bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of IMU-based gait event detection during curved walking and turning in older adults and Parkinson’s Disease patients
Authors: Romijnders Robbin , Warmerdam Elke , Hansen Clint , Welzel Julius , Schmidt Gerhard , Maetzler Walter
Published: February 2021

Background

Identification of individual gait events is essential for clinical gait analysis, because it can be used for diagnostic purposes or tracking disease progression in neurological diseases such as Parkinson’s disease. Previous research has shown that gait events can be detected from a shank-mounted inertial measurement unit (IMU), however detection performance was often evaluated only from straight-line walking. For use in daily life, the detection performance needs to be evaluated in curved walking and turning as well as in single-task and dual-task conditions.

Methods

Participants (older adults, people with Parkinson’s disease, or people who had suffered from a stroke) performed three different walking trials: (1) straight-line walking, (2) slalom walking, (3) Stroop-and-walk trial. An optical motion capture system was used a reference system. Markers were attached to the heel and toe regions of the shoe, and participants wore IMUs on the lateral sides of both shanks. The angular velocity of the shank IMUs was used to detect instances of initial foot contact (IC) and final foot contact (FC), which were compared to reference values obtained from the marker trajectories.

Results

The detection method showed high recall, precision and F1 scores in different populations for both initial contacts and final contacts during straight-line walking (IC: recall $$=$$
=
100%, precision $$=$$
=
100%, F1 score $$=$$
=
100%; FC: recall $$=$$
=
100%, precision $$=$$
=
100%, F1 score $$=$$
=
100%), slalom walking (IC: recall $$=$$
=
100%, precision $$\ge$$
≥
99%, F1 score $$=$$
=
100%; FC: recall $$=$$
=
100%, precision $$\ge$$
≥
99%, F1 score $$=$$
=
100%), and turning (IC: recall $$\ge$$
≥
85%, precision $$\ge$$
≥
95%, F1 score $$\ge$$
≥
91%; FC: recall $$\ge$$
≥
84%, precision $$\ge$$
≥
95%, F1 score $$\ge$$
≥
89%).

Conclusions

Shank-mounted IMUs can be used to detect gait events during straight-line walking, slalom walking and turning. However, more false events were observed during turning and more events were missed during turning. For use in daily life we recommend identifying turning before extracting temporal gait parameters from identified gait events.
A hybrid model based on general regression neural network and fruit fly optimization algorithm for forecasting and optimizing paclitaxel biosynthesis in Corylus avellana cell culture
Authors: Salehi Mina , Farhadi Siamak , Moieni Ahmad , Safaie Naser , Hesami Mohsen
Published: February 2021

Background

Paclitaxel is a well-known chemotherapeutic agent widely applied as a therapy for various types of cancers. In vitro culture of Corylus avellana has been named as a promising and low-cost strategy for paclitaxel production. Fungal elicitors have been reported as an impressive strategy for improving paclitaxel biosynthesis in cell suspension culture (CSC) of C. avellana. The objectives of this research were to forecast and optimize growth and paclitaxel biosynthesis based on four input variables including cell extract (CE) and culture filtrate (CF) concentration levels, elicitor adding day and CSC harvesting time in C. avellana cell culture, as a case study, using general regression neural network-fruit fly optimization algorithm (GRNN-FOA) via data mining approach for the first time.

Results

GRNN-FOA models (0.88–0.97) showed the superior prediction performances as compared to regression models (0.57–0.86). Comparative analysis of multilayer perceptron-genetic algorithm (MLP-GA) and GRNN-FOA showed very slight difference between two models for dry weight (DW), intracellular and extracellular paclitaxel in testing subset, the unseen data. However, MLP-GA was slightly more accurate as compared to GRNN-FOA for total paclitaxel and extracellular paclitaxel portion in testing subset. The slight difference was observed in maximum growth and paclitaxel biosynthesis optimized by FOA and GA. The optimization analysis using FOA on developed GRNN-FOA models showed that optimal CE [4.29% (v/v)] and CF [5.38% (v/v)] concentration levels, elicitor adding day (17) and harvesting time (88 h and 19 min) can lead to highest paclitaxel biosynthesis (372.89 µg l−1).

Conclusions

Great accordance between the predicted and observed values of DW, intracellular, extracellular and total yield of paclitaxel, and also extracellular paclitaxel portion support excellent performance of developed GRNN-FOA models. Overall, GRNN-FOA as new mathematical tool may pave the way for forecasting and optimizing secondary metabolite production in plant in vitro culture.
Feasibility of a mini-pig model of radiation-induced brain injury to one cerebral hemisphere
Authors: Athanasiadi Ilektra , Perez Whitney D. , Plantenga Jeannie M. , Jones-Hall Yava , Perez-Torres Carlos J.
Published: February 2021

Background

Radiation-induced brain injury is a common concern for survivors of adult and pediatric brain cancer. Pre-clinically, rodent models are the standard approach to evaluate mechanisms of injury and test new therapeutics for this condition. However, these rodent models fail to recapitulate the radiological and histological characteristics of the clinical disease.

Methods

Here we describe a hemispheric mini-pig model of radiation-induced brain injury generated with a clinical 6 MV photon irradiator and evaluated with a clinical 3T MRI. Two pairs of Yucatan mini-pigs each received either 15 Gy or 25 Gy to the left brain hemisphere. Quality of intensity modulated radiation therapy treatment plans was evaluated retrospectively with parameters reported according to ICRU guidelines. The pigs were observed weekly to check for any outright signs of neurological impairment. The pigs underwent anatomical MRI examination before irradiation and up to 6 months post-irradiation. Immediately after the last imaging time point, the pigs were euthanized and their brains were collected for histopathological assessment.

Results

Analysis of the dose volume histograms showed that 93% of the prescribed dose was delivered to at least 93% of the target volume in the left hemisphere. Organs at risk excluded from the target volume received doses below clinical safety thresholds. For the pigs that received a 25 Gy dose, progressive neurological impairment was observed starting at 2 months post-irradiation leading to the need for euthanasia by 3–4 months. On MRI, these two animals presented with diffuse white matter pathology consistent with the human disease that progressed to outright radiation necrosis and severe brain swelling. Histology was consistent with the final MRI evaluation. The pigs that received a 15 Gy dose appeared normal all the way to 6 months post-irradiation with no obvious neurological impairment or lesions on MRI or histopathology.

Conclusion

Based on our results, a mini-pig model of radiation-induced brain injury is feasible though some optimization is still needed. The mini-pig model produced lesions on MRI that are consistent with the human disease and which are not seen in rodent models. Our data shows that the ideal radiation dose for this model likely lies between 15 and 25 Gy.
Clinical characteristics of 93 cases of isolated macrodactyly of the foot in children
Authors: Chen Wei , Tian Xiaofei , Chen Lu , Huang Wei
Published: February 2021

Background

The purpose of this study was to describe the clinical characteristics of macrodactyly of the foot through a large cohort of cases to further understand this rare entity.

Methods

Medical records, clinical photographs, plain radiographs, pathological findings, and intraoperative photographs of 95 feet of 93 patients were reviewed. Data including age; sex; laterality; ethnicity; birthplace; family history; and history of gestation, environment, whether smoking, or drinking during pregnancy were collected and analyzed.

Results

Female patients (60%), left foot (56%), and static overgrowth (63%) were more prominent in the study cohort. Southern provinces (74%) and Han Chinese ethnicity (95%) predominated in terms of geographical region and demographic distribution, respectively. Multiple-toe involvement was 2.01-times more frequent than single-toe involvement. All five toes were involved with midline toes being most frequently affected overall and a medial distribution being more common than a lateral one. The forefoot was affected in 90 feet. The affected areas (toes and forefeet) were mostly located in the innervation of the affected medial plantar nerve (91%). The nerves showed enlargement in 49 feet, fatty infiltration in 25, a tortuous course in one, and were normal in 10 feet. Only six feet involved the musculature. Enlargement of phalanges and metatarsals were observed in 92 and 57 feet, respectively, and advanced bone maturation was seen in 63 feet. Twenty-two cases had syndactyly.

Conclusions

Macrodactyly of the foot is a rare congenital malformation with diverse clinical manifestations and multiple elements’ involvement.

It also presents the characteristics of nerve-mediated overgrowth and “nerve territory-oriented” deformity similar to that of macrodactyly of the hand.
Mesenchymal stem cell-originated exosomal lncRNA HAND2-AS1 impairs rheumatoid arthritis fibroblast-like synoviocyte activation through miR-143-3p/TNFAIP3/NF-κB pathway
Authors: Su Yuhua , Liu Yajing , Ma Chao , Guan Chunxiao , Ma Xiufen , Meng Shan
Published: February 2021

Background

Long non-coding RNA heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) was found to be elevated in rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLSs). However, whether HAND2-AS1 functions as an exosomal lncRNA related to mesenchymal stem cells (MSCs) in RA progression is unknown.

Methods

The expression of HAND2-AS1, microRNA (miR)-143-3p, and tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) was detected using quantitative real-time polymerase chain reaction and Western blot. Cell proliferation, apoptosis, migration, and invasion were detected using cell counting kit-8, flow cytometry, and wound healing and transwell assays. The levels of tumor necrosis factor-α (TNF-α) and interleukins (IL)-6 were analyzed using enzyme-linked immunosorbent assay. The level of phosphorylated-p65 was examined by Western blot. The binding interaction between miR-143-3p and HAND2-AS1 or TNFAIP3 was confirmed by the dual-luciferase reporter and RIP assays. Exosomes were isolated by ultracentrifugation and qualified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot.

Results

HAND2-AS1 was lowly expressed in RA synovial tissues, and HAND2-AS1 re-expression suppressed the proliferation, motility, and inflammation and triggered the apoptosis in RA-FLSs via the inactivation of NF-κB pathway. Mechanistically, HAND2-AS1 directly sponged miR-143-3p and positively regulated TNFAIP3 expression, the target of miR-143-3p. Moreover, the effects of HAND2-AS1 on RA-FLSs were partially attenuated by miR-143-3p upregulation or TNFAIP3 knockdown. HAND2-AS1 could be packaged into hMSC-derived exosomes and absorbed by RA-FLSs, and human MSC-derived exosomal HAND2-AS1 also repressed above malignant biological behavior of RA-FLSs.

Conclusion

MSC-derived exosomes participated in the intercellular transfer of HAND2-AS1 and suppressed the activation of RA-FLSs via miR-143-3p/TNFAIP3/NF-κB pathway, which provided a novel insight into the pathogenesis and treatment of RA.
Changes in the bony alignment of the foot after tendo-Achilles lengthening in patients with planovalgus deformity
Authors: Kim Nak Tscheol , Lee Young Tae , Park Moon Seok , Lee Kyoung Min , Kwon Oh Sang , Sung Ki Hyuk
Published: February 2021

Background

This study was performed to investigate the change in the bony alignment of the foot after tendo-Achilles lengthening (TAL) and the factors that affect these changes in patients with planovalgus foot deformity.

Methods

Consecutive 97 patients (150 feet; mean age 10 years; range 5.1–35.7) with Achilles tendon contracture (ATC) and planovalgus foot deformity who underwent TAL were included. All patients underwent preoperative and postoperative weight-bearing anteroposterior (AP) or lateral (LAT) foot radiographics. Changes in AP talo-1st metatarsal angle, AP talo-2nd metatarsal angle, LAT talo-1st metatarsal angle, and calcaneal pitch angle and the factors affecting such changes after TAL were analyzed using lineal mixed model.

Results

There were no significant change in AP talo-1st metatarsal angle and AP talo-2nd metatarsal angle after TAL in patients with cerebral palsy (CP) (p = 0.236 and 0.212). However, LAT talo-1st metatarsal angle and calcaneal pitch angle were significantly improved after TAL (13.0°, p < 0.001 and 4.5°, p < 0.001). Age was significantly associated with the change in LAT talo-1st metatarsal angle after TAL (p = 0.028). The changes in AP talo-1st metatarsal angle, AP talo-2nd metatarsal angle, and calcaneal pitch angle after TAL were not significantly associated with the diagnosis (p = 0.879, 0.903, and 0.056). However, patients with CP showed more improvement in LAT talo-1st metatarsal angle (− 5.0°, p = 0.034) than those with idiopathic cause.

Conclusion

This study showed that TAL can improve the bony alignment of the foot in patients with planovalgus and ATC. We recommend that physicians should consider this study’s findings when planning operative treatment for such patients.
Neuroprotective effects of Shende’an tablet in the Parkinson’s disease model
Authors: Sheng Xiaoyan , Yang Shuiyuan , Wen Xiaomin , Zhang Xin , Ye Yongfeng , Zhao Peng , Zang Limin , Peng Kang , Du Enming , Li Sai
Published: February 2021

Background

Shende’an tablet (SDA) is a newly capsuled Chinese herbal formula derived from the Chinese traditional medicine Zhengan Xifeng Decoction which is approved for the treatment of neurasthenia and insomnia in China. This study aimed to investigate the neuroprotective effects of SDA against Parkinson’s disease (PD) in vitro and in vivo.

Methods

In the present work, the neuroprotective effects and mechanism of SDA were evaluated in the cellular PD model. Male C57BL/6J mice were subject to a partial MPTP lesion alongside treatment with SDA. Behavioural test and tyrosine-hydroxylase immunohistochemistry were used to evaluate nigrostriatal tract integrity. HPLC analysis and Western blotting were used to assess the effect of SDA on dopamine metabolism and the expression of HO-1, PGC-1α and Nrf2, respectively.

Results

Our results demonstrated that SDA had neuroprotective effect in dopaminergic PC12 cells with 6-OHDA lesion. It had also displayed efficient dopaminergic neuronal protection and motor behavior alleviation properties in MPTP-induced PD mice. In the PC12 cells and MPTP-induced Parkinson’s disease animal models, SDA was highly efficacious in α-synuclein clearance associated with the activation of PGC-1α/Nrf2 signal pathway.

Conclusions

SDA demonstrated potential as a future therapeutic modality in PD through protecting dopamine neurons and alleviating the motor symptoms, mediated by the activation of PGC-1α/Nrf2 signal pathway.
No evidence for a pathogen associated with pulmonary MALT lymphoma: a metagenomics investigation
Authors: Borie Raphaël , Caro Valérie , Nunes Hilario , Kambouchner Marianne , Cazes Aurélie , Antoine Martine , Crestani Bruno , Leroy Karen , Copie-Bergman Christiane , Kwasiborski Aurelia , Hennequin Christophe , Vandenbogaert Mathias , Hourdel Véronique , Cadranel Jacques
Published: February 2021

Mucosa-associated lymphoid tissue (MALT) lymphoma is generally associated with chronic antigen stimulation: auto-antigens or of microbial origin. Only one study suggested association between Achromobacter xylosoxidans and pulmonary MALT lymphoma. We aimed to investigate the presence of virus or any infectious agents in pulmonary MALT lymphoma by using metagenomic next-generation sequencing (mNGS).

All lung samples were centrally reviewed. The t(11;18) (q21;q21) was evaluated by FISH analysis. The snap frozen large lung biopsies were analyzed by mNGS. After lung biopsies homogenization total nucleic acids (RNA and DNA) were extracted, amplified and classified according to their taxonomic assignment, after exclusion of host DNA.

We included 13 samples from pulmonary MALT lymphoma (mean age: 60.3 years, 7 women, 3 with auto-immune background) and 10 controls. The diagnosis of MALT lymphoma was confirmed for the 13 samples, 3 showed API2-MALT1 translocation (23%). No evidence of the presence of a specific pathogen was clearly identified in the group of patients with pulmonary MALT lymphoma. We identifiedA. xylosoxidans sequence in 4/13 patients and in 4/10 controls.

This study did not find evidence for a DNA or RNA virus, a fungi, a parasite or a bacteria associated with pulmonary MALT lymphoma either in the stroma or in tumor cells.
What is the prospect of indoleamine 2,3-dioxygenase 1 inhibition in cancer? Extrapolation from the past
Authors: Yao Yu , Liang Heng , Fang Xin , Zhang Shengnan , Xing Zikang , Shi Lei , Kuang Chunxiang , Seliger Barbara , Yang Qing
Published: February 2021

Indoleamine 2,3-dioxygenase 1 (IDO1), a monomeric heme-containing enzyme, catalyzes the first and rate-limiting step in the kynurenine pathway of tryptophan metabolism, which plays an important role in immunity and neuronal function. Its implication in different pathophysiologic processes including cancer and neurodegenerative diseases has inspired the development of IDO1 inhibitors in the past decades. However, the negative results of the phase III clinical trial of the would-be first-in-class IDO1 inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in patients with advanced malignant melanoma call for a better understanding of the role of IDO1 inhibition. In this review, the current status of the clinical development of IDO1 inhibitors will be introduced and the key pre-clinical and clinical data of epacadostat will be summarized. Moreover, based on the cautionary notes obtained from the clinical readout of epacadostat, strategies for the identification of reliable predictive biomarkers and pharmacodynamic markers as well as for the selection of the tumor types to be treated with IDO1inhibitors will be discussed.
Static compliance of the respiratory system in COVID-19 related ARDS: an international multicenter study
Authors:   for the COVADIS study group, Vandenbunder Benoit , Ehrmann Stephan , Piagnerelli Michael , Sauneuf Bertrand , Serck Nicolas , Soumagne Thibaud , Textoris Julien , Vinsonneau Christophe , Aissaoui Nadia , Blonz Gauthier , Carbutti Giuseppe , Courcelle Romain , D’hondt Alain , Gaudry Stephane , Higny Julien , Horlait Geoffroy , Hraiech Sami , Lefebvre Laurent , Lejeune Francois , Ly Andre , Lascarrou Jean-Baptiste , Grimaldi David
Published: February 2021

Background

Controversies exist on the nature of COVID-19 related acute respiratory distress syndrome (ARDS) in particular on the static compliance of the respiratory system (Crs). We aimed to analyze the association of Crs with outcome in COVID-19-associated ARDS, to ascertain its determinants and to describe its evolution at day-14.

Methods

In this observational multicenter cohort of patients with moderate to severe Covid-19 ARDS, Crs was measured at day-1 and day-14. Association between Crs or Crs/ideal body weight (IBW) and breathing without assistance at day-28 was analyzed with multivariable logistic regression. Determinants were ascertained by multivariable linear regression. Day-14 Crs was compared to day-1 Crs with paired t-test in patients still under controlled mechanical ventilation.

Results

The mean Crs in 372 patients was 37.6 ± 13 mL/cmH2O, similar to as in ARDS of other causes. Multivariate linear regression identified chronic hypertension, low PaO2/FiO2ratio, low PEEP, and low tidal volume as associated with lower Crs/IBW. After adjustment on confounders, nor Crs [OR 1.0 (CI 95% 0.98–1.02)] neither Crs/IBW [OR 0.63 (CI 95% 0.13–3.1)] were associated with the chance of breathing without assistance at day-28 whereas plateau pressure was [OR 0.93 (CI 95% 0.88–0.99)]. In a subset of 108 patients, day-14 Crs decreased compared to day-1 Crs (31.2 ± 14.4 mL/cmH2O vs 37.8 ± 11.4 mL/cmH2O,p < 0.001). The decrease in Crs was not associated with day-28 outcome.

Conclusion

In a large multicenter cohort of moderate to severe COVID-19 ARDS, mean Crs was decreased below 40 mL/cmH2O and was not associated with day-28 outcome. Crs decreased between day-1 and day-14 but the decrease was not associated with day-28 outcome.
Characterization of esophageal motor activity, gastroesophageal reflux, and evaluation of prokinetic effectiveness in mechanically ventilated critically ill patients: a high-resolution impedance manometry study
Authors: Balihar Karel , Kotyza Jan , Zdrhova Lucie , Kozeluhova Jana , Krcma Michal , Matejovic Martin
Published: February 2021

Background

Motility disorders of upper gastrointestinal tract are common in critical illness and associated with significant clinical consequences. However, detailed quantitative and qualitative analyses of esophageal motor functions are lacking. Therefore, we aimed to characterize the key features of esophageal motility functions using high-resolution impedance manometry (HRIM) and to evaluate an objective link between esophageal motor patterns, gastric emptying, and gastroesophageal reflux. We also studied the prokinetic effects of metoclopramide.

Methods

We prospectively performed HRIM for 16 critically ill hemodynamically stable patients. Patients were included if they had low gastric volume (LGV; < 100 mL/24 h, n = 8) or high gastric volume (HGV; > 500 mL/24 h, n = 8). The HRIM data were collected for 5 h with intravenous metoclopramide administration (10 mg) after the first 2 h.

Results

The findings were grossly abnormal for all critically ill patients. The esophageal contraction vigor was markedly increased, indicating prevailing hypercontractile esophagus. Ineffective propulsive force was observed for 73% of esophageal activities. Panesophageal pressurization was the most common pressurization pattern (64%). Gastroesophageal reflux predominantly occurred with transient lower esophageal sphincter relaxation. The common features of the LGV group were a hyperreactive pattern, esophagogastric outflow obstruction, and frequent reflux. Ineffective motility with reduced lower esophageal sphincter tone, and paradoxically fewer reflux episodes, was common in the HGV group. Metoclopramide administration reduced the number of esophageal activities but did not affect the number of reflux episodes in either group.

Conclusion

All critically ill patients had major esophageal motility abnormalities, and motility patterns varied according to gastric emptying status. Well-preserved gastric emptying and maintained esophagogastric barrier functions did not eliminate reflux. Metoclopramide failed to reduce the number of reflux episodes regardless of gastric emptying status.

Trial registration ISRCTN, ISRCTN14399966. Registered 3.9.2020, retrospectively registered. https://www.isrctn.com/ISRCTN14399966.
Carboxypeptidase B blocks ex vivo activation of the anaphylatoxin-neutrophil extracellular trap axis in neutrophils from COVID-19 patients
Authors: Zhang Yue , Han Kai , Du Chunjing , Li Rui , Liu Jingyuan , Zeng Hui , Zhu Liuluan , Li Ang
Published: February 2021

Background

Thrombosis and coagulopathy are highly prevalent in critically ill patients with COVID-19 and increase the risk of death. Immunothrombosis has recently been demonstrated to contribute to the thrombotic events in COVID-19 patients with coagulopathy. As the primary components of immunothrombosis, neutrophil extracellular traps (NETs) could be induced by complement cascade components and other proinflammatory mediators. We aimed to explore the clinical roles of NETs and the regulation of complement on the NET formation in COVID-19.

Methods

We recruited 135 COVID-19 patients and measured plasma levels of C5, C3, cell-free DNA and myeloperoxidase (MPO)-DNA. Besides, the formation of NETs was detected by immunofluorescent staining and the cytotoxicity to vascular endothelial HUVEC cells was evaluated by CCK-8 assay.

Results

We found that the plasma levels of complements C3 and MPO-DNA were positively related to coagulation indicator fibrin(-ogen) degradation products (C3: r = 0.300, p = 0.005; MPO-DNA: r = 0.316, p = 0.002) in COVID-19 patients. Besides, C3 was positively related to direct bilirubin (r = 0.303, p = 0.004) and total bilirubin (r = 0.304, p = 0.005), MPO-DNA was positively related to lactate dehydrogenase (r = 0.306, p = 0.003) and creatine kinase (r = 0.308, p = 0.004). By using anti-C3a and anti-C5a antibodies, we revealed that the complement component anaphylatoxins in the plasma of COVID-19 patients strongly induced NET formation. The pathological effect of the anaphylatoxin-NET axis on the damage of vascular endothelial cells could be relieved by recombinant carboxypeptidase B (CPB), a stable homolog of enzyme CPB2 which can degrade anaphylatoxins to inactive products.

Conclusions

Over-activation in anaphylatoxin-NET axis plays a pathological role in COVID-19. Early intervention in anaphylatoxins might help prevent thrombosis and disease progression in COVID-19 patients.
Using ActionADE to create information continuity to reduce re-exposures to harmful medications: study protocol for a randomized controlled trial
Authors: Hau Jeffrey P. , Brasher Penelope M. A. , Cragg Amber , Small Serena , Wickham Maeve , Hohl Corinne M.
Published: February 2021

Background

Repeat exposures to culprit medications are a common cause of preventable adverse drug events. Health information technologies have the potential to reduce repeat adverse drug events by improving information continuity. However, they rarely interoperate to ensure providers can view adverse drug events documented in other systems. We designed ActionADE to enable rapid documentation of adverse drug events and communication of standardized information across health sectors by integrating with legacy systems.

We will leverage ActionADE’s implementation to conduct two parallel, randomized trials: patients with adverse drug reactions in the main trial and those diagnosed with non-adherence in a secondary trial. Primary objective of the main trial is to evaluate the effects of providing information continuity about adverse drug reactions on culprit medication re-dispensations over 12 months. Primary objective of the secondary trial is to evaluate the effect of providing information continuity on adherence over 12 months.

Methods

We will conduct two parallel group, triple-blind randomized controlled trials in participating hospitals in British Columbia, Canada. We will enroll adults presenting to hospital with an adverse drug event to prescribed outpatient medication. Clinicians will document the adverse drug event in ActionADE. The software will use an algorithm to determine patient eligibility and allocate eligible patients to experimental or control. In the experimental arm, ActionADE will transmit information to PharmaNet, where adverse drug event information will be displayed in community pharmacies when re-dispensations are attempted. In the control arm, ActionADE will retain information in the local record. We will enroll 3600 adults with an adverse drug reaction into the main trial. The main trial’s primary outcome is re-dispensation of a culprit or same-class medication within 12 months; the secondary trial’s primary outcome will be adherence to culprit medication. Secondary outcomes include health services utilization and mortality.

Discussion

These studies have the potential to guide policy decisions and investments needed to drive health information technology integrations to prevent repeat adverse drug events. We present an example of how a health information technology implementation can be leveraged to conduct pragmatic randomized controlled trials.

Trial registration

ClinicalTrials.gov NCT04568668, NCT04574648. Registered on 1 October 2020.
Transitional care from skilled nursing facilities to home: study protocol for a stepped wedge cluster randomized trial
Authors: Toles M. , Colón-Emeric C. , Hanson L. C. , Naylor M. , Weinberger M. , Covington J. , Preisser J. S.
Published: February 2021

Background

Skilled nursing facility (SNF) patients are medically complex with multiple, advanced chronic conditions. They are dependent on caregivers and have experienced recent acute illnesses. Among SNF patients, the rate of mortality or acute care use is over 50% within 90 days of discharge, yet these patients and their caregivers often do not receive the quality of transitional care that prepares them to manage serious illnesses at home.

Methods

The study will test the efficacy of Connect-Home, a successfully piloted transitional care intervention targeting seriously ill SNF patients discharged to home and their caregivers. The study setting will be SNFs in North Carolina, USA, and, following discharge, in patients’ home. Using a stepped wedge cluster randomized trial design, six SNFs will transition at randomly assigned intervals from standard discharge planning to the Connect-Home intervention. The SNFs will contribute data for patients (N = 360) and their caregivers (N = 360), during both the standard discharge planning and Connect-Home time periods. Connect-Home is a two-step intervention: (a) SNF staff create an individualized Transition Plan of Care to manage the patient’s illness at home; and (b) a Connect-Home Activation RN visits the patient’s home to implement the written Transition Plan of Care. A key feature of the trial includes training of the SNF and Home Care Agency staff to complete the transition plan rather than using study interventionists. The primary outcomes will be patient preparedness for discharge and caregiver preparedness for caregiving role. With the proposed sample and using a two-sided test at the 5% significance level, we have 80% power to detect a 18% increase in the patient’s preparedness for discharge score. We will employ linear mixed models to compare observations between intervention and usual care periods to assess primary outcomes. Secondary outcomes include (a) patients’ quality of life, functional status, and days of acute care use and (b) caregivers’ burden and distress.

Discussion

Study results will determine the efficacy of an intervention using existing clinical staff to (a) improve transitional care for seriously ill SNF patients and their caregivers, (b) prevent avoidable days of acute care use in a population with persistent risks from chronic conditions, and (c) advance the science of transitional care within end-of-life and palliative care trajectories of SNF patients and their caregivers. While this study protocol was being implemented, the COVID-19 pandemic occurred and this protocol was revised to mitigate COVID-related risks of patients, their caregivers, SNF staff, and the study team. Thus, this paper includes additional material describing these modifications.

Trial registration

ClinicalTrials.gov NCT03810534. Registered on January 18, 2019.
Robotic natural orifice specimen extraction surgery versus traditional robotic-assisted surgery (NOTR) for patients with colorectal cancer: a study protocol for a randomized controlled trial
Authors: Luo Rui , Zheng Fangfang , Zhang Haobo , Zhu Weiquan , He Penghui , Liu Dongning
Published: February 2021

Background

Natural orifice specimen extraction surgery for colorectal cancer has been introduced in order to reduce the abdominal incision, demonstrating major development potential in minimally invasive surgery. We are conducting this randomized controlled trial to assess whether robotic NOSES is non-inferior to traditional robotic-assisted surgery for patients with colorectal cancer in terms of primary and secondary outcomes.

Method/design

Accordingly, a prospective, open-label, randomized controlled, parallel-group, multicenter, and non-inferiority trial will be conducted to discuss the safety and efficacy of robotic natural orifice extraction surgery compared to traditional robotic-assisted surgery. Here, 550 estimated participants will be enrolled to have 80% power to detect differences with a one-sided significance level of 0.025 in consideration of the non-inferiority margin of 10%. The primary outcome is the incidence of surgical complications, which will be classified using the Clavien-Dindo system.

Discussion

This trial is expected to reveal whether robotic NOSES is non-inferior to traditional robotic-assisted surgery, which is of great significance in regard to the development of robotic NOSES for patients with colorectal cancer in the minimally invasive era. Furthermore, robotic NOSES is expected to exhibit superiority to traditional robotic-assisted surgery in terms of both primary and secondary outcomes.

Trial registration

ClinicalTrials.govNCT04230772. Registered on January 15, 2020.
Correction to: Statistical analysis plan for management of hypertension and multiple risk factors to enhance cardiovascular health in Singapore: the SingHypertension pragmatic cluster randomized controlled trial
Authors:   for SingHypertension Study Group, Allen John C. , Halaand Benjamin , Shirore Rupesh M. , Jafar Tazeen H.
Published: February 2021

An amendment to this paper has been published and can be accessed via the original article.
Correction to: Combined whole cell wall analysis and streamlined in silico carbohydrate‑active enzyme discovery to improve biocatalytic conversion of agricultural crop residues
Authors: Tingley Jeffrey P. , Low Kristin E. , Xing Xiaohui , Abbott D. Wade
Published: February 2021

An amendment to this paper has been published and can be accessed via the original article.
Correction to: Host phylogeny matters: Examining sources of variation in infection risk by blood parasites across a tropical montane bird community in India
Authors: Gupta Pooja , Vishnudas C. K. , Robin V. V. , Dharmarajan Guha
Published: February 2021

An amendment to this paper has been published and can be accessed via the original article.
Cardinium symbiosis as a potential confounder of mtDNA based phylogeographic inference in Culicoides imicola (Diptera: Ceratopogonidae), a vector of veterinary viruses
Authors: Pilgrim Jack , Siozios Stefanos , Baylis Matthew , Venter Gert , Garros Claire , Hurst Gregory D. D.
Published: February 2021

Background

Culicoides imicola (Diptera: Ceratopogonidae) is an important Afrotropical and Palearctic vector of disease, transmitting viruses of animal health and economic significance including African horse sickness and bluetongue viruses. Maternally inherited symbiotic bacteria (endosymbionts) of arthropods can alter the frequency of COI (cytochrome c oxidase subunit I) mitochondrial haplotypes (mitotypes) in a population, masking the true patterns of host movement and gene flow. Thus, this study aimed to assess the mtDNA structure of C. imicola in relation to infection with Candidatus Cardinum hertigii (Bacteroides), a common endosymbiont of Culicoides spp.

Methods

Using haplotype network analysis, COI Sanger sequences from Cardinium-infected and -uninfected C. imicola individuals were first compared in a population from South Africa. The network was then extended to include mitotypes from a geographic range where Cardinium infection has previously been investigated.

Results

The mitotype network of the South African population demonstrated the presence of two broad mitotype groups. All Cardinium-infected specimens fell into one group (Fisher’s exact test, P = 0.00071) demonstrating a linkage disequilibrium between endosymbiont and mitochondria. Furthermore, by extending this haplotype network to include other C. imicola populations from the Mediterranean basin, we revealed mitotype variation between the Eastern and Western Mediterranean basins (EMB and WMB) mirrored Cardinium-infection heterogeneity.

Conclusions

These observations suggest that the linkage disequilibrium of Cardinium and mitochondria reflects endosymbiont gene flow within the Mediterranean basin but may not assist in elucidating host gene flow. Subsequently, we urge caution on the single usage of the COI marker to determine population structure and movement in C. imicola and instead suggest the complementary utilisation of additional molecular markers.

Graphical Abstract
Molecular characterization and serodiagnostic potential of Echinococcus granulosus hexokinase
Authors: Xin Qi , Yuan Miaomiao , Lv Wei , Li Huanping , Song Xiaoxia , Lu Jun , Jing Tao
Published: February 2021

Background

Cystic echinococcosis (CE), caused by the larval stage of Echinococcus granulosus (sensu stricto), is a life-threatening but neglected zoonosis. Glycolytic enzymes are crucial molecules for the survival and development of E. granulosus. The aim of this study was to investigate the molecular characterization, immunogenicity, tissue distribution and serodiagnostic potential of E. granulosus hexokinase (EgHK), the first key enzyme in the glycolytic pathway.

Methods

EgHK was cloned and expressed in Escherichia coli. Specific serum antibodies were evaluated in mice immunized with recombinant EgHK (rEgHK). The location of EgHK in the larval stage of E. granulosus was determined using fluorescence immunohistochemistry, and the potential of rEgHK as a diagnostic antigen was investigated in patients with CE using indirect enzyme-linked immunosorbent assay (ELISA).

Results

Recombinant EgHK could be identified in the sera of patients with CE and in mouse anti-rEgHK sera. High titers of specific immunoglobulin G were induced in mice after immunization with rEgHK. EgHK was mainly located in the tegument, suckers and hooklets of protoscoleces and in the germinal layer and laminated layer of the cyst wall. The sensitivity and specificity of the rEgHK-ELISA reached 91.3% (42/46) and 87.8% (43/49), respectively.

Conclusions

We have characterized the sequence, structure and location of EgHK and investigated the immunoreactivity, immunogenicity and serodiagnostic potential of rEgHK. Our results suggest that EgHK may be a promising candidate for the development of vaccines against E. granulosus and an effective antigen for the diagnosis of human CE.

Graphical Abstract
Impact of involving the community in entomological surveillance of Triatoma infestans (Klug, 1834) (Hemiptera, Triatominae) vectorial control
Authors: Abrahan L. , Cavallo M. J. , Amelotti I.
Published: February 2021

Background

Vectorial transmission is the principal path of infection by Trypanosoma cruzi, the parasite that causes Chagas disease. In Argentina, Triatoma infestans is the principal vector; therefore, vector control is the main strategy for the prevention of this illness. The Provincial Program of Chagas La Rioja (PPCHLR) carries out entomological evaluation of domiciliary units (DUs) and spraying of those where T. infestans is found. The lack of government funds has led to low visitation frequency by the PPCHLR, especially in areas with a low infestation rate, which are not prioritized. Therefore, seeking possible alternatives to complement control activities is necessary. Involving householders in entomological evaluation could be a control alternative. The major objective was to determine the cost of entomological evaluation with and without community participation.

Methods

For entomological evaluation without community participation, PPCHLR data collected in February 2017 over 359 DUs of the Castro Barros Department (CBD) were used. For entomological evaluation with community participation, 434 DUs of the same department were selected in November 2017. Each householder was trained in collecting insects, which were kept in labeled plastic bags, recovered after 2 weeks, and analyzed in the laboratory for the presence of T. cruzi. Using householders' collection data, a spatial scan statistic was used to detect clusters of different T. infestans infestations. Entomological evaluation costs with and without community participation related to the numbers of DUs visited, DUs evaluated, and DUs sprayed were calculated and compared between methodologies. In addition, the number of DUs evaluated of the DUs visited was compared.

Results

According to the results, the triatomines did not show evidence of T. cruzi infection. Spatial analysis detected heterogeneity of T. infestans infestation in the area. Costs related to the DUs visited, evaluated, and sprayed were lower with community participation (p < 0.05). In addition, more DUs were evaluated in relation to those visited and a greater surface area was covered with community participation.

Conclusion

Participation of the community in the infestation survey is an efficient complement to vertical control, allowing the spraying to be focused on infested houses and thus reducing the PPCHLR's costs and intervention times.

Graphical Abstract
Novel instructionless eye tracking tasks identify emotion recognition deficits in frontotemporal dementia
Authors: Russell Lucy L. , Greaves Caroline V. , Convery Rhian S. , Nicholas Jennifer , Warren Jason D. , Kaski Diego , Rohrer Jonathan D.
Published: February 2021

Background

Current tasks measuring social cognition are usually ‘pen and paper’ tasks, have ceiling effects and include complicated test instructions that may be difficult to understand for those with cognitive impairment. We therefore aimed to develop a set of simple, instructionless, quantitative, tasks of emotion recognition using the methodology of eye tracking, with the subsequent aim of assessing their utility in individuals with behavioural variant frontotemporal dementia (bvFTD).

Methods

Using the Eyelink 1000 Plus eye tracker, 18 bvFTD and 22 controls completed tasks of simple and complex emotion recognition that involved viewing four images (one target face (simple) or pair of eyes (complex) and the others non-target) followed by a target emotion word and lastly the original four images alongside the emotion word. A dwell time change score was then calculated as the main outcome measure by subtracting the percentage dwell time for the target image before the emotion word appeared away from the percentage dwell time for the target image after the emotion word appeared. All participants also underwent a standard cognitive battery and volumetric T1-weighted magnetic resonance imaging.

Results

Analysis using a mixed effects model showed that the average (standard deviation) mean dwell time change score in the target interest area was 35 (27)% for the control group compared with only 4 (18)% for the bvFTD group (p < 0.05) for the simple emotion recognition task, and 15 (26)% for the control group compared with only 2 (18)% for the bvFTD group (p < 0.05) for the complex emotion recognition task. Worse performance in the bvFTD group correlated with atrophy in the right ventromedial prefrontal and orbitofrontal cortices, brain regions previously implicated in social cognition.

Conclusions

In summary, eye tracking is a viable tool for assessing social cognition in individuals with bvFTD, being well-tolerated and able to overcome some of the problems associated with standard psychometric tasks.
Fixed drug eruption and anaphylaxis induced concurrently by erdosteine: a case report
Authors: Sim Da Woon , Yu Ji Eun , Koh Young-Il
Published: February 2021

Background

Erdosteine is used as a mucolytic agent and has a low incidence of adverse drug reactions, most of which are gastrointestinal and mild. Moreover, drug antigens rarely induce multiple simultaneous immunologic reactions. Only one previous case report has demonstrated hypersensitivity reaction induced by erdosteine. Here, we report a case of fixed drug eruption and anaphylaxis, which were concurrently induced by erdosteine. The association between the symptoms and erdosteine was proven by a drug provocation test.

Case presentation

A 35-year-old woman presented with recurrent angioedema and pruritic rash on the hands, which developed within 2 h following the administration of drugs, including erdosteine, for acute upper respiratory infection. Her rash was characterized by well-defined erythematous plaques, which recurred at the same site following the administration of the medications. She also experienced angioedema of the lips. Fixed drug eruption was considered after excluding other possible causes for the presented skin lesions. A drug provocation test confirmed that fixed drug eruption on both hands had occurred after administration of erdosteine, suggesting that erdosteine was the cause of the allergic reaction. However, she also experienced angioedema, isolated wheal, and laryngeal edema; thus, IgE-mediated type I hypersensitivity could also be concurrently occurring with the fixed drug eruption.

Conclusions

We report about a patient who was diagnosed with two different hypersensitivity reactions concurrently induced by erdosteine. We also demonstrate that patients may exhibit multiple simultaneous symptoms that usually arise from overlapping of different hypersensitivity mechanisms. Physicians should be aware of the possibility that some patients who are allergic to certain drugs could exhibit several symptoms caused by different mechanisms of hypersensitivity reactions simultaneously.
Abnormal electrophysiological phenotypes and sleep deficits in a mouse model of Angelman Syndrome
Authors: Copping N. A. , Silverman J. L.
Published: February 2021

Background

Angelman Syndrome (AS) is a rare genetic disorder characterized by impaired communication, motor and balance deficits, intellectual disabilities, recurring seizures and abnormal sleep patterns. The genetic cause of AS is neuronal-specific loss of expression ofUBE3A(ubiquitin-protein ligase E6-AP), an imprinted gene. Seizure and sleep disorders are highly prevalent (> 80%) in the AS population. The present experiments were designed to identify translational, neurophysiological outcome measures in a model of AS.

Methods

We used the exon-2 deletion mouse (Ube3a-del) on a C57BL/6J background to assess seizure, sleep and electrophysiological phenotypes. Seizure susceptibility has been reported inUbe3a-del mice with a variety of seizure induction methods. Here, we provoked seizures by a single high-dose injection of 80 mg/kg pentylenetetrazole. Novel experiments included the utilization of wireless telemetry devices to acquire global electroencephalogram (EEG) and neurophysiological data on electrographic seizures, power spectra, light–dark cycles, sleep stages and sleep spindles inUbe3a-del and WT mice.

Results

Ube3a-del mice exhibited reduced seizure threshold compared to WT. EEG illustrated thatUbe3a-del mice had increased epileptiform spiking activity and delta power, which corroborates findings from other laboratories and recapitulates clinical reports in AS. This is the first report to use a cortical surface-based recording by a wireless telemetry device over tethered/fixed head-mount depth recordings. Less time in both paradoxical and slow-wave sleep, longer latencies to paradoxical sleep stages and total less sleep time in Ube3a-del mice were observed compared to WT. For the first time, we detected fewer sleep spindles in the AS mouse model.

Limitations

This study was limited to the exon 2 deletion mouse model, and future work will investigate the rat model of AS, containing a completeUbe3adeletion and pair EEG with behavior.

Conclusions

Our data enhance rigor and translatability as our study provides important corroboration of previous reports on epileptiform and elevated delta power. For the first time we report neurophysiological phenotypes collected via translational methodology. Furthermore, this is the first report of reduced sleep spindles, a critical marker of memory consolidation during sleep, in an AS model. Our results are useful outcomes for therapeutic testing.