bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel compound heterozygous TMEM67 variants in a Vietnamese family with Joubert syndrome: a case report
Authors: Bui Thi Phuong Hoa , Nguyen Ngoc Tu , Ngo Van Doan , Nguyen Hoai-Nghia , Ly Thi Thanh Ha , Do Huy Duong , Huynh Minh-Tuan
Published: January 2020

Background

Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as “molar tooth sign” associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance.

Case presentation

We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03.

Conclusion

This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.
Influence of low free thyroxine on progression of chronic kidney disease
Authors: de Souza Alexandre Barbosa Câmara , Arantes Marcia Fernanda , Zatz Roberto , Elias Rosilene Motta , Lopes Roberto Iglesias , Macedo Etienne
Published: January 2020

Background

Hypothyroidism is highly prevalent in patients with chronic kidney disease (CKD) and has been associated with poorer clinical outcomes, including faster decline of kidney function. However, there is no consensus whether low free thyroxin (LFT) affects the rate of estimated glomerular filtration rate (eGFR) decline and how the presence of proteinuria influences the progression of renal dysfunction in hypothyroidism.

Methods

We assessed thyroid status, proteinuria, and progression of eGFR by Modification of Diet in Renal Disease equation and CKD-EPI equation in a cohort of CKD patients followed in general nephrology clinics. We estimated the association of LFT levels, and the degree of proteinuria on progression of eGFR. We adjusted for other covariables: age, gender, body mass index, diabetes, hypertension, HbA1c, uric acid, cholesterol, and triglycerides levels..

Results

One thousand six hundred ten patients (64 ± 15 years, 46.8% men, 25.3% diabetic) were included. At beggnining of follow up eGFR was between 45 and 60, 30–45 and 15-30 ml/min/1.73m2in 479 (29.8%), 551(34.2%), and 580(36.0%) patients, respectively. LFT levels were available at initial evaluation in 288(17.9%) patients and 735(48.5%) had assessment of proteinuria (19.6% with LFT vs. 15.4% without LFT,p = 0.032). Median follow-up time was of 21 months, and 1223(76%) had at least 1 year of follow up. Overall, eGFR decline per month was − 0.05(− 0.26, 0.23) ml/min/1.73m2, reaching 1.7(1.3, 2.4) ml/min/1.73m2by the end of study period. Similar results were obtained using CKD-EPI. Multivariable mixed linear analysis showed that proteinuria and age were independently associated with eGFR decline, with no effect of LFT, and no interaction between proteinuria and LFT. In patients without proteinuria, there was an improvement of eGFR despite the presence of LFT.

Conclusions

We confirmed a faster rate of eGFR declined in patients with proteinuria. However, despite the pathophysiological rational that hypothyroidism can lead to increased rate of CKD progression, we failed to demonstrate an association between LFT and rate of CKD progression. We conclude that the benefit of hypothyroidism treatment in CKD patients needs to be evaluate in prospective studies.
Treatment intensification with hepatic arterial infusion chemotherapy in patients with liver-only colorectal metastases still unresectable after systemic induction chemotherapy – a randomized phase II study -- SULTAN UCGI 30/PRODIGE 53 (NCT03164655)- study protocol
Authors: Boilève Alice , Maillard Aline , Wagner Mathilde , Dromain Clarisse , Laurent Christophe , Dupont Bierre Eric , Le Sourd Samuel , Audemar Franck , Ulusakarya Ayhan , Guerin-Meyer Veronique , Smisth Denis , Pezzella Veronica , De Baere Thierry , Goere Diane , Gelli Maximiliano , Taieb Julien , Boige Valérie
Published: January 2020

Background

Approximately 40% of colorectal cancer patients will develop colorectal liver metastases (CRLM). The most effective approach to increase long-term survival is CRLM complete resection. Unfortunately, only 10–15% of CRLM are initially considered resectable. The objective response rates (ORR) after current first-line systemic chemotherapy (sys-CT) regimens range from 40 to 80% and complete resection rates (CRR) range from 25 to 50% in patients with initially unresectable CRLM. When CRLM patients are not amenable to complete resection after induction of sys-CT, ORRs obtained with second-line sys-CT are much lower (between 10 and 30%) and consequently CRRs are also low (< 10%). Hepatic arterial infusion (HAI) oxaliplatin may represent a salvage therapy in patients with CRLM unresectable after one or more sys-CT regimens with ORRs and CRRs up to 60 and 30%, respectively. This study is designed to evaluate the efficacy of an intensification strategy based on HAI oxaliplatin combined with sys-CT as a salvage treatment in patients with CRLM unresectable after at least 2 months of first-line induction sys-CT.

Objectives and endpoints of the phase II study

Our main objective is to investigate the efficacy, in term of CRR (R0-R1), of treatment intensification in patients with liver-only CRLM not amenable to curative-intent resection (and/or ablation) after at least 2 months of induction sys-CT. Patients will receive either HAI oxaliplatin plus systemic FOLFIRI plus targeted therapy (i.e. anti-EGFR antibody or bevacizumab) or conventional sys-CT plus targeted therapy (i.e. anti-EGFR or antiangiogenic antibody). Secondary objectives are to compare: progression-free survival, overall survival, objective response rate, depth of response, feasibility of delivering HAI oxaliplatin including HAI catheter-related complications, and toxicity (NCI-CTCAE v4.0).

Methods

This study is a multicenter, randomized, comparative phase II trial (power, 80%; two-sided alpha-risk, 5%). Patients will be randomly assigned in a 1:1 ratio to receive HAI oxaliplatin combined with systemic FOLFIRI plus targeted therapy (experimental arm) or the best sys-CT plus targeted therapy on the basis of their first-line prior sys-CT history and current guidelines (control arm). One hundred forty patients are required to account for non-evaluable patients.

Trial registration

ClinicalTrials.gov, (NCT03164655). Trial registration date: 11th May 2017.
Clinical and cost effectiveness of a parent mediated intervention to reduce challenging behaviour in pre-schoolers with moderate to severe intellectual disability (EPICC-ID) study protocol: a multi-centre, parallel-group randomised controlled trial
Authors: Farris Olayinka , Royston Rachel , Absoud Michael , Ambler Gareth , Barnes Jacqueline , Hunter Rachael , Kyriakopoulos Marinos , Oulton Kate , Paliokosta Eleni , Panca Monica , Paulauskaite Laura , Poppe Michaela , Ricciardi Federico , Sharma Aditya , Slonims Vicky , Summerson Una , Sutcliffe Alastair , Thomas Megan , Hassiotis Angela
Published: January 2020

Background

Children with intellectual disabilities are likely to present with challenging behaviour. Parent mediated interventions have shown utility in influencing child behaviour, although there is a paucity of UK research into challenging behaviour interventions in this population. NICE guidelines favour Stepping Stones Triple P (SSTP) as a challenging behaviour intervention and this trial aims to evaluate its clinical and cost effectiveness in preschool children with moderate to severe intellectual disabilities.

Methods

This trial launched in 2017 at four sites across England, with the aim of recruiting 258 participants (aged 30–59 months). The Intervention Group receive nine weeks of SSTP parenting therapy (six group sessions and three individualised face to face or telephone sessions) in addition to Treatment as Usual, whilst the Treatment as Usual only group receive other available services in each location. Both study groups undergo the study measurements at baseline and at four and twelve months. Outcome measures include parent reports and structured observations of behaviour. Service use and health related quality of life data will also be collected to carry out a cost effectiveness and utility evaluation.

Discussion

Findings from this study will inform policy regarding interventions for challenging behaviour in young children with moderate to severe intellectual disabilities.

Trial registration number

Clinicaltrials.gov, NCT03086876. Registered 22nd March 2017, https://clinicaltrials.gov/ct2/show/NCT03086876.
Presence of eating disorder symptoms in patients with obsessive-compulsive disorder
Authors: Bang Lasse , Kristensen Unn Beate , Wisting Line , Stedal Kristin , Garte Marianne , Minde Åse , Rø Øyvind
Published: January 2020

Background

Obsessive-compulsive disorder (OCD) is common in patients with eating disorders (EDs). There is a lack of research investigating the presence of ED symptoms among patients with OCD, despite concerns that many of these patients may be at high risk for EDs. Our objective was to assess the presence of ED symptoms in patients receiving treatment for OCD.

Methods

Adult patients with OCD (n = 132, 71% females) and controls (n = 260, 90% females) completed the Eating Disorder Examination-Questionnaire (EDE-Q) at admission to a specialized OCD outpatient unit. A small subset of patients (n = 22) also completed the EDE-Q 3-months after end of treatment.

Results

At the group-level, mean EDE-Q scores did not differ significantly between female patients and controls. However, female patients compared to controls were significantly more likely to score above the EDE-Q cut-off (23% vs. 11%) and have a probable ED (9% vs. 1%), indicating elevated rates of ED symptoms in the clinical range. There was no evidence of elevated rates of ED symptoms in male patients, though sample sizes were small. Preliminary follow-up data showed that certain ED symptoms improved significantly from admission to 3-month follow-up.

Conclusions

Our findings suggest that while ED symptoms are not generally elevated in female patients with OCD, a considerable subset of female patients may have a clinical ED or be at high risk of developing one. Clinicians should be alert to ED symptoms in female patients with OCD, and our findings raise the issue of whether ED screening of female patients with OCD is warranted.
Comparing enhanced versus standard Diabetes Prevention Program among indigenous adults in an urban setting: a randomized controlled trial
Authors: Rosas Lisa G. , Vasquez Jan J. , Hedlin Haley K. , Qin Fei Fei , Lv Nan , Xiao Lan , Kendrick Adrian , Atencio Dawn , Stafford Randall S.
Published: January 2020

Background

Indigenous people in the United States are at high risk for diabetes. Psychosocial stressors like historical trauma may impede success in diabetes prevention programs.

Methods

A comparative effectiveness trial compared a culturally tailored diabetes prevention program (standard group) with an enhanced one that addressed psychosocial stressors (enhanced group) in 2015 to 2017. Participants were 207 Indigenous adults with a body mass index (BMI) of ≥30 and one additional criterion of metabolic syndrome, and were randomized to the standard or enhanced group. Both groups received a culturally tailored behavioral diabetes prevention program. Strategies to address psychosocial stressors were provided to the enhanced group only. Change in BMI over 12 months was the primary outcome. Secondary outcomes included change in quality of life, and clinical, behavioral, and psychosocial measures at 6 and 12 months.

Results

The two groups did not significantly differ in BMI change at 12 months. The two groups also did not differ in any secondary outcomes at 6 or 12 months, with the exception of unhealthy food consumption; the standard group reported a larger mean decrease (95% CI) in consumption of unhealthy food compared with the enhanced group (− 4.6 [− 6.8, − 2.5] vs. -0.7 [− 2.9, 1.4], p = 0.01). At 6 months, significant improvements in weight and the physical component of the quality of life measure were observed for both groups compared with their baseline level. Compared with baseline, at 12 months, the standard group showed significant improvement in BMI (mean [95% CI], − 0.5 [− 1.0, − 0.1]) and the enhanced group showed significant improvement in the physical component of the quality of life (2.9 [0.7, 5.2]).

Conclusions

Adding strategies to address psychosocial barriers to a culturally tailored diabetes prevention program was not successful for improving weight loss among urban Indigenous adults.

Trial Registration

(if applicable): NCT02266576. Registered October 17, 2014 on clinicaltrials.gov. The trial was prospectively registered.
Correlation between the efficacy of stem cell therapy for osteonecrosis of the femoral head and cell viability
Authors: Wu Zhan Yu , Sun Qi , Liu Ming , Grottkau Brian E. , He Zhi Xu , Zou Qiang , Ye Chuan
Published: January 2020

Background

Osteonecrosis of the femoral head (ONFH) is a common disease that greatly affects the quality of life of patients. Repair of the necrotic area is key to successful treatment. Currently, the combination of stem cell transplantation and decompression is used clinically to promote the repair of necrotic areas based on the characteristics of stem cells. However, a considerable number of patients do not achieve a satisfactory outcome in terms of repair of the femoral head necrotic area, and it is very important to determine the reasons for the poor curative effect. The aim of this study was to investigate the correlation between stem cell viability and the repair efficacy of stem cell therapy combined with core decompression for early-stage ONFH.

Methods

A total of 30 patients with idiopathic ONFH underwent core decompression combined with autologous stem cell transplantation. The Harris hip score (HHS) and difference in necrosis area before and after surgery were measured. The mean repair ratio was set as the threshold to divide the patients into group A (ratio above the mean) and group B (ratio below the mean). The ultrastructure, proliferative capacity, and multidirectional differentiation ability were compared between the groups.

Results

At 9 months after surgery, the HHS and magnetic resonance imaging (MRI) findings improved by varying degrees. Based on the mean repair ratio of (62.2 ± 27.0)%, the threshold for dividing the patients into groups A and B was set to 62.2%. Better repair (group A) was associated with more rapid proliferation and a healthier ultrastructure. The cells in group A showed stronger specific staining signifying osteogenic and chondrogenic differentiation; alkaline phosphatase (ALP) activity, an indicator of osteogenic differentiation, was higher in group A than in group B (OD, 2.39 ± 0.44 and 1.85 ± 0.52; p <  0.05).

Conclusions

The quality of implanted stem cells is closely related to treatment efficacy and determines whether the defective self-repair in the necrotic area can be corrected to enhance repair and thus achieve the desired therapeutic outcome.

Trial registration

The trial registration number: ChiCTR-ORC-17011698 (retrospectively registered at 2017-06-19).
Lifestyle and environmental contributions to ovulatory dysfunction in women of polycystic ovary syndrome
Authors: Zhang Bingqian , Zhou Wei , Shi Yuhua , Zhang Jun , Cui Linlin , Chen Zi-Jiang
Published: January 2020

Background

Polycystic ovary syndrome (PCOS) is the most common reason of anovulatory infertility. Environmental factor is one of the main causes of PCOS, but its contribution to ovulatory dysfunction in PCOS remains unknown.

Methods

A total of 2217 infertile women diagnosed as PCOS according to Rotterdam criteria were recruited, including 1979 women with oligo-anovulation (OA group) and 238 women with normal -anovulation (non OA group). Besides, 279 healthy control women of reproductive age were enrolled as controls.

Results

Frequencies of snoring (PCOS-OA group, PCOS-non-OA group, control group: 29.30% vs 18.10% vs 11.50%, P < 0.01), smoking (37.70% vs 28.10% vs 12.20%, P < 0.01), plastic tableware usage (38.30% vs 28.10% vs 25.40%, P < 0.01) and indoor decoration (32.10% vs 24.80% vs 16.80%, P < 0.01) were highest in PCOS-OA group. After adjusted for multivariable, difference remained significant between PCOS-OA group and the other two groups. PCOS-OA women preferred a meat favorable diet compared to PCOS-non-OA group (54.60% vs 41.30%, P < 0.01). There was no difference between three groups in exercise, frequency of insomnia, and alcohol consumption.

Conclusions

Smoking, snoring, hyper-caloric diet, plastic tableware usage and indoor decoration were found to be associated with an increased risk for ovulatory dysfunction in women suffering from PCOS.
Experimental implantoplasty outcomes correlate with fibroblast growth in vitro
Authors: Beheshti Maal Mehrnaz , Aanerød Ellingsen Stig , Reseland Janne Elin , Verket Anders
Published: January 2020

Background

Implantoplasty is an option in peri-implantitis treatment, but little is known about the effect on the soft tissue. The aim of the study was to characterize surface roughness following experimental implantoplasty and to examine its effect on human fibroblast growth and secretion of selected proteins.

Methods

Titanium grade IV coins were mechanically treated with six different rotating bur sequences; diamond burs or carbide burs alone, or followed by either Arkansas stone bur or silicone burs. Machined and rough-surface sandblasted, acid-etched (SLA) coins were used as control. The surface topography was characterized by scanning electron microscope and profilometer. Human gingival fibroblasts from two donors were cultured on the coins to quantify the effect on cell morphology, growth, and protein secretion by confocal microscopy and multiplex immunoassay.

Results

All surface roughness parameters were lower for the surfaces treated with experimental implantoplasty than for the SLA surface, and the sequence of carbide burs followed by silicone burs rendered the least rough surface of the test groups. The implantoplasty procedures changed the elemental composition of the titanium surface. High surface roughness showed a weak to moderate negative correlation to fibroblast growth, but induced a higher secretion of VEGF, IL-6 and MCP-3 to the cell medium compared to the least rough surfaces of the test groups. At day 30 fibronectin levels were higher in the SLA group.

Conclusions

The surface roughness following implantoplasty demonstrated a weak to moderate negative correlation with the growth of fibroblasts. The addition of Arkansas stone and silicon burs to the experimental implantoplasty bur protocol rendered an initial increase in fibroblast growth. Implantoplasty altered the elemental composition of the titanium surface, and had an effect on the fibroblast cytokine secretion and fibronectin levels.
Ethical values supporting the disclosure of incidental and secondary findings in clinical genomic testing: a qualitative study
Authors: Saelaert Marlies , Mertes Heidi , Moerenhout Tania , De Baere Elfride , Devisch Ignaas
Published: January 2020

Background

Incidental findings (IFs) and secondary findings (SFs), being results that are unrelated to the diagnostic question, are the subject of an important debate in the practice of clinical genomic medicine. Arguments for reporting these results or not doing so typically relate to the principles of autonomy, non-maleficence and beneficence. However, these principles frequently conflict and are insufficient by themselves to come to a conclusion. This study investigates empirically how ethical principles are considered when actually reporting IFs or SFs and how value conflicts are weighed.

Methods

A qualitative focus group study has been undertaken, including a multidisciplinary group of professionals from Belgian centres for medical genetics. The data were analysed thematically.

Results

All eight Belgian centres participated in this study. Ethical values were frequently referred to for disclosure policies on IFs and SFs. Participants invoked respect for patient autonomy to support the disclosure of IFs and opt-out options for IFs and SFs, non-maleficence for the professional delineation of reportable IFs and opt-out options for IFs and SFs and (the particular scope of) beneficence for the mandatory reporting of actionable IFs, the delineation of reportable IFs and a current decline of actively pursued SFs. Professional assumptions about patients’ genetic literacy were an important factor in the weighing of values.

Conclusions

In line with the traditional bioethical discourse, the mandatory reporting of actionable IFs might be interpreted as a “technological, soft paternalism”. Restricting patients’ choices might be acceptable, but then its motives should be valid and its beneficent outcomes highly plausible. Hence, the presuppositions of technological, soft paternalism - patients’ inability to make informed decisions, normative rationality, the efficacy of beneficent outcomes and the delineated spectrum of beneficence - should be approached critically. Moreover, distributive justice should be considered an important value in the delineation of the current scope of the ethical debate on IFs and SFs.

This study of guiding values may stimulate the debate on the ethical grounds for a solid policy on IFs and SFs internationally.
Novel methodology to measure pre-procedure antimicrobial prophylaxis: integrating text searches with structured data from the Veterans Health Administration’s electronic medical record
Authors: Mull Hillary J. , Stolzmann Kelly , Kalver Emily , Shin Marlena H. , Schweizer Marin L. , Asundi Archana , Mehta Payal , Stanislawski Maggie , Branch-Elliman Westyn
Published: January 2020

Background

Antimicrobial prophylaxis is an evidence-proven strategy for reducing procedure-related infections; however, measuring this key quality metric typically requires manual review, due to the way antimicrobial prophylaxis is documented in the electronic medical record (EMR). Our objective was to electronically measure compliance with antimicrobial prophylaxis using both structured and unstructured data from the Veterans Health Administration (VA) EMR. We developed this methodology for cardiac device implantation procedures.

Methods

With clinician input and review of clinical guidelines, we developed a list of antimicrobial names recommended for the prevention of cardiac device infection. We trained the algorithm using existing fiscal year (FY) 2008–15 data from the VA Clinical Assessment Reporting and Tracking-Electrophysiology (CART-EP), which contains manually determined information about antimicrobial prophylaxis. We merged CART-EP data with EMR data and programmed statistical software to flag an antimicrobial orders or drug fills from structured data fields in the EMR and hits on text string searches of antimicrobial names documented in clinician’s notes. We iteratively tested combinations of these data elements to optimize an algorithm to accurately classify antimicrobial use. The final algorithm was validated in a national cohort of VA cardiac device procedures from FY2016–2017. Discordant cases underwent expert manual review to identify reasons for algorithm misclassification.

Results

The CART-EP dataset included 2102 procedures at 38 VA facilities with manually identified antimicrobial prophylaxis in 2056 cases (97.8%). The final algorithm combining structured EMR fields and text note search results correctly classified 2048 of the CART-EP cases (97.4%). In the validation sample, the algorithm measured compliance with antimicrobial prophylaxis in 16,606 of 18,903 cardiac device procedures (87.8%). Misclassification was due to EMR documentation issues, such as antimicrobial prophylaxis documented only in hand-written clinician notes in a format that cannot be electronically searched.

Conclusions

We developed a methodology with high accuracy to measure guideline concordant use of antimicrobial prophylaxis before cardiac device procedures using data fields present in modern EMRs. This method can replace manual review in quality measurement in the VA and other healthcare systems with EMRs; further, this method could be adapted to measure compliance in other procedural areas where antimicrobial prophylaxis is recommended.
A zooprophylaxis strategy using l-lactic acid (Abate) to divert host-seeking malaria vectors from human host to treated non-host animals
Authors: Kemibala Elison E. , Mafra-Neto Agenor , Dekker Teun , Saroli Jesse , Silva Rodrigo , Philbert Anitha , Nghabi Kija , Mboera Leonard E. G.
Published: January 2020

Background

Zooprophylaxis is a technique in which blood-seeking vectors are diverted to non-host animals in order to lower blood-feeding rates on human hosts. The success of this technique depends on the host preference of the vector being targeted. The objective of this study was to evaluate the effect of l-lactic acid (Abate) to divert malaria mosquito, Anopheles gambiae from feeding on human host.

Methods

A 14-month-old female goat was treated with Abate, a formulation incorporating l-lactic acid into a slow-release matrix. This formulation was applied on the fur of the goat’s back and neck. The treated animal was then presented to Anopheles gambiae sensu stricto (s.s.) as a prospective host in a semi-field environment (‘mosquito sphere’) together with either an untreated animal or a human. The number of mosquitoes caught to each host choice offered were compared.

Results

Goat treated with the l-lactic acid formulation successfully attracted An. gambiae at higher rates (70.2%) than the untreated ones (29.8%). Furthermore, An. gambiae s.s. were attracted to a treated goat at an equivalent degree (47.3%) as to their preferred human host (52.7%), even when the preferred host was present in the same environment.

Conclusions

The findings indicate that human host-seeking mosquitoes can be diverted into feeding on non-preferred hosts despite the close proximity of their favoured host, hence reducing chances for the transmission of blood-borne parasites.
Whole transcriptional analysis identifies markers of B, T and plasma cell signaling pathways in the mesenteric adipose tissue associated with Crohn’s disease
Authors: da Silva Francesca Aparecida Ramos , Pascoal Lívia Bitencourt , Dotti Isabella , Setsuko Ayrizono Maria de Lourdes , Aguilar Daniel , Rodrigues Bruno Lima , Arroyes Montserrat , Ferrer-Picon Elena , Milanski Marciane , Velloso Lício Augusto , Fagundes João José , Salas Azucena , Leal Raquel Franco
Published: January 2020

Background

Crohn’s disease (CD) is a multifactorial disease characterized by chronic intestinal inflammation. The increased visceral adiposity near the affected intestinal area, of which mesenteric adipose tissue (MAT) is the main component, is a feature of CD. Both protective and pathological roles have been attributed to this disease-associated tissue in CD. To understand the contribution of MAT to CD pathophysiology, a molecular and cellular signature of disease-associated MAT in CD patients was provided.

Methods

We performed an observational study with whole transcriptional analysis by RNA sequencing (RNA-seq) of MAT and ileal mucosa from CD patients with active disease and controls. qPCR and immunohistology were performed for validation analysis.

Results

RNA-seq identified 17 significantly regulated genes (|FC| > 1.5; FDR < 0.05) in CD-MAT compared to non-IBD controls, with a marked upregulation of plasma cell genes (i.e., IGLL5, MZB1, CD79A, POU2AF1, FCRL5, JCHAIN, DERL3, SDC1, PIM2). A less strict statistical cutoff value (|FC| > 1.5, nominal p ≤ 0.05) yielded a larger list of 651 genes in CD-MAT compared to controls. CD ileum showed the significant regulation compared to control ileum of 849 genes (|FC| > 1.5; FDR < 0.05) or 2654 genes (|FC| > 1.5, nominal p ≤ 0.05). Ingenuity Pathway Analysis revealed the significant regulation of pathways related to T- and B cell functionality in the MAT of CD patients. Despite the differences between the MAT and ileal signatures of CD patients, we identified a subset of 204 genes significantly modulated in both tissues compared to controls. This common signature included genes related to the plasma cell signature. Genes such as S100A8, S100A9 (calprotectin) and IL1B, which are associated with acute inflammatory response, were exclusively regulated in the ileal mucosa of CD disease. In contrast, some genes encoding for lymphocyte receptors such as MS4A1, CD3D and CD79A were exclusively regulated in CD-MAT, exhibiting a different pattern of immune cell activation compared to the ileal mucosa in CD patients. qPCR and immunohistology confirmed the presence of large infiltrates of CD3+CD20+lymphocytes and CD138+plasma cells in CD-MAT.

Conclusion

Our data strongly supports the role of CD-associated MAT as a site for T-, B- and plasma cell activation, and suggests that it could also act as a reservoir of memory immune responses.
Bioinformatics-based screening of key genes for transformation of liver cirrhosis to hepatocellular carcinoma
Authors: Jiang Chen Hao , Yuan Xin , Li Jiang Fen , Xie Yu Fang , Zhang An Zhi , Wang Xue Li , Yang Lan , Liu Chun Xia , Liang Wei Hua , Pang Li Juan , Zou Hong , Cui Xiao Bin , Shen Xi Hua , Qi Yan , Jiang Jin Fang , Gu Wen Yi , Li Feng , Hu Jian Ming
Published: January 2020

Background

Hepatocellular carcinoma (HCC) is the most common type of liver tumour, and is closely related to liver cirrhosis. Previous studies have focussed on the pathogenesis of liver cirrhosis developing into HCC, but the molecular mechanism remains unclear. The aims of the present study were to identify key genes related to the transformation of cirrhosis into HCC, and explore the associated molecular mechanisms.

Methods

GSE89377, GSE17548, GSE63898 and GSE54236 mRNA microarray datasets from Gene Expression Omnibus (GEO) were analysed to obtain differentially expressed genes (DEGs) between HCC and liver cirrhosis tissues, and network analysis of protein–protein interactions (PPIs) was carried out. String and Cytoscape were used to analyse modules and identify hub genes, Kaplan–Meier Plotter and Oncomine databases were used to explore relationships between hub genes and disease occurrence, development and prognosis of HCC, and the molecular mechanism of the main hub gene was probed using Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis.

Results

In total, 58 DEGs were obtained, of which 12 and 46 were up- and down-regulated, respectively. Three hub genes (CDKN3, CYP2C9 and LCAT) were identified and associated prognostic information was obtained. CDKN3 may be correlated with the occurrence, invasion, and recurrence of HCC. Genes closely related to changes in the CDKN3 hub gene were screened, and Kyoto Encyclopedia of Genes and Genomes (KEGGs) pathway analysis identified numerous cell cycle-related genes.

Conclusion

CDKN3 may affect the transformation of liver cirrhosis into HCC, and represents a new candidate molecular marker of the occurrence and progression of HCC.
A comparison study of metabolic profiles, immunity, and brain gray matter volumes between patients with bipolar disorder and depressive disorder
Authors: Bai Ya-Mei , Chen Mu-Hong , Hsu Ju-Wei , Huang Kai-Lin , Tu Pei-Chi , Chang Wan-Chen , Su Tung-Ping , Li Cheng Ta , Lin Wei-Chen , Tsai Shih-Jen
Published: January 2020

Background

Previous individual studies have shown the differences in inflammatory cytokines and gray matter volumes between bipolar disorder (BD) and unipolar depression (UD). However, few studies have investigated the association between pro-inflammatory cytokines and differences in brain gray matter volumes between BD and UD.

Methods

In this study, 72 BD patients and 64 UD patients were enrolled, with comparable gender and age distributions (33.8% males and an average age of 39.3 ± 13.7 years). Each participant underwent metabolic profiling (including body mass index (BMI), glucose, triglyceride, high-density lipoprotein (HDL), leptin, insulin, adiponectin), pro-inflammatory cytokine (including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1) examinations, and structural magnetic resonance imaging exams. Voxel-based morphometry was performed to investigate the gray matter volume differences between BD and UD patients. Correlations between pro-inflammatory cytokines and the gray matter volume difference were analyzed.

Results

Compared to UD patients, the BD group had significantly higher BMI, and higher levels of sIL-6R and sTNF-R1 than the UD patients. The BMI significantly correlated with the level of pro-inflammatory cytokines. Adjusted for age, sex, BMI, duration of illness and total intracranial volume, the BD individuals had significantly more reduced gray matter volumes over 12 areas: R. cerebellar lobule VIII, R. putamen, L. putamen, R. superior frontal gyrus, L. lingual gyrus, L. precentral gyrus, R. fusiform gyrus, L. calcarine, R. precuneus, L. inferior temporal gyrus, L. hippocampus, and L. superior frontal gyrus. These 12 gray matter volume differences between BP and UD patients negatively correlated with sIL-6R and sTNF-R1 levels.

Conclusions

Our results suggested that BD patients had higher BMI and pro-inflammatory cytokine levels in comparison to UD patients, especially IL-6 and sTNF-R1, which may contribute to greater gray matter reductions in BD patients in comparison to UD patients. The results support the neuro-inflammation pathophysiology mechanism in mood disorder. It is clinically important to monitor BMI, which, in this investigation, positively correlated with levels of inflammatory cytokines.
Non-inferiority of cleavage-stage versus blastocyst-stage embryo transfer in poor prognosis IVF patients (PRECiSE trial): study protocol for a randomized controlled trial
Authors: Neuhausser Werner M. , Vaughan Denis A. , Sakkas Denny , Hacker Michele R. , Toth Tom , Penzias Alan
Published: January 2020

Background

With improvements in in vitro culture techniques there has been a steady shift in practice to transfer embryos at the blastocyst stage (post fertilization day (p.f.d.) 5–7), when embryos reach the endometrial cavity during natural conception. For patients with > 5 zygotes on day 1 of embryo development, fresh blastocyst embryo transfer (ET) increases live birth rates when compared to cleavage stage (p.f.d. 3) transfer. In poorer prognosis patients (≤ 5 zygotes) cleavage stage ET is commonly performed to reduce the risk of cycle cancellation if no embryo survives to the blastocyst stage. However, there is a dearth of randomized controlled trial (RCT) data demonstrating improved live birth rates per cycle for cleavage vs blastocyst stage ET in this subgroup of patients. The hypothesis of the PRECiSE (PooR Embryo Yield Cleavage Stage Versus blaStocyst Embryo Transfer) trial is that blastocyst ET is not inferior to cleavage stage ET with regard to live birth rates per retrieval in poorer prognosis patients. The adoption of routine blastocyst culture for all patients would result in higher rates of single embryo transfers (SET), reduced incidence of multiple pregnancies and simplified laboratory protocols, thereby reducing costs.

Methods/design

Multicenter, non-inferiority randomized controlled trial (RCT) comparing blastocyst to cleavage stage embryo transfer in poorer prognosis patients with ≤5 zygotes on day 1 after fertilization. The primary outcome is live birth per retrieval. Secondary outcomes include: time to pregnancy, clinical pregnancy, ongoing pregnancy, miscarriage and multiple pregnancy rate (per retrieval). This trial will enroll 658 women with ≤5 zygotes on day 1 at 6 IVF centers over the course of 22 months.

Discussion

If the hypothesis is proven true, the data from this trial may facilitate the adoption of uniform blastocyst culture in all IVF patients.

Trial registration

ClinicalTrials.gov Identifier:NCT03764865. Registered 5 December 2019, Protocol issue date: 4 December 2018, Original.
Vocal tract anatomy of king penguins: morphological traits of two-voiced sound production
Authors: Kriesell Hannah Joy , Le Bohec Céline , Cerwenka Alexander F. , Hertel Moritz , Robin Jean-Patrice , Ruthensteiner Bernhard , Gahr Manfred , Aubin Thierry , Düring Daniel Normen
Published: January 2020

Background

The astonishing variety of sounds that birds can produce has been the subject of many studies aiming to identify the underlying anatomical and physical mechanisms of sound production. An interesting feature of some bird vocalisations is the simultaneous production of two different frequencies. While most work has been focusing on songbirds, much less is known about dual-sound production in non-passerines, although their sound production organ, the syrinx, would technically allow many of them to produce “two voices”. Here, we focus on the king penguin, a colonial seabird whose calls consist of two fundamental frequency bands and their respective harmonics. The calls are produced during courtship and for partner and offspring reunions and encode the birds’ identity. We dissected, μCT-scanned and analysed the vocal tracts of six adult king penguins from Possession Island, Crozet Archipelago.

Results

King penguins possess a bronchial type syrinx that, similarly to the songbird’s tracheobronchial syrinx, has two sets of vibratory tissues, and thus two separate sound sources. Left and right medial labium differ consistently in diameter between 0.5 and 3.2%, with no laterality between left and right side. The trachea has a conical shape, increasing in diameter from caudal to cranial by 16%. About 80% of the king penguins’ trachea is medially divided by a septum consisting of soft elastic tissue (septum trachealis medialis).

Conclusions

The king penguins’ vocal tract appears to be mainly adapted to the life in a noisy colony of a species that relies on individual vocal recognition. The extent between the two voices encoding for individuality seems morphologically dictated by the length difference between left and right medial labium. The septum trachealis medialis might support this extent and could therefore be an important anatomical feature that aids in the individual recognition process.
Spatio-temporal gait variables predicted incident disability
Authors: Doi Takehiko , Nakakubo Sho , Tsutsumimoto Kota , Kim Min-Ji , Kurita Satoshi , Ishii Hideaki , Shimada Hiroyuki
Published: January 2020

Background

Assessing the risk of disability in older adults is important for developing prevention and intervention strategies to decrease potential disability and dependency. The aim of this study was to examine the association between spatio-temporal gait variables and disability among older adults.

Methods

We conducted a prospective study in a community setting. We collected data from 4121 subjects (≥ 65 years, mean age: 71.9 years). Gait speed, cadence, stride length, and stride length variability were measured at baseline. Participants were instructed to walk at their usual pace along a 6.4 m straight and flat path on which an electronic gait measuring device was mounted at mid 2.4 m. Subsequent disability was confirmed from long-term care insurance records.

Results

During follow-up duration (mean: 49.6 months), 425 participants had incident disability. The cut-off value to detect high or low function in each gait variable was determined using the Youden index. Cox proportional hazard analysis adjusted for covariates showed that disability was significantly predicted by low function in each gait variable using the cut-off values: gait speed (hazard ratio [95% confidential intervals]: 2.06 [1.65–2.57]), stride length (2.17 [1.72–2.73]), cadence (1.49 [1.20–1.86], and stride length variability (1.46 [1.19–1.80]). The number of gait variables that scored in the low function category were also cumulatively related to subsequent disability (p < .001).

Conclusions

This study revealed that spatio-temporal gait variables had a significant predictive value for incident disability. Multifaceted and quantitative gait analysis can contribute to disability risk assessment.
Effects of robot therapy on upper body kinematics and arm function in persons post stroke: a pilot randomized controlled trial
Authors: Carpinella Ilaria , Lencioni Tiziana , Bowman Thomas , Bertoni Rita , Turolla Andrea , Ferrarin Maurizio , Jonsdottir Johanna
Published: January 2020

Background

Robot-based rehabilitation for persons post-stroke may improve arm function and daily-life activities as measured by clinical scales, but its effects on motor strategies during functional tasks are still poorly investigated. This study aimed at assessing the effects of robot-therapy versus arm-specific physiotherapy in persons post-stroke on motor strategies derived from upper body instrumented kinematic analysis, and on arm function measured by clinical scales.

Methods

Forty persons in the sub-acute and chronic stage post-stroke were recruited. This sample included all those subjects, enrolled in a larger bi-center study, who underwent instrumented kinematic analysis and who were randomized in Center 2 into Robot (R_Group) and Control Group (C_Group). R_Group received robot-assisted training. C_Group received arm-specific treatment delivered by a physiotherapist. Pre- and post-training assessment included clinical scales and instrumented kinematic analysis of arm and trunk during a virtual untrained task simulating the transport of an object onto a shelf. Instrumented outcomes included shoulder/elbow coordination, elbow extension and trunk sagittal compensation. Clinical outcomes included Fugl-Meyer Motor Assessment of Upper Extremity (FM-UE), modified Ashworth Scale (MAS) and Functional Independence Measure (FIM).

Results

R_Group showed larger post-training improvements of shoulder/elbow coordination (Cohen’s d = − 0.81,p = 0.019), elbow extension (Cohen’s d = − 0.71,p = 0.038), and trunk movement (Cohen’s d = − 1.12,p = 0.002). Both groups showed comparable improvements in clinical scales, except proximal muscles MAS that decreased more in R_Group (Cohen’s d = − 0.83,p = 0.018). Ancillary analyses on chronic subjects confirmed these results and revealed larger improvements after robot-therapy in the proximal portion of FM-UE (Cohen’s d = 1.16,p = 0.019).

Conclusions

Robot-assisted rehabilitation was as effective as arm-specific physiotherapy in reducing arm impairment (FM-UE) in persons post-stroke, but it was more effective in improving motor control strategies adopted during an untrained task involving vertical movements not practiced during training. Specifically, robot therapy induced larger improvements of shoulder/elbow coordination and greater reduction of abnormal trunk sagittal movements. The beneficial effects of robot therapy seemed more pronounced in chronic subjects. Future studies on a larger sample should be performed to corroborate present findings.

Trial registration

www.ClinicalTrials.govNCT03530358. Registered 21 May 2018. Retrospectively registered.
Identification of cellular microRNA miR-188-3p with broad-spectrum anti-influenza A virus activity
Authors: Cui Huan , Zhang Chunmao , Zhao Zongzheng , Zhang Cheng , Fu Yingying , Li Jiaming , Chen Guanxi , Lai Mengxi , Li Zhixiang , Dong Shishan , Chen Ligong , Li Zhaoyang , Wang Chengyu , Liu Juxiang , Gao Yuwei , Guo Zhendong
Published: January 2020

Background

Influenza A virus (IAV) continues to pose serious threats to public health. The current prophylaxis and therapeutic interventions for IAV requires frequent changes due to the continuous antigenic drift and antigenic shift of IAV. Emerging evidence indicates that the host microRNAs (miRNAs) play critical roles in intricate host-pathogen interaction networks. Cellular miRNAs may directly target virus to inhibit its infection and be developed as potential anti-virus drugs.

Methods

In this study, we established a broad-spectrum anti-IAV miRNA screening method using miRanda software. The screened miRNAs were further verified by luciferase assay, viral protein expression assay and virus replication assay.

Results

Five cellular miRNAs (miR-188-3p, miR-345-5p, miR-3183, miR-15-3p and miR-769-3p), targeting 99.96, 95.31, 92.9, 94.58 and 97.24% of human IAV strains recorded in NCBI, respectively, were chosen for further experimental verification. Finally, we found that miR-188-3p downregulated PB2 expression at both mRNA and protein levels by directly targeted the predicted sites on PB2 and effectively inhibited the replication of IAV (H1N1, H5N6 and H7N9) in A549 cells.

Conclusions

This is the first report screening cellular miRNAs that broad-spectrum inhibiting IAV infection. These findings suggested that cellular miR-188-3p could be used for RNAi-mediated anti-IAV therapeutic strategies.
No evidence for European bats serving as reservoir for Borna disease virus 1 or other known mammalian orthobornaviruses
Authors: Nobach Daniel , Herden Christiane
Published: January 2020

Background

The majority of emerging infectious diseases are zoonotic in nature and originate from wildlife reservoirs. Borna disease, caused by Borna disease virus 1 (BoDV-1), is an infectious disease affecting mammals, but recently it has also been shown to cause fatal encephalitis in humans. The endemic character of Borna disease points towards a nature-bound reservoir, with only one shrew species identified as reservoir host to date. Bats have been identified as reservoirs of a variety of zoonotic infectious agents. Endogenous borna-like elements in the genome of certain bat species additionally point towards co-evolution of bats with bornaviruses and therefore raise the question whether bats could serve as a potential reservoir of orthobornaviruses.

Methods

Frozen brain samples (n = 257) of bats of seven different genera from Germany were investigated by orthobornaviral RT-PCR. Additionally, tissue slides of formalin-fixed paraffin-embedded material of a subset of these bats (n = 140) were investigated for orthobornaviral phosphoprotein by immunohistochemistry.

Results

The brain samples were tested by RT-PCR without any evidence of orthobornavirus specific amplicons. Immunohistochemistry revealed a faint immunoreaction in 3/140 bats but with an untypical staining pattern for viral antigen.

Conclusions

RT-PCR-screening showed no evidence for orthobornaviral RNA in the investigated bats. However, immunohistochemistry results should be investigated further to elucidate whether the reaction might be associated with expressed endogenous bornaviral elements or other so far unknown bornaviruses.