bluuebunny/crossref_metadata_2025_split huggingface dataset:
A very early diagnosis of Alstrӧm syndrome by next generation sequencing
Authors: Gatticchi Leonardo , Miertus Jan , Maltese Paolo Enrico , Bressan Simone , De Antoni Luca , Podracká Ludmila , Piteková Lucia , Rísová Vanda , Mällo Mari , Jaakson Kaie , Joost Kairit , Colombo Leonardo , Bertelli Matteo 
Published: September 2020

Abstract
Background
Alström syndrome is a rare recessively inherited disorder caused by variants in the ALMS1 gene. It is characterized by multiple organ dysfunction, including cone-rod retinal dystrophy, dilated cardiomyopathy, hearing loss, obesity, insulin resistance, hyperinsulinemia, type 2 diabetes mellitus and systemic fibrosis. Heterogeneity and age-dependent development of clinical manifestations make it difficult to obtain a clear diagnosis, especially in pediatric patients.

Case presentation
Here we report the case of a girl with Alström syndrome. Genetic examination was proposed at age 22 months when suspected macular degeneration was the only major finding. Next generation sequencing of a panel of genes linked to eye-related pathologies revealed two compound heterozygous variants in the ALMS1 gene. Frameshift variants c.1196_1202del, p.(Thr399Lysfs*11), rs761292021 and c.11310_11313del, (p.Glu3771Trpfs*18), rs747272625 were detected in exons 5 and 16, respectively. Both variants cause frameshifts and generation of a premature stop-codon that probably leads to mRNA nonsense-mediated decay. Validation and segregation of ALMS1 variants were confirmed by Sanger sequencing.

Conclusions
Genetic testing makes it possible, even in childhood, to increase the number of correct diagnoses of patients who have ambiguous phenotypes caused by rare genetic variants. The development of high-throughput sequencing technologies offers an exceptionally valuable screening tool for clear genetic diagnoses and ensures early multidisciplinary management and treatment of the emerging symptoms.
A case report of severe tuberous sclerosis complex detected in utero and linked to a novel duplication in the TSC2 gene
Authors: Mongrain Valérie , van Doesburg Nicolaas H. , Rypens Françoise , Fallet-Bianco Catherine , Maassen Justine , Dufort-Gervais Julien , Côté Lucie , Major Philippe 
Published: September 2020

Abstract
Background
Disease severity is tremendously variable in tuberous sclerosis complex (TSC). In contrast with the detailed guidelines available for TSC diagnosis and management, clinical practice lacks adequate tools to evaluate the prognosis, especially in the case of in utero diagnosis. In addition, the correlation between genotypes and phenotypes remains a challenge, in part due to the large number of mutations linked to TSC. In this report, we describe a case of severe TSC diagnosed in utero and associated with a specific mutation in the gene tuberous sclerosis complex 2 (TSC2).

Case presentation
A mother was referred for a thorough investigation following the observation by ultrasound of cardiac abnormalities in her fetus. The mother was healthy and reported frequent, intense and long-lasting hiccups/spasms in the fetus. The fetus of gestational age 33 weeks and 4 days was found to have multiple cardiac tumors with cardiac ultrasound. Brain magnetic resonance imaging (MRI) performed in utero revealed the presence of sub-ependymal nodules and of abnormal signals disseminated in the white matter, in the cerebral cortex and in the cerebellum. Following diagnosis of definite TSC, pregnancy interruption was chosen by the parents. Genetic testing of the fetus exposed a duplication in exon 41 of TSC2 (c.5169dupA), which was absent in the parents. The autopsy ascertained the high severity of brain damage characterized by an extensive disorganisation of white and grey matter in most cerebral lobes.

Conclusions
This case presentation is the first to depict the association between a de novo TSC2 c.5169dupA and multi-organ manifestation together with indications of a particularly high disease severity. This report can help physicians to perform early clinical diagnosis of TSC and to evaluate the prognosis.
A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disability, and autism: a case report
Authors: Santoro Claudia , Giugliano Teresa , Bernardo Pia , Palladino Federica , Torella Annalaura , del Vecchio Blanco Francesca , Onore Maria Elena , Carotenuto Marco , Nigro Vincenzo , Piluso Giulio 
Published: September 2020

Abstract
Background
Mutations in RAB39B at Xq28 causes a rare form of X-linked intellectual disability (ID) and Parkinson’s disease. Neurofibromatosis type 1 (NF1) is caused by heterozygous mutations in NF1 occurring de novo in about 50% of cases, usually due to paternal gonadal mutations. This case report describes clinical and genetic findings in a boy with the occurrence of two distinct causative mutations in NF1 and RAB39B explaining the observed phenotype.

Case presentation
Here we report a 7-year-old boy with multiple café-au-lait macules (CALMs) and freckling, severe macrocephaly, peculiar facial gestalt, severe ID with absent speech, epilepsy, autistic traits, self-harming, and aggressiveness. Proband is an only child born to a father aged 47. Parents did not present signs of NF1, while a maternal uncle showed severe ID, epilepsy, and tremors.By RNA analysis of NF1, we identified a de novo splicing variant (NM_000267.3:c.6579+2T>C) in proband, which explained NF1 clinical features but not the severe ID, behavioral problems, and aggressiveness. Family history suggested an X-linked condition and massively parallel sequencing of X-exome identified a novel RAB39B mutation (NM_171998.2:c.436_447del) in proband, his mother, and affected maternal uncle, subsequently validated by Sanger sequencing in these and other family members.

Conclusions
The case presented here highlights how concurrent genetic defects should be considered in NF1 patients when NF1 mutations cannot reasonably explain all the observed clinical features.
Racial differences in 5-year relative survival rates of cervical cancer by stage at diagnosis, between African American (black) and white women, living in the state of Alabama, USA
Authors: Abdalla Ehsan , Troy Roberta , Fall Souleymane , Elhussin Isra , Egiebor-Aiwan Oyoyo , Nganwa David 
Published: September 2020

AbstractBackgroundOur objective was to assess racial differences in the 5-year relative survival rates (RSRs) of Cervical Cancer (CerCancer) by stage at diagnosis, between Black and White women, living in Alabama, USA.MethodsData for 3484 Blacks and 21,059 Whites diagnosed with CerCancer were extracted from the 2004 to 2013 Surveillance, Epidemiology, and End Results (SEER) database. We incorporated age groups, CerCancer stages, county, and year of diagnosis to compare the RSR between Blacks and Whites, using SEER*Stat software.ResultsIn urban, Black Belt (BB) and other rural counties, Whites diagnosed with localized stage of CerCancer always had better chances of survival because their RSRs were always more than 77%, compared to Blacks. Only exception was in Blacks living in other rural counties, who had a significantly higher RSR of 83.8% (95% Cl, 74.2–90.1). Which was the same as in Whites (83.8% (95% CI 74.5–89.9) living in BBC. Although, in other rural counties, Whites had a slightly lower RSR of 83.7% (95% CI 79.9–86.8%), their RSR was better compared to Blacks and Whites living in BB and other rural counties who had slightly higher RSRs of 83.8%. This was due to statistical precision, which depended on their larger sample size and a lower variability therefore, more reliability resulting in a tighter confidence interval with a smaller margin of error. In all the three county groups, Whites 15–44 years old diagnosed with localized stage of CerCancer had a higher RSR of 93.6% (95% CI 91.4–95.2%) for those living in urban and BB counties, and 94.6% (95% CI 93.6–95.4) for those living in other rural counties. The only exception was in Blacks 65–74 years old living in other rural counties who had the highest RSR of 96.9% (95% Cl, 82.9–99.5). However, Whites were considered to have a better RSR. This was also due to the statistical precision as mentioned above.ConclusionThere were significant racial differences in the RSRs of CerCancer. Overall, Black women experienced the worst RSRs compared to their White counterparts.
Dose-dense TPF induction chemotherapy for locally advanced head and neck cancer: a phase II study
Authors: Hsieh Ching-Yun , Lein Ming-Yuh , Yang Shih-Neng , Wang Yao-Ching , Lin Yin-Jun , Lin Chen-Yuan , Hua Chun-Hung , Tsai Ming-Hsul , Lin Ching-Chan 
Published: September 2020

Abstract
Background
Phase 3 studies suggest that induction chemotherapy (ICT) of cisplatin and 5-fluorouracil plus docetaxel (TPF) is effective but toxic for patients with squamous-cell carcinoma of the head and neck (SCCHN). Dose-dense chemotherapy may yield favorable outcomes compared with standard-dose chemotherapy, yet the optimal induction regimen remains undefined. We assessed the efficacy and tolerability of biweekly dose-dense TPF ICT in patients with SCCHN.

Methods
In this prospective phase II study, We enrolled patients with stage III/IV (AJCC 7th edition) unresectable squamous cell carcinoma of head and neck cancer. Patients received dose-dense TPF (ddTPF) with cisplatin and docetaxel 50 mg/m2 on day 1, leucovorin 250 mg/m2 on day1, followed by 48-h continuous infusion of 2500 mg/m2 of 5-fluorouracil on day 1 and 2, every 2 weeks for 6 cycles followed by radiotherapy. The primary endpoint was the response rate (RR) after ICT.

Results
Fifty-eight patients were enrolled from June 2014 to September 2015. Overall RR after ICT was 89.6% [complete response (CR), 31%; partial response (PR), 58.6%]. Grade 3/4 neutropenia, mucositis, and diarrhea incidences were 25.9, 1.7, and 1.7%, respectively. 94.8% of patients completed all treatment courses of ICT without dose reduction. The 3-year overall survival (OS) was 54.3% (95%CI: 39.7 to 66.8%) and progression-free survival (PFS) was 34.3% (95%CI: 22.0 to 46.9%). Multivariate analysis showed that CR after ICT is an independent prognostic factor for OS and PFS.

Conclusions
Six cycles of ddTPF is an active, well-tolerated induction regimen for patients with SCCHN. The presence of CR after ICT predicted long-term survival.

Trial registration
ClinicalTrials.gov Identifier: NCT04397341, May 21, 2020, retrospectively registered.
Calculating the overall survival probability in patients with cervical cancer: a nomogram and decision curve analysis-based study
Authors: Xie Guilan , Wang Ruiqi , Shang Li , Qi Cuifang , Yang Liren , Huang Liyan , Yang Wenfang , Chung Mei Chun 
Published: September 2020

Abstract
Background
Cervical cancer has long been a common malignance troubling women. However, there are few studies developing nomogram with comprehensive factors for the prognosis of cervical cancer. Hence, we aimed to build a nomogram to calculate the overall survival (OS) probability in patients with cervical cancer.

Methods
Data of 9876 female patients in SEER database and diagnosed as cervical cancer during 2010–2015, was retrospectively analyzed. Univariate and multivariate Cox proportional hazard regression model were applied to select predicted factors and a nomogram was developed to visualize the prediction model. The nomogram was compared with the FIGO stage prediction model. Harrell’s C-index, receiver operating curve, calibration plot and decision curve analysis were used to assess the discrimination, accuracy, calibration and clinical utility of the prediction models.

Result
Eleven independent prognostic variables, including age at diagnosis, race, marital status at diagnosis, grade, histology, tumor size, FIGO stage, primary site surgery, regional lymph node surgery, radiotherapy and chemotherapy, were used to build the nomogram. The C-index of the nomogram was 0.826 (95% CI: 0.818 to 0.834), which was better than that of the FIGO stage prediction model (C-index: 0.785, 95% CI: 0.776 to 0.793). Calibration plot of the nomogram was well fitted in 3-year overall OS prediction, but overfitting in 5-year OS prediction. The net benefit of the nomogram was higher than the FIGO prediction model.

Conclusion
A clinical useful nomogram for calculating the overall survival probability in cervical cancer patients was developed. It performed better than the FIGO stage prediction model and could help clinicians to choose optimal treatments and precisely predict prognosis in clinical care and research.
Toxicity of Povidone-iodine to the ocular surface of rabbits
Authors: Kim Sunyoung , Ahn Yongsun , Lee Yeojin , Kim Hyunseung 
Published: September 2020

Abstract
Background
We evaluated the toxicity of 5% (w/v) povidone-iodine (PI) applied to the ocular surface of rabbits.

Methods
Twenty-three white rabbits were divided into four groups; these were a control group and three study groups in which the ocular surface was exposed to PI for different times. In control group, one drop of phosphate-buffered saline (PBS) was applied once for 10 min. In study groups, one drop of 5% (w/v) PI was topically applied once for 1 min, 3 min, and 10 min, and then the animals were observed for 7 days. The Schirmer test, Rose Bengal staining, corneal fluorescein staining and conjunctival impression cytology were performed on day 0, 3, and 7. After 7 days, the rabbits were sacrificed and conjunctiva and cornea were collected and evaluated by light and electron microscope. Immunofluorescence staining was also performed to detect mucin 5 subtype AC (MUC5AC).

Results
The decrease in goblet cell density, reductions in MUC5AC level and histopathological and ultrastructural changes of conjunctiva and cornea were more prominent in the 5% (w/v) PI groups than the control group (p < 0.05). Moreover, these changes were more prominent when PI was applied for 3 and 10 min rather than 1 min (both p values < 0.05).

Conclusions
5% (w/v) povidone-iodine caused damages to the ocular surface in a time-dependent manner. Therefore, we should be aware of that excessive PI exposure during ophthalmic procedures could be a pathogenic factor of dry eye syndrome after surgery.
Children with COVID-19 behaving milder may challenge the public policies: a systematic review and meta-analysis
Authors: Liu Chan , He Yu , Liu Lian , Li Fang , Shi Yuan 
Published: September 2020

Abstract
Background
The emerging virus is rampaging globally. A growing number of pediatric infected cases have been reported. Great efforts are needed to cut down the transmission.

Methods
A single-arm meta-analysis was conducted. We searched PubMed, Google Scholar, Web of Science, and several Chinese databases for studies presenting characteristics of children confirmed with Coronavirus Disease 2019 (COVID-19) from December 12, 2019 to May 10, 2020. Quality Appraisal of Case Series Studies Checklist was used to assess quality and publication bias was analyzed by Egger’s test. Random-effect model was used to calculate the pooled incidence rate (IR) or mean difference (MD) with 95% confidence intervals (CI), or a fixed model instead when I2 < 50%. We conducted subgroup analysis according to geographic region. Additionally, we searched United Nations Educational Scientific and Cultural Organization to see how different countries act to the education disruption in COVID-19.

Results
29 studies with 4300 pediatric patients were included. The mean age was 7.04 (95% CI: 5.06–9.08) years old. 18.9% of children were asymptomatic (95% CI: 0.121–0.266), 37.4% (95% CI: 0.280–0.474) had no radiographic abnormalities. Besides, a proportion of 0.1% patients were admitted to intensive care units (0, 95% CI: 0.000–0.013) and four deaths were reported (0, 95% CI: 0.000–0.000). Up to 159 countries have implemented nationwide school closures, affecting over 70% of the world’s students.

Conclusion
Children were also susceptible to SARS-CoV-2, while critical cases or deaths were rare. Characterized by mild presentation, the dilemma that children may become a potential spreader in the pandemic, while strict managements like prolonged school closures, may undermine their well-beings. Thus, the public policies are facing challenge.
Child acceptability of a novel provitamin A carotenoid, iron and zinc-rich complementary food blend prepared from pumpkin and common bean in Uganda: a randomised control trial
Authors: Buzigi Edward , Pillay Kirthee , Siwela Muthulisi 
Published: September 2020

Abstract
Background
Ugandan children are fed homemade complementary foods (CFs) which are usually deficient in vitamin A, iron and zinc. Novel homemade CFs rich in vitamin A, iron and zinc need to be developed, and assessed for their acceptability among target children.

Objective
Homemade provitamin A carotenoids (PVACs), iron and zinc-rich complementary food (CF), common bean pumpkin blend (BPB) formulated from pumpkin (Sweet cream) and common bean (Obwelu) and PVAC-rich pumpkin blend (PB) from Sweet cream were prepared by expert peer mothers. This study compared child acceptability of BPB and PB (control).

Methods
The crossover acceptability study randomly assigned Ugandan children 6 to 24 months old to either receive 100 g of BPB (n = 35) or 100 g of PB (n = 35) on day one. After a washout period of one day, children crossed over to receive either BPB (n = 35) or PB (n = 35). The amount of CF consumed, duration of consumption, and micronutrient intake were assessed. The CF was acceptable if children consumed ≥50 g (50%) of served food (100 g). A paired t-test was used to determine the mean differences within participants between BPB and PB. The level of statistical significant difference was set at a probability value of 5% (p = 0.05).

Results
The mean consumption of BPB and PB was 53.9 g and 54.4 g, respectively. The mean duration for consumption of BPB and PB was 20.6 and 20.3 min, respectively. There was no significant difference in the amounts consumed, and duration of consumption in BPB and PB (p > 0.05). The mean intake of vitamin A was significantly higher (p < 0.00001) in PB (152.5 μgRAE) compared to BPB (100.9 μgRAE). The mean iron intake was significantly higher in BPB (1.1 mg) (p < 0.00001) compared to PB (0.3 mg). Furthermore, zinc intake was significantly higher (p < 0.00001) in BPB (0.58 mg) compared to PB (0.13 mg).

Conclusion
A homemade complementary food, BPB, made from locally available common bean and pumpkin is rich in PVACs, iron and zinc and is acceptable to children in the age range of complementary feeding in Uganda.

Trial registration
Pan African Clinical Trials Registry www.pactr.org as PACTR202002576768667.
Retrospectively registered.
Date of registration: 29/January/2020.
Muscular involvement and tendon contracture in limb-girdle muscular dystrophy 2Y: a mild adult phenotype and literature review
Authors: Feng Xuelin , Wu Jinlang , Xian Wenbiao , Liao Bing , Liao Songjie , Yao Xiaoli , Zhang Weixi 
Published: September 2020

Abstract
Background
Limb girdle muscular dystrophy type 2Y (LGMD2Y) is a rare subgroup of limb girdle muscular dystrophy featuring limb-girdle weakness, tendon contracture and cardiac involvement. It is caused by the mutation of TOR1AIP1, which encodes nuclear membrane protein LAP1 (lamina-associated polypeptide 1) and comprises heterogeneous phenotypes. The present study reported a patient with a novel homozygous TOR1AIP1 mutation that presented with selective muscle weakness, which further expanded the phenotype of LGMD2Y- and TOR1AIP1-associated nuclear envelopathies.

Case presentation
A 40-year-old male presented with Achilles tendon contracture and muscle weakness that bothered him from 8 years old. While the strength of his distal and proximal upper limbs was severely impaired, the function of his lower limbs was relatively spared. Muscle pathology showed dystrophic features, and electron microscopy showed ultrastructural abnormalities of disrupted muscle nuclei envelopes. Whole-exome sequencing showed a frameshift mutation in TOR1AIP1 (c.98dupC).

Conclusion
We reported a novel mild phenotype of LGMD2Y with relatively selective distal upper limb weakness and joint contracture and revealed the heterogeneity of LGDM2Y and the role of the LAP1 isoform by literature review.
Implementing clinical ethics committees as a complex intervention: presentation of a feasibility study in community care
Authors: Magelssen Morten , Karlsen Heidi , Pedersen Reidar , Thoresen Lisbeth 
Published: September 2020

AbstractBackgroundHow should clinical ethics support services such as clinical ethics committees (CECs) be implemented and evaluated? We argue that both the CEC itself and theimplementationof the CEC should be considered as ‘complex interventions’.Main textWe present a research project involving the implementation of CECs in community care in four Norwegian municipalities. We show that when both the CEC and its implementation are considered as complex interventions, important consequences follow – both for implementation and the study thereof. Emphasizing four such sets of consequences, we argue, first, that the complexity of the intervention necessitates small-scale testing before larger-scale implementation and testing is attempted; second, that it is necessary to theorize the intervention in sufficient depth; third, that the identification of casual connections charted in so-called logic models allows the identification of factors that are vital for the intervention to succeed and which must therefore be studied; fourth, that an important part of a feasibility study must be to identify and chart as many as possible of the causally important contextual factors.ConclusionThe conceptualization of the implementation of a CEC as a complex intervention shapes the intervention and the way evaluation research should be performed, in several significant ways. We recommend that researchers consider whether a complex intervention approach is called for when studying CESS implementation and impact.
Ethics parallel research: an approach for (early) ethical guidance of biomedical innovation
Authors: Jongsma Karin R. , Bredenoord Annelien L. 
Published: September 2020

AbstractBackgroundOur human societies and certainly also (bio) medicine are more and more permeated with technology. There seems to be an increasing awareness among bioethicists that an effective and comprehensive approach to ethically guide these emerging biomedical innovations into society is needed. Such an approach has not been spelled out yet for bioethics, while there are frequent calls for ethical guidance of biomedical innovation, also by biomedical researchers themselves. New and emerging biotechnologies require anticipation of possible effects and implications, meaning the scope is not evaluative after a technology has been fully developed or about hypothetical technologies, but real-time for a real biotechnology.Main textIn this paper we aim to substantiate and discuss six ingredients that we increasingly see adopted by ethicists and that together constitute “ethics parallel research”. This approach allows to fulfil two aims: guiding the development process of technologies in biomedicine and providing input for the normative evaluation of such technologies. The six ingredients of ethics parallel research are: (1) disentangling wicked problems, (2) upstream or midstream ethical analysis, (3) ethics from within, (4) inclusion of empirical research, (5) public participation and (6) mapping societal impacts, including hard and soft impacts. We will draw on gene editing, organoid technology and artificial intelligence as examples to illustrate these six ingredients.ConclusionEthics parallel research brings together these ingredients to ethically analyse and proactively or parallel guide technological development. It widens the roles and judgements from the ethicist to a more anticipatory and constructively guiding role. Ethics parallel research is characterised by a constructive, rather than a purely critical perspective, it focusses on developing best-practices rather than outlining worst practice, and draws on insights from social sciences and philosophy of technology.