bluuebunny/crossref_metadata_2025 huggingface dataset:
Accuracy of the tuberculosis point-of-care Alere determine lipoarabinomannan antigen diagnostic test using α-mannosidase treated and untreated urine in a cohort of people living with HIV in Guatemala
Authors: García Juan Ignacio , Meléndez Johanna , Álvarez Rosa , Mejía-Chew Carlos , Kelley Holden V. , Sidiki Sabeen , Castillo Alejandra , Mazariegos Claudia , López-Téllez Cesar , Forno Diana , Ayala Nancy , Balada-Llasat Joan-Miquel , Mejía-Villatoro Carlos Rodolfo , Wang Shu-Hua , Torrelles Jordi B. , Ikeda Janet
Published: October 2020

Background

Improved point-of-care diagnostic tests for tuberculosis (TB) in severe immune suppressed people living with HIV (PLWH) are needed to decrease morbidity and mortality outcomes. The aim of the study is to evaluate the performance of the lipoarabinomannan antigen test (LAM-test) with and without α-mannosidase pre-treated urine in a cohort of PLWH in primary care clinics in Guatemala. We further determined TB incidence, and mortality rates and its risk factors in PLWH with TB symptoms.

Methods

Prospective longitudinal study of PLWH with TB symptoms. Urine samples were collected at 2 HIV sites to test the sensitivity of the LAM-test in urine with and without α-mannosidase pre-treatment. A composite reference standard of either a positive Mycobacterium tuberculosis complex culture and/or GeneXpert® MTB/RIF (Xpert, Cepheid, Sunnyvale, CA, USA) results was used in the LAM-test diagnostic accuracy studies. Cox proportional hazards regression was used to study mortality predictors.

Results

The overall sensitivity of the LAM-test was of 56.1% with 95% CI of (43.3–68.3). There were no differences in the LAM-test sensitivity neither by hospital nor by CD4 T cell values. LAM-test sensitivity in PLWH with < 200 CD4 T cells/µl was of 62.2% (95% CI 46.5–76.2). There were no significant differences in sensitivity when comparing LAM-test results obtained from untreated vs. α-mannosidase treated urine [55.2% (95% CI 42.6–67.4) vs. 56.9% (95% CI 44–69.2), respectively]. TB incidence in our cohort was of 21.4/100 person years (PYs) (95% CI 16.6–27.6), and mortality rate was of 11.1/100 PYs (95% CI 8.2–15.0). Importantly, PLWH with a positive LAM-test result had an adjusted hazard ratio (aHR) of death of 1.98 (1.0–3.8) with a significant p value of 0.044 when compared to PLWH with a negative LAM-test result.

Conclusions

In this study, α-mannosidase treatment of urine did not significantly increase the LAM-test performance, however; this needs to be further evaluated in a large-scale study due to our study limitations. Importantly, high rates of TB incidence and mortality were found, and a positive LAM-test result predicted mortality in PLWH with TB clinical symptoms.
A comparison of the effects and usability of two exoskeletal robots with and without robotic actuation for upper extremity rehabilitation among patients with stroke: a single-blinded randomised controlled pilot study
Authors: Park Jin Ho , Park Gyulee , Kim Ha Yeon , Lee Ji-Yeong , Ham Yeajin , Hwang Donghwan , Kwon Suncheol , Shin Joon-Ho
Published: October 2020

Background

Robotic rehabilitation of stroke survivors with upper extremity dysfunction may yield different outcomes depending on the robot type. Considering that excessive dependence on assistive force by robotic actuators may interfere with the patient’s active learning and participation, we hypothesised that the use of an active-assistive robot with robotic actuators does not lead to a more meaningful difference with respect to upper extremity rehabilitation than the use of a passive robot without robotic actuators. Accordingly, we aimed to evaluate the differences in the clinical and kinematic outcomes between active-assistive and passive robotic rehabilitation among stroke survivors.

Methods

In this single-blinded randomised controlled pilot trial, we assigned 20 stroke survivors with upper extremity dysfunction (Medical Research Council scale score, 3 or 4) to the active-assistive robotic intervention (ACT) and passive robotic intervention (PSV) groups in a 1:1 ratio and administered 20 sessions of 30-min robotic intervention (5 days/week, 4 weeks). The primary (Wolf Motor Function Test [WMFT]-score and -time: measures activity), and secondary (Fugl-Meyer Assessment [FMA] and Stroke Impact Scale [SIS] scores: measure impairment and participation, respectively; kinematic outcomes) outcome measures were determined at baseline, after 2 and 4 weeks of the intervention, and 4 weeks after the end of the intervention. Furthermore, we evaluated the usability of the robots through interviews with patients, therapists, and physiatrists.

Results

In both the groups, the WMFT-score and -time improved over the course of the intervention. Time had a significant effect on the WMFT-score and -time, FMA-UE, FMA-prox, and SIS-strength; group × time interaction had a significant effect on SIS-function and SIS-social participation (all, p < 0.05). The PSV group showed better improvement in participation and smoothness than the ACT group. In contrast, the ACT group exhibited better improvement in mean speed.

Conclusions

There were no differences between the two groups regarding the impairment and activity domains. However, the PSV robots were more beneficial than ACT robots regarding participation and smoothness. Considering the high cost and complexity of ACT robots, PSV robots might be more suitable for rehabilitation in stroke survivors capable of voluntary movement.

Trial registration The trial was registered retrospectively on 14 March 2018 at ClinicalTrials.gov (NCT03465267).
The global diet and activity research (GDAR) network: a global public health partnership to address upstream NCD risk factors in urban low and middle-income contexts
Authors: Oni Tolu , Assah Felix , Erzse Agnes , Foley Louise , Govia Ishtar , Hofman Karen J. , Lambert Estelle Victoria , Micklesfield Lisa K. , Shung-King Maylene , Smith Joanne , Turner-Moss Eleanor , Unwin Nigel , Wadende Pamela , Woodcock James , Mbanya Jean Claude , Norris Shane A. , Obonyo Charles O. , Tulloch-Reid Marshall , Wareham Nicholas J. ,   on behalf of the GDAR network, Bennett Nadia , Brugulat Anna , Guthrie-Dixon Nathalie , Hambleton Ian , Lebar Kelsey , Mabena Gugulethu , Mapa Clarisse , Mogo Ebele , Mba Camille , Motlhalhedi Molebogeng , Musuva Rosemary , Odunitan-Wayas Feyisayo A. , Okop Kufre J. , Tatah Lambed , Wasnyo Yves , Weimann Amy , Were Vincent
Published: October 2020

Background

Non-communicable diseases (NCDs) are the leading cause of death globally. While upstream approaches to tackle NCD risk factors of poor quality diets and physical inactivity have been trialled in high income countries (HICs), there is little evidence from low and middle-income countries (LMICs) that bear a disproportionate NCD burden. Sub-Saharan Africa and the Caribbean are therefore the focus regions for a novel global health partnership to address upstream determinants of NCDs.

Partnership

The Global Diet and Activity research Network (GDAR Network) was formed in July 2017 with funding from the UK National Institute for Health Research (NIHR) Global Health Research Units and Groups Programme. We describe the GDAR Network as a case example and a potential model for research generation and capacity strengthening for others committed to addressing the upstream determinants of NCDs in LMICs. We highlight the dual equity targets of research generation and capacity strengthening in the description of the four work packages. The work packages focus on learning from the past through identifying evidence and policy gaps and priorities, understanding the present through adolescent lived experiences of healthy eating and physical activity, and co-designing future interventions with non-academic stakeholders.

Conclusion

We present five lessons learned to date from the GDAR Network activities that can benefit other global health research partnerships. We close with a summary of the GDAR Network contribution to cultivating sustainable capacity strengthening and cutting-edge policy-relevant research as a beacon to exemplify the need for such collaborative groups.
Biomechanical evaluation of type p condylar head osteosynthesis using conventional small-fragment screws reinforced by a patient specific two-component plate
Authors: Pavlychuk Tetiana , Chernogorskyi Denis , Chepurnyi Yurii , Neff Andreas , Kopchak Andrii
Published: October 2020

Background

The aim of this study was to evaluate via finite element analysis (FEA) the biomechanical behavior of conventional small-fragment screws reinforced by a patient-specific plate in type p condylar head.

Methods

A finite element model of the mandible was created using Mimics 12.1 software. A type p condylar head fracture was simulated in the right condyle, and the left condyle was used as a control. Two patterns of fixation were investigated: conventional two-screw fixation and the same fixation system reinforced with a small, patient-specific plate. Surface models were imported into the software Ansys 5.7for further volume mesh generation.

Results

The highest stress gradients were observed in the cortical layer of the lateral fragment, located near the screw. The conventional fixation method resulted in equivalent stresses 2 to 10 times greater than the reinforced method. Rigidity of fixation in the reinforced method increased up to 1.25–3 times compared to the conventional two-screw technique.

Conclusion

This study’s findings suggest significant benefits in unfavorable biomechanical conditions from reinforcement of the standard two-screw fixation of condylar head fractures with a small, patient-specific plate acting as a washer.
Design of a robot-assisted system for transforaminal percutaneous endoscopic lumbar surgeries: study protocol
Authors: Fan Ning , Yuan Shuo , Du Peng , Zhu Wenyi , Li Liang , Hai Yong , Ding Hui , Wang Guangzhi , Zang Lei
Published: October 2020

Background

Transforaminal percutaneous endoscopic lumbar surgeries (PELS) for lumbar disc herniation and spinal stenosis are growing in popularity. However, there are some problems in the establishment of the working channel and foraminoplasty such as nerve and blood vessel injuries, more radiation exposure, and steeper learning curve. Rapid technological advancements have allowed robotic technology to assist surgeons in improving the accuracy and safety of surgeries. Therefore, the purpose of this study is to develop a robot-assisted system for transforaminal PELS, which can provide navigation and foraminoplasty.

Methods

The robot-assisted system consists of three systems: preoperative planning system, navigation system, and foraminoplasty system. In the preoperative planning system, 3D visualization of the surgical segment and surrounding tissues are realized using the multimodal image fusion technique of computed tomography and magnetic resonance imaging, and the working channel planning is carried out to reduce the risk for injury to vital blood vessels and nerves. In the navigation system, the robot can obtain visual perception ability from a visual receptor and automatically adjust the robotic platform and robot arm to the appropriate positions according to the patient’s position and preoperative plan. In addition, the robot can automatically register the surgical levels through intraoperative fluoroscopy. After that, the robot will provide navigation using the 6 degree-of-freedom (DOF) robot arm according to the preoperative planning system and guide the surgeon to complete the establishment of the working channel. In the foraminoplasty system, according to the foraminoplasty planning in the preoperative planning system, the robot performs foraminoplasty automatically using the high speed burr at the end of the robot arm. The system can provide real-time feedback on the working status of the bur through multi-mode sensors such as multidimensional force, position, and acceleration. Finally, a prototype of the system is constructed and performance tests are conducted.

Discussion

Our study will develop a robot-assisted system to perform transforaminal PELS, and this robot-assisted system can also be used for other percutaneous endoscopic spinal surgeries such as interlaminar PELS and percutaneous endoscopic cervical and thoracic surgeries through further research. The development of this robot-assisted system can be of great significance. First, the robot can improve the accuracy and efficiency of endoscopic spinal surgeries. In addition, it can avoid multiple intraoperative fluoroscopies, minimize exposure to both patients and the surgical staff, shorten the operative time, and improve the learning curve of beginners, which is beneficial to the popularization of percutaneous endoscopic spinal surgeries.
Small molecule drug development for rare genodermatoses – evaluation of the current status in epidermolysis bullosa
Authors: Wally Verena , Reisenberger Manuela , Kitzmüller Sophie , Laimer Martin
Published: October 2020

Background

Hereditary epidermolysis bullosa (EB) comprises a heterogeneous group of rare genodermatoses, which are caused by mutations in genes involved in the maintenance of the structural and functional integrity of dermo-epidermal adhesion in various stratified epithelia. In severe variants, generalized skin disease, extracutaneous manifestations and multi-organ involvement cause considerable morbidity and mortality. Causal and early treatment by re-expression of a respective mutated gene is the major long-term goal in therapy development. However, characterization and targeted modulation of pathogenic molecular cascades in EB also holds great promise as a symptom-relieving approach to ameliorate phenotype, complications and quality of life. Small molecules are chemical structures of less than 900 Da that can diffuse across cell membranes and interfere with target biomolecules, thus influencing their function at different levels. They constitute the vast majority of active components of all approved drugs.

Methods

We performed PubMed and Google Scholar search for publications and screened FDA- and EMA-hosted clinical trial registries to identify studies using small molecule-based drugs for epidermolysis bullosa. Upon detailed analysis this resulted in the identification of a total of 84 studies.

Results

We identified 52 publications and 32 registered trials that investigate small molecules for their safety and efficacy as treatment for different aspects of epidermolysis bullosa. Further, a total of 38 different small molecules clinically used in EB were found. Most frequent outcome measures concerned wound healing, reduction in blister numbers, as well as reduction of itch and pain, predominantly for EBS and RDEB.

Conclusion

We provide a comprehensive summary of the current status of clinical small molecule development for EB and discuss prospects and limitations in orphan drug development for rare conditions like EB.
Coping with Wolf-Hirschhorn syndrome: quality of life and psychosocial features of family carers
Authors: Berrocoso Sarah , Amayra Imanol , Lázaro Esther , Martínez Oscar , López-Paz Juan Francisco , García Maitane , Pérez Manuel , Al-Rashaida Mohammad , Rodríguez Alicia Aurora , Luna Paula Maria , Pérez-Núñez Paula , Blanco Raquel , Nevado Julián
Published: October 2020

Background

Wolf-Hirschhorn Syndrome (WHS) is a rare, congenital disease characterized by a distinctive facial phenotype, seizures, intellectual disability and developmental delay, and pre and postnatal growth requiring lifelong care. The psychosocial status of the family caregivers of children diagnosed with WHS is unknown. This study aims to characterize the sociodemographic and psychosocial profile of WHS caregivers and analyze how these variables impact their quality of life (QoL) and well-being.

Results

The sociodemographic and clinical profile of 22 Spanish caregivers of children with WHS and the characteristics of those affected have been described. Significant relationships were found between sociodemographic and psychosocial characteristics among caregivers. The impact on the parents’ QoL and negative relationship with the symptomatology were assessed. The use of engagement strategies such as problem focused coping was associated with improved psychological QoL and social support.

Conclusions

WHS caregivers share similarities in their profile and needs with caregivers of children with other rare diseases. Pychosocial support groups involving parents caring for children with the same disease could improve caregivers’ well-being and QoL by strengthening their social support network and using positive coping styles.
Modeling the β-secretase cleavage site and humanizing amyloid-beta precursor protein in rat and mouse to study Alzheimer’s disease
Authors: Serneels Lutgarde , T’Syen Dries , Perez-Benito Laura , Theys Tom , Holt Matthew G. , De Strooper Bart
Published: October 2020

Background

Three amino acid differences between rodent and human APP affect medically important features, including β-secretase cleavage of APP and Aβ peptide aggregation (De Strooper et al., EMBO J 14:4932-38, 1995; Ueno et al., Biochemistry 53:7523-30, 2014; Bush, 2003, Trends Neurosci 26:207–14). Most rodent models for Alzheimer’s disease (AD) are, therefore, based on the human APP sequence, expressed from artificial mini-genes randomly inserted in the rodent genome. While these models mimic rather well various biochemical aspects of the disease, such as Aβ-aggregation, they are also prone to overexpression artifacts and to complex phenotypical alterations, due to genes affected in or close to the insertion site(s) of the mini-genes (Sasaguri et al., EMBO J 36:2473-87, 2017; Goodwin et al., Genome Res 29:494-505, 2019). Knock-in strategies which introduce clinical mutants in a humanized endogenous rodent APP sequence (Saito et al., Nat Neurosci 17:661-3, 2014) represent useful improvements, but need to be compared with appropriate humanized wildtype (WT) mice.

Methods

Computational modelling of the human β-CTF bound to BACE1 was used to study the differential processing of rodent and human APP. We humanized the three pivotal residues we identified G676R, F681Y and R684H (labeled according to the human APP770 isoform) in the mouse and rat genomes using a CRISPR-Cas9 approach. These new models, termed mouse and rat Apphu/hu, express APP from the endogenous promotor. We also introduced the early-onset familial Alzheimer’s disease (FAD) mutation M139T into the endogenous Rat Psen1 gene.

Results

We show that introducing these three amino acid substitutions into the rodent sequence lowers the affinity of the APP substrate for BACE1 cleavage. The effect on β-secretase processing was confirmed as both humanized rodent models produce three times more (human) Aβ compared to the original WT strain. These models represent suitable controls, or starting points, for studying the effect of transgenes or knock-in mutations on APP processing (Saito et al., Nat Neurosci 17:661-3, 2014). We introduced the early-onset familial Alzheimer’s disease (FAD) mutation M139T into the endogenous Rat Psen1 gene and provide an initial characterization of Aβ processing in this novel rat AD model.

Conclusion

The different humanized APP models (rat and mouse) expressing human Aβ and PSEN1 M139T are valuable controls to study APP processing in vivo allowing the use of a human Aβ ELISA which is more sensitive than the equivalent system for rodents. These animals will be made available to the research community.
Antibiotic-related gut dysbiosis induces lung immunodepression and worsens lung infection in mice
Authors: Dessein Rodrigue , Bauduin Marvin , Grandjean Teddy , Le Guern Rémi , Figeac Martin , Beury Delphine , Faure Karine , Faveeuw Christelle , Guery Benoit , Gosset Philippe , Kipnis Eric
Published: October 2020

Background

Gut dysbiosis due to the adverse effects of antibiotics affects outcomes of lung infection. Previous murine models relied on significant depletion of both gut and lung microbiota, rendering the analysis of immune gut-lung cross-talk difficult.

Here, we study the effects of antibiotic-induced gut dysbiosis without lung dysbiosis on lung immunity and the consequences on acute P. aeruginosa lung infection.

Methods

C57BL6 mice received 7 days oral vancomycin-colistin, followed by normal regimen or fecal microbial transplant or Fms-related tyrosine kinase 3 ligand (Flt3-Ligand) over 2 days, and then intra-nasal P. aeruginosa strain PAO1. Gut and lung microbiota were studied by next-generation sequencing, and lung infection outcomes were studied at 24 h. Effects of vancomycin-colistin on underlying immunity and bone marrow progenitors were studied in uninfected mice by flow cytometry in the lung, spleen, and bone marrow.

Results

Vancomycin-colistin administration induces widespread cellular immunosuppression in both the lung and spleen, decreases circulating hematopoietic cytokine Flt3-Ligand, and depresses dendritic cell bone marrow progenitors leading to worsening of P. aeruginosa lung infection outcomes (bacterial loads, lung injury, and survival). Reversal of these effects by fecal microbial transplant shows that these alterations are related to gut dysbiosis. Recombinant Flt3-Ligand reverses the effects of antibiotics on subsequent lung infection.

Conclusions

These results show that gut dysbiosis strongly impairs monocyte/dendritic progenitors and lung immunity, worsening outcomes of P. aeruginosa lung infection. Treatment with a fecal microbial transplant or immune stimulation by Flt3-Ligand both restore lung cellular responses to and outcomes of P. aeruginosa following antibiotic-induced gut dysbiosis.
Predicted functional interactome of Caenorhabditis elegans and a web tool for the functional interpretation of differentially expressed genes
Authors: Chen Peng-Cheng , Ruan Li , Jin Jie , Tao Yu-Tian , Ding Xiao-Bao , Zhang Hai-bo , Guo Wen-Ping , Yang Qiao-lei , Yao Heng , Chen Xin
Published: October 2020

Background

The nematode worm, Caenorhabditis elegans, is a saprophytic species that has been emerging as a standard model organism since the early 1960s. This species is useful in numerous fields, including developmental biology, neurobiology, and ageing. A high-quality comprehensive molecular interaction network is needed to facilitate molecular mechanism studies in C. elegans.

Results

We present the predicted functional interactome of Caenorhabditis elegans (FIC), which integrates functional association data from 10 public databases to infer functional gene interactions on diverse functional perspectives. In this work, FIC includes 108,550 putative functional associations with balanced sensitivity and specificity, which are expected to cover 21.42% of all C. elegans protein interactions, and 29.25% of these associations may represent protein interactions. Based on FIC, we developed a gene set linkage analysis (GSLA) web tool to interpret potential functional impacts from a set of differentially expressed genes observed in transcriptome analyses.

Conclusion

We present the predicted C. elegans interactome database FIC, which is a high-quality database of predicted functional interactions among genes. The functional interactions in FIC serve as a good reference interactome for GSLA to annotate differentially expressed genes for their potential functional impacts. In a case study, the FIC/GSLA system shows more comprehensive and concise annotations compared to other widely used gene set annotation tools, including PANTHER and DAVID. FIC and its associated GSLA are available at the website http://worm.biomedtzc.cn.
TREAT Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid arthritis (TREAT EARLIER): a randomized, double-blind, placebo-controlled clinical trial protocol
Authors: Niemantsverdriet Ellis , Dakkak Yousra J. , Burgers Leonie E. , Bonte-Mineur Femke , Steup-Beekman Gerda M. , van der Kooij Sjoerd M. , Boom Hido D. , Allaart Cornelia F. , de Jong Pascal H. P. , van der Helm-van Mil Annette H. M.
Published: October 2020

Background

We present a study protocol for a randomized, double-blind, placebo-controlled trial that investigates the hypothesis if intervention in the symptomatic phase preceding clinical arthritis (clinically suspect arthralgia (CSA)) is effective in preventing progression from subclinical inflammation to clinically apparent persistent arthritis. Currently, rheumatoid arthritis (RA) can be recognized and diagnosed when arthritis (joint swelling) has become detectable at physical examination. Importantly, at this time, the immune processes have already matured, chronicity is established, and patients require long-standing treatment with disease-modifying anti-rheumatic drugs. The TREAT EARLIER trial studies the hypothesis that intervention in the symptomatic phase preceding clinical arthritis is more often successful in permanent disease modification because of less matured underlying disease processes.

Methods

A two-level definition to identify patients that are prone to develop RA is used. First, patients should have CSA and recent-onset arthralgia (< 1 year) that is suspect to progress to RA according to the expertise of the treating rheumatologist. Second, patients need to have subclinical inflammation of the hand or foot joints at 1.5 T MRI. The trial aims to recruit 230 participants from secondary care hospital settings across the south-west region of The Netherlands. Intervention will be randomly assigned and includes a single-dose of intramuscular 120 mg methylprednisolon followed by methotrexate (increasing dose to 25 mg/week orally) or placebo (both; injection and tablets) over the course of 1 year. Thereafter, participants are followed for another year. The primary endpoint is the development of clinically detectable arthritis, either fulfilling the 2010 criteria for RA or unclassified clinical arthritis of ≥ 2 joints, which persists for at least 2 weeks. DMARD-free status is a co-primary endpoint. The patient-reported outcomes functioning, along with workability and symptoms, are key secondary endpoints. Participants, caregivers (including those assessing the endpoints), and scientific staff are all blinded to the group assignment.

Discussion

This proof-of-concept study is the logical consequence of pre-work on the identification of patients with CSA with MRI-detected subclinical joint inflammation. It will test the hypothesis whether intervention in patients in this early phase with the cornerstone treatment of classified RA (methotrexate) hampers the development of persistent RA and reduce the disease burden of RA.

Trial registration

Dutch Trial Register NL4599 (NTR4853). Registered on 20 October 2014
Implementation of a stepped wedge cluster randomized trial to evaluate a hospital mobility program
Authors: Hastings Susan N. , Stechuchak Karen M. , Choate Ashley , Mahanna Elizabeth P. , Van Houtven Courtney , Allen Kelli D. , Wang Virginia , Sperber Nina , Zullig Leah , Bosworth Hayden B. , Coffman Cynthia J.
Published: October 2020

Background

Stepped wedge cluster randomized trials (SW-CRT) are increasingly used to evaluate new clinical programs, yet there is limited guidance on practical aspects of applying this design. We report our early experiences conducting a SW-CRT to examine an inpatient mobility program (STRIDE) in the Veterans Health Administration (VHA). We provide recommendations for future research using this design to evaluate clinical programs.

Methods

Based on data from study records and reflections from the investigator team, we describe and assess the design and initial stages of a SW-CRT, from site recruitment to program launch in 8 VHA hospitals.

Results

Site recruitment consisted of thirty 1-h conference calls with representatives from 22 individual VAs who expressed interest in implementing STRIDE. Of these, 8 hospitals were enrolled and randomly assigned in two stratified blocks (4 hospitals per block) to a STRIDE launch date. Block 1 randomization occurred in July 2017 with first STRIDE launch in December 2017; block 2 randomization occurred in April 2018 with first STRIDE launch in January 2019. The primary study outcome of discharge destination will be assessed using routinely collected data in the electronic health record (EHR). Within randomized blocks, two hospitals per sequence launched STRIDE approximately every 3 months with primary outcome assessment paused during the 3-month time period of program launch. All sites received 6–8 implementation support calls, according to a pre-specified schedule, from the time of recruitment to program launch, and all 8 sites successfully launched within their assigned 3-month window. Seven of the eight sites initially started with a limited roll out (for example on one ward) or modified version of STRIDE (for example, using existing staff to conduct walks until new positions were filled).

Conclusions

Future studies should incorporate sufficient time for site recruitment and carefully consider the following to inform design of SW-CRTs to evaluate rollout of a new clinical program: (1) whether a blocked randomization fits study needs, (2) the amount of time and implementation support sites will need to start their programs, and (3) whether clinical programs are likely to include a “ramp-up” period. Successful execution of SW-CRT designs requires both adherence to rigorous design principles and also careful consideration of logistical requirements for timing of program roll out.

Trial registration

ClinicalsTrials.gov NCT03300336. Prospectively registered on 3 October 2017.
Harnessing pongamia shell hydrolysate for triacylglycerol agglomeration by novel oleaginous yeast Rhodotorula pacifica INDKK
Authors: Kumar Kukkala Kiran , Deeba Farha , Sauraj  , Negi Yuvraj Singh , Gaur Naseem A.
Published: October 2020

Background

To meet the present transportation demands and solve food versus fuel issue, microbial lipid-derived biofuels are gaining attention worldwide. This study is focussed on high-throughput screening of oleaginous yeast by microwave-aided Nile red spectrofluorimetry and exploring pongamia shell hydrolysate (PSH) as a feedstock for lipid production using novel oleaginous yeast Rhodotorula pacifica INDKK.

Results

A new oleaginous yeast R. pacifica INDKK was identified and selected for microbial lipid production. R. pacifica INDKK produced maximum 12.8 ± 0.66 g/L of dry cell weight and 6.78 ± 0.4 g/L of lipid titre after 120 h of growth, showed high tolerance to pre-treatment-derived inhibitors such as 5-hydroxymethyl furfural (5-HMF), (2 g/L), furfural (0.5 g/L) and acetic acid (0.5 g/L), and ability to assimilate C3, C5 and C6 sugars. Interestingly, R. pacifica INDKK showed higher lipid accumulation when grown in alkali-treated saccharified PSH (AS-PSH) (0.058 ± 0.006 g/L/h) as compared to acid-treated detoxified PSH (AD-PSH) (0.037 ± 0.006 g/L/h) and YNB medium (0.055 ± 0.003 g/L/h). The major fatty acid constituents are oleic, palmitic, linoleic and linolenic acids with an estimated cetane number (CN) of about 56.7, indicating the good quality of fuel.

Conclusion

These results suggested that PSH and R. pacifica INDKK could be considered as potential feedstock for sustainable biodiesel production.
Association of TERT and DSP variants with microscopic polyangiitis and myeloperoxidase-ANCA positive vasculitis in a Japanese population: a genetic association study
Authors: Kawasaki Aya , Namba Natsumi , Sada Ken-ei , Hirano Fumio , Kobayashi Shigeto , Nagasaka Kenji , Sugihara Takahiko , Ono Nobuyuki , Fujimoto Takashi , Kusaoi Makio , Tamura Naoto , Yamagata Kunihiro , Sumida Takayuki , Hashimoto Hiroshi , Ozaki Shoichi , Makino Hirofumi , Arimura Yoshihiro , Harigai Masayoshi , Tsuchiya Naoyuki
Published: October 2020

Background

Interstitial lung disease (ILD) is a severe complication with poor prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Prevalence of AAV-associated ILD (AAV-ILD) in Japan is considerably higher than that in Europe. Recently, we reported that aMUC5Bvariant rs35705950, the strongest susceptibility variant to idiopathic pulmonary fibrosis (IPF), was strikingly increased in AAV-ILD patients but not in AAV patients without ILD; however, due to the low allele frequency in the Japanese population, theMUC5Bvariant alone cannot account for the high prevalence of AAV-ILD in Japan. In this study, we examined whether other IPF susceptibility alleles inTERTandDSPgenes are associated with susceptibility to AAV subsets and AAV-ILD.

Methods

Five hundred and forty-four Japanese patients with AAV and 5558 controls were analyzed. Among the AAV patients, 432 were positive for myeloperoxidase (MPO)-ANCA (MPO-AAV). A total of 176 MPO-AAV patients were positive and 216 were negative for ILD based on CT or high-resolution CT. Genotypes ofTERTandDSPvariants were determined by TaqMan SNP Genotyping Assay, and their association was tested by chi-square test.

Results

When the frequencies of the IPF risk allelesTERTrs2736100A andDSPrs2076295G were compared between AAV subsets and healthy controls, both alleles were significantly increased in microscopic polyangiitis (MPA) (TERT P = 2.3 × 10−4,Pc = 0.0023, odds ratio [OR] 1.38;DSP P = 6.9 × 10−4,Pc = 0.0069, OR 1.32) and MPO-AAV (TERT P = 1.5 × 10−4,Pc = 0.0015, OR 1.33;DSP P = 0.0011,Pc = 0.011, OR 1.26). On the other hand, no significant association was detected when the allele frequencies were compared between MPO-AAV patients with and without ILD.

Conclusions

Unexpectedly,TERTandDSPIPF risk alleles were found to be associated with MPA and MPO-AAV, regardless of the presence of ILD. These findings suggest thatTERTandDSPmay be novel susceptibility genes to MPA/MPO-AAV and also that some susceptibility genes may be shared between IPF and MPA/MPO-AAV.
Epigenetic silencing of miR-342-3p in B cell lymphoma and its impact on autophagy
Authors: Zhang Min Yue , Calin George A. , Yuen Kit San , Jin Dong Yan , Chim Chor Sang
Published: October 2020

Background

miR-342-3p, localized to 14q32, is a tumor suppressor miRNA implicated in carcinogenesis. Given the presence of a promotor-associated CpG island for its host gene, EVL, we hypothesized that intronic miR-342-3p is a tumor suppressor co-regulated with host gene by promoter DNA methylation in B cell lymphoma.

Results

By bisulfite pyrosequencing-verified methylation-specific PCR (MSP), EVL/MIR342 methylation was detected in five (50%) lymphoma cell lines but not normal peripheral blood and tonsils. EVL/MIR342 methylation correlated with repression of both miR-342-3p and EVL in cell lines. In completely methylated SU-DHL-16 cells, 5-AzadC treatment resulted in promoter demethylation and re-expression of miR-342-3p and EVL. In 132 primary lymphoma samples, EVL/MIR342 was preferentially methylated in B cell lymphomas (N = 68; 68.7%) than T cell lymphoma (N = 8; 24.2%) by MSP (P < 0.0001). Moreover, EVL/MIR342 methylation was associated with lower miR-342-3p expression in 79 primary NHL (P = 0.0443). In SU-DHL-16 cells, the tumor suppressor function of miR-342-3p was demonstrated by the inhibition of cellular proliferation and increase of cell death upon over-expression of miR-342-3p. Mechanistically, overexpression of miR-342-3p resulted in a decrease of LC3-II, a biomarker of autophagy, which was pro-survival for SU-DHL-16. Pre-treatment with 3-methyladenine, an autophagy inhibitor, abrogated tumor suppression associated with miR-342-3p overexpression. By luciferase assay, MAP1LC3B, a precursor of LC3-II, was confirmed as a direct target of miR-342-3p. Finally, in SU-DHL-16 cells, overexpression of miR-342-3p downregulated the known target DNMT1, with promoter demethylation and re-expression of tumor suppressor E-cadherin.

Conclusions

Intronic miR-342-3p is co-regulated with its host gene EVL by tumor-specific promoter DNA methylation in B cell lymphoma. The tumor suppressor function of miR-342-3p was mediated via inhibition of pro-survival autophagy by targeting MAP1LC3B and downregulation of DNMT1 with demethylation and re-expression of tumor suppressor genes.
Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome
Authors: Binder Gerhard , Ziegler Julian , Schweizer Roland , Habhab Wisam , Haack Tobias B. , Heinrich Tilman , Eggermann Thomas
Published: October 2020

Background

Pathogenic CDKN1C gain-of-function variants on the maternal allele were initially reported as a cause of IMAGe syndrome characterized by intrauterine growth retardation, metaphyseal dysplasia, primary adrenal insufficiency and genital anomalies. Recently, a maternally inherited CDKN1C missense mutation (p.Arg279Leu) was identified in several members of a single family clinically diagnosed with Silver–Russell syndrome (SRS) but without adrenal insufficiency. Thereafter, two half siblings from UK with familial SRS were described who carried the same mutation. This specific amino acid change is located within a narrow functional region containing the mutations previously associated with IMAGe syndrome.

Results

Here, we describe a third familial case with maternally inherited SRS due to a missense variant affecting the same amino acid position 279 but leading to a different amino acid substitution (p. (Arg279Ser)). The two affected family members (mother and son) presented with the complete SRS phenotype (both Netchine–Harbison CSS score 5 of 6) but without body asymmetry or adrenal insufficiency.

Conclusions

In comparison with loss-of-function genomic IGF2 mutations, CDKN1C gain-of-function mutations are a less frequent cause of SRS and seem to affect a cluster of few amino acids.
Efficacy and safety of stem cell therapy for the early-stage osteonecrosis of femoral head: a systematic review and meta-analysis of randomized controlled trials
Authors: Mao Lianghao , Jiang Pan , Lei Xuan , Ni Chenlie , Zhang Yiming , Zhang Bing , Zheng Qiping , Li Dapeng
Published: October 2020

Background

Osteonecrosis of femoral head (ONFH) is a seriously degenerative disease with no effective therapies to slow its progression. Several studies have reported short-term efficacy of stem cells on early-stage ONFH. However, its long-term effect was still unclear especially on progression events. This study was performed to evaluate the long-term efficacy and safety of stem cells and analyze its optimal age group and cell number.

Methods

Our review was registered on PROSPERO (http://www.crd.york.ac.uk/PROSPERO), registration number CRD42020136094. Following PRISMA guideline, we searched 8 electronic databases on January 5, 2020, and rigorous random controlled trials (RCTs) utilizing stem cell therapy on early-stage ONFH were included. Quality and bias were analyzed. Pooled analysis was performed to assess difference between various outcomes.

Results

A total of 13 RCTs (619 patients with 855 hips) were included. The application of stem cells significantly delayed collapse of femoral head(I2, 70%; RR, 0.54; 95% CI, 0.33 to 0.89;P < .00001) and total hip replacement (THR) (I2, 68%; RR, 0.55; 95% CI, 0.34 to 0.90;P = .02) in the long term. It effectively decreased the events of collapse of femoral head (≥ 60 months) (I2, 0%; RR, 0.37; 95% CI, 0.28 to 0.49;P < .00001) and THR (> 36 months) (I2, 0%; RR, 0.32; 95% CI, 0.23 to 0.44;P < .00001). There existed a beneficial effect for patients under 40 (Collapse of femoral head:I2, 56%; RR, 0.41; 95% CI, 0.23 to 0.76;P = .004) (THR:I2, 0%; RR, 0.31; 95% CI, 0.23 to 0.42;P < .00001). In addition, quantity of stem cells at 108magnitude had better effects on disease progression events (I2, 0%; RR, 0.34; 95%CI, 0.16 to 0.74;P = .007). Besides, there were no significant differences on adverse events between the stem cell group and control group (I2, 0%; RR, 0.82; 95% CI, 0.39 to 1.73;P = .60).

Conclusion

Our findings build solid evidence that stem cell therapy could be expected to have a long-term effect on preventing early-stage ONFH patients from progression events, such as collapse of femoral head and total hip replacement. Furthermore, patients under 40 may be an ideal age group and the optimal cell number could be at 108magnitude for this therapy. Further studies including strict RCTs are required to evaluate a clear effect of stem cells on ideal patient profile and the procedures of implantation.
[11C]PIB amyloid quantification: effect of reference region selection
Authors: Heeman Fiona , Hendriks Janine , Lopes Alves Isadora , Ossenkoppele Rik , Tolboom Nelleke , van Berckel Bart N. M. , Lammertsma Adriaan A. , Yaqub Maqsood ,   on behalf of the AMYPAD Consortium
Published: October 2020

Background

The standard reference region (RR) for amyloid-beta (Aβ) PET studies is the cerebellar grey matter (GMCB), while alternative RRs have mostly been utilized without prior validation against the gold standard. This study compared five commonly used RRs to gold standard plasma input-based quantification using the GMCB.

Methods

Thirteen subjects from a test–retest (TRT) study and 30 from a longitudinal study were retrospectively included (total: 17 Alzheimer’s disease, 13 mild cognitive impairment, 13 controls). Dynamic [11C]PiB PET (90 min) and T1-weighted MR scans were co-registered and time–activity curves were extracted for cortical target regions and the following RRs: GMCB, whole cerebellum (WCB), white matter brainstem/pons (WMBS), whole brainstem (WBS) and eroded subcortical white matter (WMES). A two-tissue reversible plasma input model (2T4k_Vb) with GMCB as RR, reference Logan and the simplified reference tissue model were used to derive distribution volume ratios (DVRs), and standardized uptake value (SUV) ratios were calculated for 40–60 min and 60–90 min intervals. Parameter variability was evaluated using TRT scans, and correlations and agreements with the gold standard (DVR from 2T4k_Vb with GMCB RR) were also assessed. Next, longitudinal changes in SUVs (both intervals) were assessed for each RR. Finally, the ability to discriminate between visually Aβ positive and Aβ negative scans was assessed.

Results

All RRs yielded stable TRT performance (max 5.1% variability), with WCB consistently showing lower variability. All approaches were able to discriminate between Aβ positive and Aβ negative scans, with highest effect sizes obtained for GMCB (range − 0.9 to − 0.7), followed by WCB (range − 0.8 to − 0.6). Furthermore, all approaches provided good correlations with the gold standard (r ≥ 0.78), while the highest bias (as assessed by the regression slope) was observed using WMES (range slope 0.52–0.67), followed by WBS (range slope 0.58–0.92) and WMBS (range slope 0.62–0.91). Finally, RR SUVs were stable across a period of 2.6 years for all except WBS and WMBS RRs (60–90 min interval).

Conclusions

GMCB and WCB are considered the best RRs for quantifying amyloid burden using [11C]PiB PET.
New construction of type 2 degenerate central Fubini polynomials with their certain properties
Authors: Sharma Sunil Kumar , Khan Waseem A. , Araci Serkan , Ahmed Sameh S.
Published: October 2020

Kim et al. (Proc. Jangjeon Math. Soc. 21(4):589–598, 2018) have studied the central Fubini polynomials associated with central factorial numbers of the second kind. Motivated by their work, we introduce degenerate version of the central Fubini polynomials. We show that these polynomials can be represented by the fermionic p-adic integral on $\mathbb{Z}_{p}$

Z
p

. From the fermionic p-adic integral equations, we derive some new properties related to degenerate central factorial numbers of the second kind and degenerate Euler numbers of the second kind.
Protective effects of taurine against muscle damage induced by diquat in 35 days weaned piglets
Authors: Wen Chaoyue , Li Fengna , Guo Qiuping , Zhang Lingyu , Duan Yehui , Wang Wenlong , Li Jianzhong , He Shanping , Chen Wen , Yin Yulong
Published: October 2020

Background

Oxidative stress is a key factor that influences piglets’ health. Taurine plays an imperative role in keeping the biological system from damage. This study was conducted to investigate the protective effect of taurine against muscle injury due to the secondary effect of diquat toxicity.

Results

Our study found that taurine effectively and dose-dependently alleviated the diquat toxicity induced rise of feed/gain, with a concurrent improvement of carcass lean percentage. The plasma content of taurine was considerably increased in a dose-dependent manner. Consequently, dietary taurine efficiently improved the activity of plasma antioxidant enzymes. Furthermore, taurine attenuated muscle damage by restoring mitochondrial micromorphology, suppressing protein degradation and reducing the percentage of apoptotic cells in the skeletal muscle. Taurine supplementation also suppressed the genes expression levels of the antioxidant-, mitochondrial biogenesis-, and muscle atrophy-related genes in the skeletal muscle of piglets with oxidative stress.

Conclusions

These results showed that the dose of 0.60% taurine supplementation in the diet could attenuate skeletal muscle injury induced by diquat toxicity. It is suggested that taurine could be a potential nutritional intervention strategy to improve growth performance.
Compare the epidemiological and clinical features of imported and local COVID-19 cases in Hainan, China
Authors: Wu Biao , Lei Zi-Ying , Wu Kun-Liang , He Jian-Rong , Cao Hui-Juan , Fu Juan , Chen Feng , Chen Yuan , Chen Bao , Zhou Xiao-Li , Huang Tao , Wu Tao , Du Yong-Guo , Chen Suo-Xian , Xiao Fu-Rong , Gao Zhi-Liang , He Jing , Lin Feng , Lin Bing-Liang
Published: October 2020

Background

Effective management of imported cases is an important part of epidemic prevention and control. Hainan Province, China reported 168 coronavirus disease 2019 (COVID-19), including 112 imported cases on February 19, 2020, but successfully contained the epidemic within 1 month. We described the epidemiological and clinical characteristics of COVID-19 in Hainan and compared these features between imported and local cases to provide information for other international epidemic areas.

Methods

We included 91 patients (56 imported and 35 local cases) from two designated hospitals for COVID-19 in Haikou, China, from January 20 to February 19, 2020. Data on the demographic, epidemiological, clinical and laboratory characteristics were extracted from medical records. Patients were followed until April 21, 2020, and the levels of antibodies at the follow-ups were also analysed by the Wilcoxon matched-pairs signed ranks test.

Results

Of the 91 patients, 78 (85.7%) patients were diagnosed within the first three weeks after the first case was identified (Day 1: Jan 22, 2020), while the number of local cases started to increase during the third week. No new cases occurred after Day 29. Fever and cough were two main clinical manifestations. In total, 15 (16.5%) patients were severe, 14 (15.4%) had complicated infections, nine (9.9%) were admitted to the intensive care unit, and three died. The median duration of viral shedding in feces was longer than that in nasopharyngeal swabs (19 days vs 16 days, P = 0.007). Compared with local cases, imported cases were older and had a higher incidence of fever and concurrent infections. There was no difference in outcomes between the two groups. IgG was positive in 92.8% patients (77/83) in the follow-up at week 2 after discharge, while 88.4% patients (38/43) had a reduction in IgG levels in the follow-up at week 4 after discharge, and the median level was lower than that in the follow-up at week 2 (10.95 S/Cut Off (S/CO) vs 15.02 S/CO, P <  0.001).

Conclusion

Imported cases were more severe than local cases but had similar prognoses. The level of IgG antibodies declined from week 6 to week 8 after onset. The short epidemic period in Hainan suggests that the epidemic could be quickly brought under control if proper timely measures were taken.