outcome was the number of mature oocytes per cycle. The secondary outcome was the number of vitrified blastocysts per cycle for embryo freezing cases.

Results
No significant differences were noted in the number of days of stimulation, total dose of gonadotropin preparation, and the number of mature oocytes and vitrified blastocysts. The number of hospital visits for monitoring was significantly lower in the PPOS group. The start of menstruation before oocyte collection was significantly less in the PPOS group.

Conclusions
Random-start PPOS and GnRH-ant were similar in oocyte collection results. PPOS can reduce the number of hospital visits, thus reducing patient stress. PPOS at the start of the luteal phase can prevent the start of menstruation during ovarian stimulation.
Germline HOXB13 mutation p.G84E do not confer an increased bladder or kidney cancer risk in polish population
Authors: Złowocka-Perłowska Elżbieta , Tołoczko-Grabarek Aleksandra , Lubiński Jan 
Published: January 2022

Abstract
Introduction
The role of HOXB13 in bladder and renal tumorigenesis is unclear. Our goal was to determine the prevalence of HOXB13 p.G84E mutation in bladder and kidney cancer patients from Poland.

Materials and methods
1418 patients with bladder cancer and 813 cases with kidney cancer and 4497 controls were genotyped for HOXB13 p.G84E.

Results
p.G84E mutation of HOXB13 gene was detected in three of 1418 (0.2%) bladder cancer cases and in six of 4497 controls (odds ratio [OR], 1.6; 95% CI 0.39–6.36; p = 0.8). Among 813 kidney cancer cases HOXB13 mutations was reported in three patients (0,4%) (odds ratio [OR], (OR = 2,8; 95% CI 0.69–11.11; p = 0.3). In cases with mutations in the HOXB13 gene, the family history of cancer was negative.

Conclusion
HOXB13 mutation was not associated with bladder or kidney cancer. Mutation p.G84E in HOXB13 seem not to play a role in bladder and kidney cancer development in Polish patients.
Persistence of live virus in critically ill patients infected with SARS-COV-2: a prospective observational study
Authors: Funk Duane J. , Bullard Jared , Lother Sylvan , Grande Gloria Vazquez , Garnett Lauren , Doan Kaylie , Dust Kerry , Kumar Anand , Poliquin Guillaume , Strong Jim 
Published: January 2022

Abstract
Background
Research on the duration of infectivity of ICU patients with COVID-19 has been sparse. Tests based on Reverse Transcriptase polymerase chain reaction (RT-PCR) detect both live virus and non-infectious viral RNA. We aimed to determine the duration of infectiousness based on viral culture of nasopharyngeal samples of patients with COVID-19.

Methods
Prospective observational study in adult intensive care units with a diagnosis of COVID-19 Pneumonia. Patients had repeated nasopharyngeal sampling performed after day 10 of ICU admission. Culture positive rate (based on viral culture on Vero cells in a level 4 lab) and Cycle threshold from RT-PCR were measured.

Results
Nine patients of the 108 samples (8.3%, 95% CI 3.9–15.2%) grew live virus at a median of 13 days (interquartile range 11–19) after their initial positive test. 74.1% of patients were RT-PCR positive but culture negative, and the remaining (17.6%) were RT-PCR and culture negative. Cycle threshold showed excellent ability to predict the presence of live virus, with a Ct < 25 with an AUC of 0.90 (95% CI 0.83–0.97, p < 0.001). The specificity of a Ct > 25 to predict negative viral culture was 100% (95% CI 70–100%).

Conclusion
8.3% of our ICU patients with COVID-19 grew live virus at a median of 13 days post-initial positive RT-PCR test. Severity of illness, use of mechanical ventilation, and time between tests did not predict the presence of live virus. Cycle threshold of > 25 had the best ability to determine the lack of live virus in these patents.
Efficacy of acupuncture and its influence on the emotional network in adult insomnia patients: protocol for a randomized controlled clinical trial
Authors: Jiang Tongfei , Zhang Qi , Yuan Fang , Zhang Fan , Guo Jing 
Published: January 2022

Abstract
Introduction
Insomnia disorder (ID) is characterized by dissatisfaction with the quantity or quality of sleep and is often accompanied by negative emotions such as anxiety and depression. Patients with insomnia become trapped in a vicious circle of bad moods and poor sleep. Resting-state functional magnetic resonance imaging (r-fMRI) studies have shown abnormalities in emotion-related brain networks in patients with ID. And it has been proven that reducing negative emotions improves sleep quality. As a traditional alternative therapy, acupuncture has been demonstrated to be effective not only in improving sleep quality but also in stabilizing emotions; however, the mode of action needs to be further explored. Therefore, a clinical trial was designed to explore the effect of acupuncture in improving sleep and mood and to intuitively investigate the regulation of the emotional network using fMRI.

Methods and analysis
A total of 60 participants with ID will be randomly allocated to a spirit-regulating group or a control group using non-effective acupoints acupuncture at a ratio of 1:1. All participants will receive 3 acupuncture treatment sessions per week for 4 weeks. In addition, 30 healthy individuals will be included in the healthy group. The primary outcome is the Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes are the Hamilton Anxiety Scale (HAMA), the Hamilton Depression Scale (HAMD), the Hyperarousal Scale (HAS), and the Fatigue Scale-14 (FS-14), r-fMRI data, sleep diary, and actigraphy. The data will be collected prior to treatment, following treatment, and during the 12-week follow-up period; a sleep diary will be kept during the entire process.

Ethics and dissemination
This protocol has been approved by the Research Ethical Committee of Beijing Hospital of Traditional Chinese Medicine (Bejing TCM Hospital). The results will be published in peer-reviewed journals or presented at academic conferences.

Trial registration
Chinese Clinical Trials Register ChiCTR1800015282.
Protocol version: Version 1.0. Date: Dec.2020
Deformation of the nucleus by TGFβ1 via the remodeling of nuclear envelope and histone isoforms
Authors: Chi Ya-Hui , Wang Wan-Ping , Hung Ming-Chun , Liou Gunn-Guang , Wang Jing-Ya , Chao Pen-Hsiu Grace 
Published: January 2022

AbstractThe cause of nuclear shape abnormalities which are often seen in pre-neoplastic and malignant tissues is not clear. In this study we report that deformation of the nucleus can be induced by TGFβ1 stimulation in several cell lines including Huh7. In our results, the upregulated histone H3.3 expression downstream of SMAD signaling contributed to TGFβ1-induced nuclear deformation, a process of which requires incorporation of the nuclear envelope (NE) proteins lamin B1 and SUN1. During this process, the NE constitutively ruptured and reformed. Contrast to lamin B1 which was relatively stationary around the nucleus, the upregulated lamin A was highly mobile, clustering at the nuclear periphery and reintegrating into the nucleoplasm. The chromatin regions that lost NE coverage formed a supra-nucleosomal structure characterized by elevated histone H3K27me3 and histone H1, the formation of which depended on the presence of lamin A. These results provide evidence that shape of the nucleus can be modulated through TGFβ1-induced compositional changes in the chromatin and nuclear lamina.
Influence of lincomycin-spectinomycin treatment on the outcome of Enterococcus cecorum infection and on the cecal microbiota in broilers
Authors: Schreier Jana , Karasova Daniela , Crhanova Magdalena , Rychlik Ivan , Rautenschlein Silke , Jung Arne 
Published: January 2022

AbstractBackgroundEnterococcus cecorum(EC) is one of the main reasons for skeletal disease in meat type chickens. Intervention strategies are still rare and focus mainly on early antibiotic treatment of the disease, although there are no data available concerning the effectivity of this procedure. The present study aimed to investigate the effectivity of early lincomycin-spectinomycin treatment during the first week of life after EC-infection. Furthermore, the impact of lincomycin-spectinomycin treatment and EC infection on the development of cecal microbiota was investigated.MethodsA total of 383 day-old broiler chicks were randomly assigned to four groups (non-infected and non-treated, non-infected and treated, EC-infected and non-treated, and EC-infected and treated). The EC-infected groups were inoculated orally with an EC suspension at the day of arrival and at study day 3. The treatment groups were treated with lincomycin-spectinomycin via the drinking water for six consecutive days, starting two hours after the first inoculation. Necropsy of 20 chickens per group was performed at study days 7, 14, 21, and 42. Bacteriological examination via culture and real-time PCR was performed to detect EC in different extraintestinal organs. Cecal samples of nine chickens per group and necropsy day were analyzed to characterize the composition of the cecal microbiota.ResultsNo clinical signs or pathologic lesions were found at necropsy, and EC was not detected in extraintestinal organs of the EC-infected and treated birds. Lincomycin-spectinomycin promoted the growth of the bacterial genusEscherichia/Shigellaand reduced the amount of potentially beneficialLactobacillus spp.in the ceca regardless of EC-infection. Unexpectedly, the highest abundances of the genus Enterococcus were found directly after ending antibiotic treatment in both treatment groups, suggesting the growth of resistant enterococcal species. EC was not detected among the most abundant members of the genusEnterococcus.Oral EC-infection at the first day of life did not influence the development of cecal microbiota in the present study.ConclusionsLincomycin-spectinomycin treatment during the first week of life can prevent the EC-associated disease in broiler type chickens and has a direct impact on the development of the cecal microbiota. The low abundance of EC in the ceca of infected chickens underlines the pathogenic nature of the disease-causing EC strains. Further research on alternative prevention and intervention strategies is needed with regard to current efforts on reducing the use of antibiotics in livestock animals.
Genomic characteristics and comparative genomics of Salmonella enterica subsp. enterica serovar Schwarzengrund strain S16 isolated from chicken feces
Authors: Yang Seung-Min , Kim Eiseul , Lee Woojung , Kim Hae-Yeong 
Published: January 2022

Abstract
Background
Salmonella enterica subsp. enterica serovar Schwarzengrund (S. Schwarzengrund) is most frequently isolated from commensals humans or poultry. Here we report S. Schwarzengrund strain S16, the first sequenced genome in the Republic of Korea. Additionally, genome sequencing for strain S16 was performed and compared with other S. Schwarzengrund genomes obtained from public database.

Results
Strain S16 was isolated from chicken feces. The complete genome consists of one chromosome and one plasmid. The genome size is 4,822,755 bp with 4852 coding sequences. Strain S16 was determined as serovar Schwarzengrund by in silico serotyping and typed as sequence type (ST) 96. Forty-six S. Schwarzengrund genomes yielded a pangenome of 7112 genes, core-genome of 3374 genes, accessory-genome of 2906 genes, and unique-genome of 835 genes. Eighty-one genes were unique to strain S16, including hypothetical proteins and transcriptional regulators. Genotypic analysis of antibiotic resistance of strain S16 confirmed resistance to amikacin, ciprofloxacin, sulfamethoxazole, streptomycin, and tetracycline. Unlike other S. Schwarzengrund genomes, strain S16 had a mutation of gyrB. Moreover, similar to other S. Schwarzengrund genomes reported in other countries, strain S16 was harbored for 153 virulence genes including Saf operon and cdtB gene. All the antibiotic resistance genes and virulence genes were present in the core- or accessory-genomes.

Conclusions
Complete genome of strain S16 was sequenced. Comparative genomic analysis revealed several genes responsible for antibiotic resistance and specific genomic features of strain S16 and identified virulence factors that might contribute to the human and animal pathogenicity of other S. Schwarzengrund genomes.
Delineating the autistic phenotype in children with neurofibromatosis type 1
Authors: Chisholm Anita K. , Haebich Kristina M. , Pride Natalie A. , Walsh Karin S. , Lami Francesca , Ure Alex , Maloof Tiba , Brignell Amanda , Rouel Melissa , Granader Yael , Maier Alice , Barton Belinda , Darke Hayley , Dabscheck Gabriel , Anderson Vicki A. , Williams Katrina , North Kathryn N. , Payne Jonathan M. 
Published: January 2022

AbstractBackgroundExisting research has demonstrated elevated autistic behaviours in children with neurofibromatosis type 1 (NF1), but the autistic phenotype and its relationship to other neurodevelopmental manifestations of NF1 remains unclear. To address this gap, we performed detailed characterisation of autistic behaviours in children with NF1 and investigated their association with other common NF1 child characteristics.MethodsParticipants were drawn from a larger cross-sectional study examining autism in children with NF1. The population analysed in this study scored above threshold on the Social Responsiveness Scale-Second Edition (T-score ≥ 60; 51% larger cohort) and completed the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). All participants underwent evaluation of their intellectual function, and behavioural data were collected via parent questionnaires.ResultsThe study cohort comprised 68 children (3–15 years). Sixty-three per cent met the ADOS-2 ‘autism spectrum’ cut-off, and 34% exceeded the more stringent threshold for ‘autistic disorder’ on the ADI-R. Social communication symptoms were common and wide-ranging, while restricted and repetitive behaviours (RRBs) were most commonly characterised by ‘insistence on sameness’ (IS) behaviours such as circumscribed interests and difficulties with minor changes. Autistic behaviours were weakly correlated with hyperactive/impulsive attention deficit hyperactivity disorder (ADHD) symptoms but not with inattentive ADHD or other behavioural characteristics. Language and verbal IQ were weakly related to social communication behaviours but not to RRBs.LimitationsLack of genetic validation of NF1, no clinical diagnosis of autism, and a retrospective assessment of autistic behaviours in early childhood.ConclusionsFindings provide strong support for elevated autistic behaviours in children with NF1. While these behaviours were relatively independent of other NF1 comorbidities, the importance of taking broader child characteristics into consideration when interpreting data from autism-specific measures in this population is highlighted. Social communication deficits appear similar to those observed in idiopathic autism and are coupled with a unique RRB profile comprising prominent IS behaviours. This autistic phenotype and its relationship to common NF1 comorbidities such as anxiety and executive dysfunction will be important to examine in future research. Current findings have important implications for the early identification of autism in NF1 and clinical management.
Sodium–glucose cotransporter 2 inhibitor-induced euglycemic diabetic ketoacidosis in a patient with coronavirus disease 2019: a case report
Authors: Yii Edwin Sze Sian , Azli Athirah Wan , Sitaram Premela Naidu 
Published: January 2022

Abstract
Background
Sodium–glucose cotransporter 2 inhibitors are among the new-generation oral antihyperglycemic agents that have been used in the treatment of type 2 diabetes mellitus. With the recent coronavirus disease 2019 pandemic and rise of cases in the third wave, diagnosis of life-threatening euglycemic diabetic ketoacidosis may easily be overlooked or missed.

Case presentation
We present the case of a 37-year-old Malay gentleman with underlying type 2 diabetes mellitus on empagliflozin, who presented to our hospital with symptomatic coronavirus disease 2019 infection and diabetic ketoacidosis. He developed severe rebound euglycemic diabetic ketoacidosis due to the continuous usage of empagliflozin for glycemic control alongside intravenous insulin.

Conclusions
Physicians should have a high index of suspicion in diagnosing and managing euglycemic diabetic ketoacidosis, including withholding treatment of sodium–glucose cotransporter 2 inhibitors during the acute management of diabetic ketoacidosis.
Equalities and inequalities for several variables mappings
Authors: Bodaghi Abasalt 
Published: January 2022

AbstractIn this paper, some special mappings of several variables such as the multicubic and the multimixed quadratic–cubic mappings are introduced. Then, the systems of equations defining a multicubic and a multimixed quadratic–cubic mapping are unified to a single equation. Under some mild conditions, it is shown that a multimixed quadratic–cubic mapping can be multiquadratic, multicubic and multiquadratic–cubic. Furthermore, by applying a known fixed-point theorem, the Hyers–Ulam stability of multimixed quadratic–cubic, multiquadratic, multicubic and multiquadratic–cubic are studied in non-Archimedean normed spaces.
A note on optimal Hermite interpolation in Sobolev spaces
Authors: Xu Guiqiao , Yu Xiaochen 
Published: January 2022

AbstractThis paper investigates the optimal Hermite interpolation of Sobolev spaces$W_{\infty }^{n}[a,b]$W∞n[a,b],$n\in \mathbb{N}$n∈Nin space$L_{\infty }[a,b]$L∞[a,b]and weighted spaces$L_{p,\omega }[a,b]$Lp,ω[a,b],$1\le p< \infty $1≤p<∞withωa continuous-integrable weight function in$(a,b)$(a,b)when the amount of Hermite data isn. We proved that the Lagrange interpolation algorithms based on the zeros of polynomial of degreenwith the leading coefficient 1 of the least deviation from zero in$L_{\infty }$L∞(or$L_{p,\omega }[a,b]$Lp,ω[a,b],$1\le p<\infty $1≤p<∞) are optimal for$W_{\infty }^{n}[a,b]$W∞n[a,b]in$L_{\infty }[a,b]$L∞[a,b](or$L_{p,\omega }[a,b]$Lp,ω[a,b],$1\le p<\infty $1≤p<∞). We also give the optimal Hermite interpolation algorithms when we assume the endpoints are included in the interpolation systems.
A variational inequality arising from optimal surrender of variable annuity with lookback benefit
Authors: Jeon Junkee , Kwak Minsuk 
Published: January 2022

AbstractWe introduce a variable annuity (VA) contract with a surrender option and lookback benefit, that is, the benefit of the VA contract is linked to the maximum process of the policyholder’s account value. In contrast to the constant guarantee model provided in Bernard et al. (Insur. Math. Econ. 55:116–128, 2014), it is optimal for the policyholder of the VA contract with lookback benefit to surrender the VA contract when the policyholder’s account value is below or equal to the optimal surrender boundary. Thus, from the perspective of the insurer to construct a portfolio of VA contracts, utilizing the VA contracts with lookback benefit along with VA contracts with constant guarantee provides the diversification of early surrenders. The valuation of this contract can be described as a two-dimensional parabolic variational inequality. By converting this into the one-dimensional problem, we obtain the integral equations for the value function and the free boundary. The recursive integration method is applied to obtain the numerical solutions. We also provide comparative statics of the optimal surrender boundaries with respect to various parameters.
On three-term conjugate gradient method for optimization problems with applications on COVID-19 model and robotic motion control
Authors: Sulaiman Ibrahim Mohammed , Malik Maulana , Awwal Aliyu Muhammed , Kumam Poom , Mamat Mustafa , Al-Ahmad Shadi 
Published: January 2022

AbstractThe three-term conjugate gradient (CG) algorithms are among the efficient variants of CG algorithms for solving optimization models. This is due to their simplicity and low memory requirements. On the other hand, the regression model is one of the statistical relationship models whose solution is obtained using one of the least square methods including the CG-like method. In this paper, we present a modification of a three-term conjugate gradient method for unconstrained optimization models and further establish the global convergence under inexact line search. The proposed method was extended to formulate a regression model for the novel coronavirus (COVID-19). The study considers the globally infected cases from January to October 2020 in parameterizing the model. Preliminary results have shown that the proposed method is promising and produces efficient regression model for COVID-19 pandemic. Also, the method was extended to solve a motion control problem involving a two-joint planar robot.