bluuebunny/crossref_metadata_2025 huggingface dataset:
Different signaling pathways involved in the anti-inflammatory effects of unfractionated heparin on lipopolysaccharide-stimulated human endothelial cells
Authors: Li Xu , Li Lu , Shi Yuequan , Yu Sihan , Ma Xiaochun
Published: February 2020

Background

There is a complex interplay between inflammatory response and coagulation in sepsis. Heparin is used as a recognized anticoagulant and possesses multiple biological properties that possibly affect sepsis. This study aimed to determine the possible signaling pathways involved in the anti-inflammatory effects of unfractionated heparin (UFH) on lipopolysaccharide (LPS)-stimulated human pulmonary microvascular endothelial cells (HPMECs).

Methods

HPMECs were transfected with siRNA targeting IκB-α. Cells were treated with UFH (0.01 U/ml~ 10 U/ml) 15 min before adding LPS (10 μg/ml). We detected the markers of systemic inflammatory response. Release of interleukin (IL)-6, IL-8 were evaluated at 3 h by ELISA and at 1 h by qRT-PCR. After 1 h, nuclear factor-κB (NF-κB) as well as phosphorylated inhibitor κB-α (IκB-α), signal transducer and activator of transcription-3 (STAT3) and ERK1/2, JNK, p38 mitogen-activated protein kinase (MAPK) expressions were evaluated by Western blot. DNA binding was conducted to further prove the activation of NF-κB pathway.

Results

In HPMECs, UFH obviously inhibited LPS-stimulated production of IL-6 and IL-8, especially in 10 U/ml. UFH inhibited LPS-induced phosphorylation of IκB-α, ERK1/2, JNK, p38 MAPK and STAT3. UFH also suppressed LPS-stimulated nuclear translocation of NF-κB. Importantly, transfection with siRNA targeting IκB-α induced more obvious inflammatory response. UFH suppressed cytokines production and phosphorylation of different signaling pathways in IκB-α silencing cells.

Conclusion

These results demonstrate that UFH exerts the anti-inflammatory effects on LPS-stimulated HPMECs by different signaling pathways.
Retrograde en bloc resection for non-muscle invasive bladder tumor can reduce the risk of seeding cancer cells into the peripheral circulation
Authors: Huang Haichao , Wang Tao , Ahmed Metages Gashaw , Zhu Lin , Yang Chaoyong , Li Wei , Wu Zhun , Wang Xuegang , Zhang Kaiyan , Xing Jinchun
Published: February 2020

Objective

To ascertain whether en bloc resection could reduce the risk of seeding cancer cells into the circulation during the resection of non-muscle invasive bladder cancer (NMIBC).

Methods

Patients with primary NMIBC were enrolled in this prospective study from October 2017 to May 2018. Patients were allocated to receive conventional transurethral resection of the bladder (TURB) or retrograde en bloc resection technique of the bladder tumor (RERBT). Blood samples (1 ml) for circulating tumor cell (CTC) enumeration were drawn from the peripheral vein prior to resection (PV1), immediately after resection of the tumor base (PV2), and at 12 h after resection (PV3). Intra-group comparisons of the changes in the number of CTCs identified among the PV1, PV2, and PV3 blood samples were performed in each group.

Results

A total of 21 patients (12 in the RERBT group and 9 in the TURB group) were recruited. For patients receiving TURB, the level of CTCs identified in PV3 was significantly higher than that in PV1 (p = 0.047). However, there was no significant difference in CTC counts before and after resection in the RERBT group.

Conclusion

RERBT did not increase the number of tumor cells in the bloodstream.
Evaluation of the cost-effectiveness of dexrazoxane for the prevention of anthracycline-related cardiotoxicity in children with sarcoma and haematologic malignancies: a European perspective
Authors: Dewilde Sarah , Carroll Kevin , Nivelle Emilia , Sawyer James
Published: February 2020

Background

Anthracycline-treated childhood cancer survivors are at higher risk of cardiotoxicity, especially with cumulative doses received above 250 mg/m2. Dexrazoxane is the only option recommended for cardiotoxicity prevention in high-risk patients supported by randomised trials but its cost-effectiveness in paediatric cancer patients has not been established.

Methods

A cost-effectiveness model applicable to different national healthcare system perspectives, which simulates 10,000 patients with either sarcoma or haematologic malignancies, based upon baseline characteristics including gender, age at diagnosis, cumulative anthracycline dose and exposure to chest irradiation. Risk equations for developing congestive heart failure and death from recurrence of the original cancer, secondary malignant neoplasms, cardiac death, pulmonary death, and death from other causes were derived from published literature. These are applied to the individual simulated patients and time until development of these events was determined. The treatment effect of dexrazoxane on the risk of CHF or death was based upon a meta-analysis of randomised and non-randomised dexrazoxane studies in each tumour type. The model includes country specific data for drug and administration costs, all aspects of heart failure diagnosis and management, and death due to different causes for each of the five countries considered; France, Germany, the UK, Italy, and Spain.

Results

Dexrazoxane treatment resulted in a mean QALY benefit across the five countries ranging from 0.530 to 0.683 per dexrazoxane-treated patient. Dexrazoxane was cost-effective for paediatric patients receiving anthracycline treatment for sarcoma and for haematologic malignancies, irrespective of the cumulative anthracycline dose received. The Incremental Cost Effectiveness Ratio (ICER) was favourable in all countries irrespective of anthracycline dose for both sarcoma and haematological malignancies (range: dominant to €2196). Individual ICER varied considerably according to country with dominance demonstrated for dexrazoxane in Spain and Italy and ratios approximately double the European average in the UK and Germany.

Conclusions

Dexrazoxane is a highly cost-effective therapy for the prevention of anthracycline cardiotoxicity in paediatric patients with sarcoma or haematological malignancies in Europe, irrespective of the healthcare system in which they receive treatment. These benefits persist when patients who receive doses of anthracycline > 250 mg/m2 are included in the model.
HIV-1 acquired drug resistance to integrase inhibitors in a cohort of antiretroviral therapy multi-experienced Mexican patients failing to raltegravir: a cross-sectional study
Authors: Orta-Resendiz Aurelio , Rodriguez-Diaz Roberto A. , Angulo-Medina Luis A. , Hernandez-Flores Mario , Soto-Ramirez Luis E.
Published: February 2020

Background

In resource-limited settings, multi-experienced HIV infected patients are often prescribed raltegravir for salvage therapy. Patients failing raltegravir-containing regimens require other drugs including other integrase inhibitors. In this context, real-life data about the resistance and cross-resistance pathways between integrase inhibitors is limited. The aim of this study was to investigate integrase resistance pathways in a cohort of Mexican multi-experienced patients failing of a raltegravir-containing salvage regimen.

Methods

Twenty-five plasma samples from subjects failing antiretroviral regimens which included raltegravir were obtained from various healthcare centres from 2009 to 2017 in Mexico. Antiretroviral history and demographics were collected. Samples were processed for integrase resistance genotyping testing by sequencing. The viral sequences were analysed with the Stanford HIV drug resistance database algorithm. Data was analysed with SPSS Statistics software.

Results

We found a mean viral load of 4.17 log10 c/mL (SD 1.11) at the time of virologic failure. Forty-eight percent of the samples were raltegravir resistant. The Y143R/H/C substitutions were the most prevalent, followed by the N155H, and both Q148H/K and G140S/A in the same proportion. The Q148 + G140 combination was found in (12%) of the samples. Cross-resistance to elvitegravir was found in 83.3% and in 18.2% for both dolutegravir and bictegravir. Thirteen samples (52%) were susceptible to the four integrase strand-transfer inhibitors.

Conclusions

Our findings suggest a high occurrence of resistance and cross-resistance to other integrase inhibitors among multi-experienced subjects failing raltegravir. We found a modestly lower proportion of cross-resistance to dolutegravir than data from clinical trials. Likely this drug could be used for salvage therapy. Explanations for the absence of mutations in half of the samples, other than reduced adherence, should be further investigated. Close surveillance is needed.
GEARing smart environments for pediatric motor rehabilitation
Authors: Kokkoni Elena , Mavroudi Effrosyni , Zehfroosh Ashkan , Galloway James C. , Vidal Renè , Heinz Jeffrey , Tanner Herbert G.
Published: February 2020

Background

There is a lack of early (infant) mobility rehabilitation approaches that incorporate natural and complex environments and have the potential to concurrently advance motor, cognitive, and social development. The Grounded Early Adaptive Rehabilitation (GEAR) system is a pediatric learning environment designed to provide motor interventions that are grounded in social theory and can be applied in early life. Within a perceptively complex and behaviorally natural setting, GEAR utilizes novel body-weight support technology and socially-assistive robots to both ease and encourage mobility in young children through play-based, child-robot interaction. This methodology article reports on the development and integration of the different system components and presents preliminary evidence on the feasibility of the system.

Methods

GEAR consists of the physical and cyber components. The physical component includes the playground equipment to enrich the environment, an open-area body weight support (BWS) device to assist children by partially counter-acting gravity, two mobile robots to engage children into motor activity through social interaction, and a synchronized camera network to monitor the sessions. The cyber component consists of the interface to collect human movement and video data, the algorithms to identify the children’s actions from the video stream, and the behavioral models for the child-robot interaction that suggest the most appropriate robot action in support of given motor training goals for the child. The feasibility of both components was assessed via preliminary testing. Three very young children (with and without Down syndrome) used the system in eight sessions within a 4-week period.

Results

All subjects completed the 8-session protocol, participated in all tasks involving the selected objects of the enriched environment, used the BWS device and interacted with the robots in all eight sessions. Action classification algorithms to identify early child behaviors in a complex naturalistic setting were tested and validated using the video data. Decision making algorithms specific to the type of interactions seen in the GEAR system were developed to be used for robot automation.

Conclusions

Preliminary results from this study support the feasibility of both the physical and cyber components of the GEAR system and demonstrate its potential for use in future studies to assess the effects on the co-development of the motor, cognitive, and social systems of very young children with mobility challenges.
Successfully transfected primary peripherally mobilized human CD34+ hematopoietic stem and progenitor cells (HSPCs) demonstrate increased susceptibility to retroviral infection
Authors: Sebrow Jeffrey , Goff Stephen P. , Griffin Daniel O.
Published: February 2020

Transfection, the process of introducing purified nucleic acids into cells, and viral transduction, viral-mediated nucleic acid transfer, are two commonly utilized techniques for gene delivery in the research setting. Transfection allows purified nucleic acid to be introduced into target cells through chemical-based techniques, nonchemical methods or particle-based methods, while viral transduction employs genomes or vectors based on adenoviruses, retroviruses (e.g. lentiviruses), adeno-associated viruses, or hybrid viruses. Transfected DNAs are often tested for potential effects on subsequent transduction, but it is not clear whether transfection itself rather than the particular nucleic acid being introduced might impact subsequent viral transfection. We observed a significant association between successfully transfected mobilized peripheral blood CD34+ human stem and progenitor cells (HSPCs) and permissiveness to subsequent lentiviral transduction, which was not evident in other cells such as 293 T cells and Jurkat cells. This association, apparently specific to CD34+ human stem and progenitor cells (HSPCs), is critical to both research and clinical applications as these cells are a frequent target of transfection and viral transduction owing to the durable nature of these cells in living systems. This finding may also present a significant opportunity to enhance the success of viral transduction for clinical applications.
Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage
Authors: Barna Lilla , Walter Fruzsina R. , Harazin András , Bocsik Alexandra , Kincses András , Tubak Vilmos , Jósvay Katalin , Zvara Ágnes , Campos-Bedolla Patricia , Deli Mária A.
Published: February 2020

Background

Excitotoxicity is a central pathological pathway in many neurological diseases with blood–brain barrier (BBB) dysfunction. Kainate, an exogenous excitotoxin, induces epilepsy and BBB damage in animal models, but the direct effect of kainate on brain endothelial cells has not been studied in detail. Our aim was to examine the direct effects of kainate on cultured cells of the BBB and to test three anti-inflammatory and antioxidant drugs used in clinical practice, simvastatin, edaravone and dexamethasone, to protect against kainate-induced changes.

Methods

Primary rat brain endothelial cell, pericyte and astroglia cultures were used to study cell viability by impedance measurement. BBB permeability was measured on a model made from the co-culture of the three cell types. The production of nitrogen monoxide and reactive oxygen species was followed by fluorescent probes. The mRNA expression of kainate receptors and nitric oxide synthases were studied by PCR.

Results

Kainate damaged brain endothelial cells and made the immunostaining of junctional proteins claudin-5 and zonula occludens-1 discontinuous at the cell border indicating the opening of the barrier. The permeability of the BBB model for marker molecules fluorescein and albumin and the production of nitric oxide in brain endothelial cells were increased by kainate. Simvastatin, edaravone and dexamethasone protected against the reduced cell viability, increased permeability and the morphological changes in cellular junctions caused by kainate. Dexamethasone attenuated the elevated nitric oxide production and decreased the inducible nitric oxide synthase (NOS2/iNOS) mRNA expression increased by kainate treatment.

Conclusion

Kainate directly damaged cultured brain endothelial cells. Simvastatin, edaravone and dexamethasone protected the BBB model against kainate-induced changes. Our results confirmed the potential clinical usefulness of these drugs to attenuate BBB damage.
Cerebrospinal fluid dynamics modulation by diet and cytokines in rats
Authors: Alimajstorovic Zerin , Pascual-Baixauli Ester , Hawkes Cheryl A. , Sharrack Basil , Loughlin A. Jane , Romero Ignacio A. , Preston Jane E.
Published: February 2020

Background

Idiopathic intracranial hypertension (IIH) is a neurological disorder characterised by raised cerebrospinal fluid (CSF) pressure in the absence of any intracranial pathology. IIH mainly affects women with obesity between the ages of 15 and 45. Two possible mechanisms that could explain the increased CSF pressure in IIH are excessive CSF production by the choroid plexus (CP) epithelium or impaired CSF drainage from the brain. However, the molecular mechanisms controlling these mechanisms in IIH remain to be determined.

Methods

In vivo ventriculo-cisternal perfusion (VCP) and variable rate infusion (VRI) techniques were used to assess changes in rates of CSF secretion and resistance to CSF drainage in female and male Wistar rats fed either a control (C) or high-fat (HF) diet (under anaesthesia with 20 μl/100 g medetomidine, 50 μl/100 g ketamine i.p). In addition, CSF secretion and drainage were assessed in female rats following treatment with inflammatory mediators known to be elevated in the CSF of IIH patients: C–C motif chemokine ligand 2 (CCL2), interleukin (IL)-17 (IL-17), IL-6, IL-1β, tumour necrosis factor-α (TNF-α), as well as glucocorticoid hydrocortisone (HC).

Results

Female rats fed the HF diet had greater CSF secretion compared to those on control diet (3.18 ± 0.12 μl/min HF, 1.49 ± 0.15 μl/min control). Increased CSF secretion was seen in both groups following HC treatment (by 132% in controls and 114% in HF) but only in control rats following TNF-α treatment (137% increase). The resistance to CSF drainage was not different between control and HF fed female rats (6.13 ± 0.44 mmH2O min/μl controls, and 7.09 ± 0.26 mmH2O min/μl HF). and when treated with CCL2, both groups displayed an increase in resistance to CSF drainage of 141% (controls) and 139% (HF) indicating lower levels of CSF drainage.

Conclusions

Weight loss and therapies targeting HC, TNF-α and CCL2, whether separately or in combination, may be beneficial to modulate rates of CSF secretion and/or resistance to CSF drainage pathways, both factors likely contributing to the raised intracranial pressure (ICP) observed in female IIH patients with obesity.
Combination of post-fascia iliaca compartment block and dexmedetomidine in pain and inflammation control after total hip arthroplasty for elder patients: a randomized control study
Authors: Liu Xiaofen , Hu Xianwen , Li Rui , Zhang Ye
Published: February 2020

Objective

This study aims to investigate the efficiency of fascia iliaca compartment block (FICB) combined with dexmedetomidine (DEX) in postoperative and inflammation management for elder patients after total hip arthroplasty.

Methods

The present randomized controlled study included a total of 119 elder patients who received total hip arthroplasty in our hospital from March 2016 to December 2018. These patients were divided into three groups: control group, patients received routine general anesthesia; FICB group, patients received additional FICB after surgery; and combined group, patients received both pre-treatment of DEX and post-treatment of fascia iliaca compartment block. The serum levels of interleukin (IL)-1β, IL-6, and C-reactive protein (CRP) were measured by ELISA. The visual analog scale (VAS) score was measured at 12, 24, 48, and 72 h after surgery, and the patient-controlled intravenous analgesia (PCIA) pressing time within 48 h after surgery was also recorded. The Pittsburgh sleep quality index (PSQI) was used to measure the sleep quality before and at 1 month after surgery.

Results

The VAS scores were significantly lower in patients in the combined group, when compared with the other two groups, at 12, 24, 48, and 72 h after surgery. In addition, the VAS scores at all time points were significantly lower in the FICB group than the control group. The PCIA pressing times were also remarkably lower in the combined group. At 4, 24, 48, and 72 h after surgery, the serum levels of these inflammatory factors were the lowest in the combined group, and the PSQI scores were significantly lower in the combined group, when compared with the other two groups, while the control group had the highest PSQI scores among the three groups. There was no severe side effects and significant difference observed.

Conclusion

FICB combined with DEX reduced the postoperative pain, improved the sleep condition, and decreased the serum levels of inflammatory factors after total hip arthroplasty.
Do storage solutions protect endothelial function of arterialized vein graft in an experimental rat model?
Authors: Fouquet Olivier , Blossier Jean-David , Dang Van Simon , Robert Pauline , Barbelivien Agnès , Pinaud Frédéric , Binuani Patrice , Eid Maroua , Henrion Daniel , Baufreton Christophe , Loufrani Laurent
Published: February 2020

Background

This study aims to compare the effects of storage solutions commonly used in coronary artery bypass grafting on the vascular reactivity in vein graft interposed in arterial position in syngeneic rats.

Methods

Twenty-seven male Lewis rats were sacrified to sample a vein graft implanted 6 weeks ago into abdominal aorta position. The vein grafts were inferior venae cavae initially pretreated with heparinized saline solution (HS) or autologous heparinized blood (AHB) or our referent solution, GALA. The endothelial functionality, the in situ Reactive Oxygen Species (ROS) levels and the histological characteristics were conducted from segments of arterialized vein graft.

Results

At 6 weeks, graft thrombosis occurred respectively in 22% of AHB group, 62.5% in the HS group and 82.5% in the GALA group. In each group, significative intimal hyperplasia was observed. After 6 weeks, an endothelium-remodeling layer associated with an increase of wall thickness was observed in each group. Endothelium-dependent tone was reduced in the vein graft regardless of the group. No difference was observed concerning the ROS in vein graft between the different groups. In distal aortic sections, ROS levels were increased in HS and GALA groups.

Conclusions

Storage solutions used in this experimental model of vein graft implanted in arterial position cause graft injury and a complete disappearance of vascular reactivity. GALA solution did not reduce intimal risk hyperplasia when the vein graft was exposed to arterial flow in a rat model.
Targeting NF-κB pathway for treating ulcerative colitis: comprehensive regulatory characteristics of Chinese medicines
Authors: Lu Peng-De , Zhao Yong-Hua
Published: February 2020

Nuclear factor-kappa B (NF-κB) is a kind of multi-functional nuclear transcription factor involved in regulating gene transcription to influence pathological evolution of inflammatory and immune diseases. Numerous literature evidence that NF-κB pathway plays an essential role in pathogenic development of ulcerative colitis (UC). UC is a chronic non-specific inflammatory bowel disease, and until now, therapeutic agents for UC including aminosalicylates, corticosteroids and immune inhibitors still cannot exert satisfied effects on patients. In recent years, Chinese medicines suggest the advantages of alleviating symptoms and signs, decreasing side-effects and recurrence, whose one of mechanisms is related to regulation of NF-κB pathway. In this review, we categorize Chinese medicines according to their traditional therapeutic functions, and summarize the characteristics of Chinese medicines targeting NF-κB pathway in UC treatment. It indicates that 85 kinds of Chinese medicines’ compounds and formulae can directly act on NF-κBp65; while 58 Chinese medicines’ ingredients and formulae indirectly suppress NF-κBp65 by regulation of its upstream or other related pathways. Moreover, by the analysis of Chinese medicines’ category based on their traditional functions, we conclude the category of dampness-drying and detoxificating medicine targeting NF-κB pathway accounts for primary status for amelioration of UC. Simultaneously, this review also contributes to the choices of Chinese medicine category and provides curative potential of Chinese medicines for clinical UC treatment.
Oral disorders in children with Prader-Willi syndrome: a case control study
Authors: Munné-Miralvés Carla , Brunet-Llobet Lluís , Cahuana-Cárdenas Abel , Torné-Durán Sergi , Miranda-Rius Jaume , Rivera-Baró Alejandro
Published: February 2020

Introduction

Prader-Willi Syndrome (PWS) is a genetic disorder caused by the lack of expression of certain paternal genes located on chromosome 15q11-q13. This anomaly causes cognitive, neurological and endocrine abnormalities, among which one of the most important is hyperphagia. The aim of this study was to assess the oral health of children with PWA and to establish preventive criteria.

Results

Thirty patients with PWS (mean age 10.2 years) and 30 age- and gender-matched controls were included in the study. Twenty-six patients with PWS(86.6%) followed dietary treatment prescribed by their endocrinologist. Individuals with PWS had a mean caries index of 53.3% and Decayed Missing Filled teeth (DMFT) index 2.5, and 53.3% had gingivitis, in the control group the respective figures were 43.3%, 0.93, and 60%. Only the DMFT index (p 0.017) presented significant differences. Regarding stimulated salivary secretion, patients with PWS presented a mean of 0.475 ml/min with a pH of 6.15, while controls presented a mean of 0.848 ml/min with a pH of 7.53; the differences between the groups were statistically significant in both cases (p 0.032 and p 0.0001 respectively). The population with PWS presented a higher plaque index (> 2) than their healthy peers, but the differences were not significant.

Conclusion

Pediatric patients with Prader-Willi syndrome have an increased risk of caries and gingivitis. The children with this syndrome have a decreased salivary flow and a more acidic salivary pH. In these patients, dental care is an essential part of their multidisciplinary medical treatment.
Lactate kinetics in ICU patients using a bolus of 13C-labeled lactate
Authors: Grip Jonathan , Falkenström Tobias , Promsin Panuwat , Wernerman Jan , Norberg Åke , Rooyackers Olav
Published: February 2020

Background

Plasma lactate concentrations and their trends over time are used for clinical prognosis, and to guide treatment, in critically ill patients. Although heavily relied upon for clinical decision-making, lactate kinetics of these patients is sparsely studied.

Aim

To establish and validate a feasible method to study lactate kinetics in critically ill patients.

Methods

Healthy volunteers (n = 6) received a bolus dose of 13C-labeled lactate (20 μmol/kg body weight), and 43 blood samples were drawn over 2 h to determine the decay in labeled lactate. Data was analyzed using non-compartmental modeling calculating rates of appearance (Ra) and clearance of lactate. The area under the curve (AUC) was calculated using a linear-up log-down trapezoidal approach with extrapolation beyond 120 min using the terminal slope to obtain the whole AUC. After evaluation, the same protocol was used in an unselected group of critically ill patients (n = 10).

Results

Ra for healthy volunteers and ICU patients were 12.8 ± 3.9 vs 22.7 ± 11.1 μmol/kg/min and metabolic clearance 1.56 ± 0.39 vs 1.12 ± 0.43 L/min, respectively. ICU patients with normal lactate concentrations showed kinetics very similar to healthy volunteers. Simulations showed that reducing the number of samples from 43 to 14 gave the same results. Our protocol yielded results on lactate kinetics very similar to previously published data using other techniques.

Conclusion

This simple and user-friendly protocol using an isotopically labeled bolus dose of lactate was accurate and feasible for studying lactate kinetics in critically ill ICU patients.

Trial registration

ANZCTR, ACTRN12617000626369, registered 8 March 2017. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372507&isReview=true
Emotion regulation training in the treatment of obesity in young adolescents: protocol for a randomized controlled trial
Authors: Debeuf Taaike , Verbeken Sandra , Boelens Elisa , Volkaert Brenda , Van Malderen Eva , Michels Nathalie , Braet Caroline
Published: February 2020

Background

The prevalence rates of childhood obesity are increasing. The current multidisciplinary treatments for (childhood) obesity are effective but only moderately and in the short term. A possible explanation for the onset and maintenance of childhood obesity is that it reflects a maladaptive mechanism for regulating high levels of stress and emotions. Therefore, the current RCT study aims to test the effectiveness of adding an emotion regulation training to care as usual (multidisciplinary obesity treatment) in young inpatients (10–14) involved in an obesity treatment program compared to care as usual alone.

The research model for this RCT study states that when high levels of stress are regulated in a maladaptive way, this can contribute to the development of obesity.

Methods

The current study will recruit 140 youngsters (10–14 years) who are involved in an inpatient multidisciplinary obesity treatment (MOT) program. After giving consent to participate in the study, youngsters will be randomly assigned, during consecutive waves, to one of two conditions: care as usual (receiving MOT) or intervention (receiving MOT in addition to emotion regulation training). The training itself consists of 12 weekly sessions, followed by a booster session after 3 and 5 months. The participants will be tested pretraining, post-training, and at 6 months’ follow-up. We hypothesize that, compared to the control condition, youngsters in the intervention condition will (1) use more adaptive emotion regulation strategies and (2) report less emotional eating, both primary outcome measures. Moreover, on the level of secondary outcome measures, we hypothesize that youngsters in the intervention condition, compared with the control condition, will (3) report better sleep quality, (4) undergo improved weight loss and weight loss maintenance, and (5) experience better long-term (6-months) psychological well-being.

Discussion

This study will add to both the scientific and clinical literature on the role of emotion regulation in the development and maintenance of different psychopathologies, as emotion regulation is a transdiagnostic factor.

Trial registration

The RCT study protocol is registered at ISRCTN Registry, with study ID “ISRCTN 83822934.” Registered on 13 December 2017.
Comparison of two techniques used in routine care for the treatment of inflammatory macular oedema, subconjunctival triamcinolone injection and intravitreal dexamethasone implant: medical and economic importance of this randomized controlled trial
Authors: Couret Chloé , Poinas Alexandra , Volteau Christelle , Riche Valery-Pierre , Le Lez Marie-Laure , Errera Marie-Hélène , Creuzot-Garcher Catherine , Baillif Stéphanie , Kodjikian Laurent , Ivan Catherine , Le Jumeau de Kergaradec Laurence Mathilde , Chiffoleau Anne , Jobert Alexandra , Jaulin Julie , Biron Laetitia , Hervouet Elisabeth , Weber Michel
Published: February 2020

Background

Whether they are injected peri- or intraocularly, corticosteroids are still essential tools in the therapeutic arsenal for treating inflammatory macular oedema. A few years ago, however, only triamcinolone acetonide was available to ophthalmologists. While this compound was initially developed for rheumatological or dermatological use, it has been increasingly deployed in ophthalmology, despite still being off-label. In 2011, the system for delivery of dexamethasone from a biodegradable, injectable implant into the vitreous cavity obtained approval for use in inflammatory macular oedema. While the efficacy and safety of triamcinolone in macular oedema, including inflammatory oedema, have already been studied, there are currently no publications on subconjunctival triamcinolone injections, which are simple, effective and well tolerated. To date, the dexamethasone 700 μg implant has been authorized for the treatment of noninfectious intermediate and posterior uveitis, but there have been no studies to evaluate the efficacy and safety of the different peri- and intraocular strategies, including the treatment of inflammatory macular oedema.

Methods

This protocol is therefore designed to compare the efficacy and safety of peri- and intraocular corticosteroid injections in the treatment of inflammatory macular oedema. In this ongoing study, 142 patients will be included, and the oedematous eye will be randomised to treatment with either subconjunctival triamcinolone injection or an intravitreal implant containing 700 μg dexamethasone. Follow-up is planned for 6 months with monthly visits. Each visit will include visual acuity measurement, a slit lamp examination, fundoscopy, intraocular pressure measurement, laser flare measurement (if available) and spectral domain optical coherence tomography.

Discussion

The results of this trial will have a real impact on public health if it is shown that a Kenacort retard® (i.e. triamcinolone) injection costing just €2.84 and performed in the physician’s office (with no additional overhead costs) is at least as effective as the dexamethasone 700 μg implant (Ozurdex®; costing approximately €960 with the injection performed in a dedicated room), with no increased side effects.

Trial registration

ClinicalTrials.gov, NCT02556424. Registered on 22 September 2015.
Machine learning analysis plans for randomised controlled trials: detecting treatment effect heterogeneity with strict control of type I error
Authors: Watson James A. , Holmes Chris C.
Published: February 2020

Background

Retrospective exploratory analyses of randomised controlled trials (RCTs) seeking to identify treatment effect heterogeneity (TEH) are prone to bias and false positives. Yet the desire to learn all we can from exhaustive data measurements on trial participants motivates the inclusion of such analyses within RCTs. Moreover, widespread advances in machine learning (ML) methods hold potential to utilise such data to identify subjects exhibiting heterogeneous treatment response.

Methods

We present a novel analysis strategy for detecting TEH in randomised data using ML methods, whilst ensuring proper control of the false positive discovery rate. Our approach uses random data partitioning with statistical or ML-based prediction on held-out data. This method can test for both crossover TEH (switch in optimal treatment) and non-crossover TEH (systematic variation in benefit across patients). The former is done via a two-sample hypothesis test measuring overall predictive performance. The latter is done via ‘stacking’ the ML predictors alongside a classical statistical model to formally test the added benefit of the ML algorithm. An adaptation of recent statistical theory allows for the construction of a valid aggregate p value. This testing strategy is independent of the choice of ML method.

Results

We demonstrate our approach with a re-analysis of the SEAQUAMAT trial, which compared quinine to artesunate for the treatment of severe malaria in Asian adults. We find no evidence for any subgroup who would benefit from a change in treatment from the current standard of care, artesunate, but strong evidence for significant TEH within the artesunate treatment group. In particular, we find that artesunate provides a differential benefit to patients with high numbers of circulating ring stage parasites.

Conclusions

ML analysis plans using computational notebooks (documents linked to a programming language that capture the model parameter settings, data processing choices, and evaluation criteria) along with version control can improve the robustness and transparency of RCT exploratory analyses. A data-partitioning algorithm allows researchers to apply the latest ML techniques safe in the knowledge that any declared associations are statistically significant at a user-defined level.
Sinako, a study on HIV competent households in South Africa: a cluster-randomised controlled trial protocol
Authors: Masquillier Caroline , Knight Lucia , Campbell Linda , Sematlane Neo , Delport Anton , Dube Tanyaradzwa , Wouters Edwin
Published: February 2020

Background

With 7.7 million South Africans currently infected with human immunodeficiency virus (HIV) and 4.8 million currently receiving antiretroviral treatment (ART), the epidemic represents a considerable burden for the country’s resource-limited health system. In response to the health and human resource shortages, task shifting to community health workers (CHWs) and empowering people living with HIV (PLWH) are integral parts of a sustainable ART strategy. Despite the success of the ART programme, South Africa still faces both prevention and treatment challenges. To tackle these challenges, future endeavours need to focus on the role played by the households of PLWH in mediating between the community and PLWH themselves. Building health-enabling “HIV competent” households with the capacity to actively stimulate lifestyles that foster health, offers a potential strategy to tackle South Africa’s HIV-related challenges. The aim of the “Sinako: Households and HIV” study is to investigate to what extent and how an intervention can increase HIV competence in PLWH and their households, and subsequently optimise the impact of CHW support on individual ART outcomes.

Methods

The “Sinako” study is a cluster-randomised controlled trial with two arms. In the control arm, CHWs offer a standard package of support to PLWH during home visits, focused on the individual. The intervention arm includes both a focus on the individual and the household to enable the patient to self-manage their treatment within an HIV competent household.

A longitudinal mixed methods design is adopted to analyse the data. For the quantitative data analysis, methods including latent cross-lagged modelling, multilevel modelling and logistic regression will be used. To assess the acceptability and feasibility of the intervention and to construct a comprehensive picture of the mechanisms underlying the impact on the household and the PLWH, qualitative data (in-depth interviews and focus group discussions) will be collected and analysed.

Discussion

Stimulating HIV competence in households could be a feasible and sustainable strategy to optimise the outcomes of CHW interventions and thus be important for HIV treatment interventions in resource-limited settings.

Trial registration

Pan African Clinical Trial Registry, PACTR201906476052236. Registered on 24 June 2019.
A randomised, double-blind, active placebo-controlled, parallel groups, dose-response study of scopolamine hydrobromide (4–6 μg/kg) in patients with major depressive disorder
Authors: Chen Joseph C. C. , Sumner Rachael L. , Krishnamurthy Naga Venkat , Hoeh Nicholas , Ayeni Hafis Adetokunbo , Singh Vikrant , Sundram Frederick , Campbell Douglas , Muthukumaraswamy Suresh
Published: February 2020

Background

Depressive disorders are a leading cause of disability, but current behavioural and pharmacological therapies have a slow onset of response, typically taking several weeks before achieving efficacy. Prior studies using triplicate intravenous scopolamine infusions have been shown to reduce depressive symptomologies within days compared to saline placebo infusions. However, several parameters of scopolamine’s potential antidepressant effect remain unknown, such as its dose–response profile and its washout period. There is also the question as to whether the previously reported antidepressant responses were confounded by unblinding effects due to the lack of an active placebo control. Glycopyrronium bromide was selected as placebo for this trial given it has similar antimuscarinic properties to scopolamine hydrobromide but an inability to cross the blood–brain barrier, thereby hypothetically mimicking only the peripheral effects of scopolamine.

Methods/Design

A parallel group trial of single intravenous scopolamine infusions at three doses (4, 5, and 6 μg/kg) along with one glycopyrronium bromide 4 μg/kg group will be administered to 40 participants with major depressive disorder in a 1:1:1:2 ratio, respectively. The primary outcome measure will be the Montgomery–Åsberg Depression Rating Scale (MADRS) administered at baseline, 4 hours, 1 day, 3 days, 1 week, 2 weeks, 4 weeks, and 6 weeks post-infusion to determine antidepressant efficacy. As a secondary measure, the Quick Inventory of Depressive Symptomatology will be administered alongside the MADRS to further track potential antidepressant responses. Other secondary measures include electroencephalography, blood samples, and Bowdle visual acuity scales recorded at baseline, 5, 10, 15, 20, 30, 60, 120, and 240 min post-infusion to determine the pharmacokinetic-pharmacodynamic profile of scopolamine in depressed participants.

Discussion

This trial contributes to the literature surrounding the efficacy of scopolamine as an antidepressant. Determining the dose–response profile and washout period of scopolamine’s antidepressant effect will also provide important information for designing and conducting crossover trials. The use of an active placebo is important to reduce potentially confounding expectancy effects.

Trial registration

The trial was registered in the Australian New Zealand Clinical Trials Registry (registration number ACTRN12619000569101). Registered on 11 April 2019.
Comparing methotrexate monotherapy with methotrexate plus leflunomide combination therapy in psoriatic arthritis: protocol of a randomized, placebo-controlled, double-blind clinical trial (COMPLETE-PsA)
Authors: Mulder Michelle L. M. , Vriezekolk Johanna E. , den Broeder Nathan , Mahler Elien A. M. , Helliwell Philip S. , van den Hoogen Frank H. J. , den Broeder Alfons A. , Wenink Mark H.
Published: February 2020

Background

Both methotrexate (MTX) and leflunomide (LEF) are registered and regularly prescribed as first-line treatments for the use in patients with psoriatic arthritis (PsA) and they are occasionally used in combination. However, evidence about their individual, and especially combined efficacy, in PsA is lacking. The aim of this study is to compare the effectiveness and safety of MTX and LEF combination therapy to MTX monotherapy in patients with PsA.

Methods

COMPLETE-PsA is a randomized, placebo-controlled, double-blind clinical trial. Disease-modifying antirheumatic drug (DMARD)-untreated patients (n = 78) with clinical diagnosis of active (i.e. ≥2 swollen joints) PsA will be randomized 1:1 (stratified for high disease activity, Psoriatic Arthritis Disease Activity Score [PASDAS] ≥ 5.4) to the combination or monotherapy. The intervention group receives MTX 25 mg (oral or subcutaneous) once weekly plus LEF 20 mg daily, and the control group receives the same but with placebo instead of LEF daily. Primary endpoint is between-group difference in PASDAS at 16 weeks, adjusted for baseline PASDAS. Key secondary parameters include between-group comparisons in change in Disease Activity in Psoriatic Arthritis (DAPSA) score, skin score, enthesitis score, dactylitis score, and swollen/tender joint count, as well as the proportion of patients fulfilling minimal disease activity (MDA), American College of Rheumatology (ACR) 20/50/70 response criteria at week 16. Furthermore, safety, function and quality of life (Health Assessment Questionnaire [HAQ], Psoriatic Arthritic Impact of Disease [PSAID], Short Form 12 [SF-12]) will be assessed.

Discussion

This is, to our knowledge, the first randomized, placebo-controlled, double-blind clinical trial assessing the effectiveness of MTX and LEF combination therapy in patients with PsA. The study will provide important information for treatment strategies and treatment recommendations.

Trial registration

Dutch Trial Register NTR7632 (3 December 2018). CMO NL66544.091.18 (19 November 2018).
Wolbachia strain wAlbB blocks replication of flaviviruses and alphaviruses in mosquito cell culture
Authors: Ekwudu O’mezie , Devine Gregor J. , Aaskov John G. , Frentiu Francesca D.
Published: February 2020

Background

Wolbachia pipientis are bacterial endosymbionts of arthropods currently being implemented as biocontrol agents to reduce the global burden of arboviral diseases. Some strains of Wolbachia, when introduced into Aedes aegypti mosquitoes, reduce or block the replication of RNA viruses pathogenic to humans. The wAlbB strain of Wolbachia was originally isolated from Aedes albopictus, and when transinfected into Ae. aegypti, persists in mosquitoes under high temperature conditions longer than other strains. The utility of wAlbB to block a broad spectrum of RNA viruses has received limited attention. Here we test the ability of wAlbB to reduce or block the replication of a range of Flavivirus and Alphavirus species in cell culture.

Methods

The C6/36 mosquito cell line was stably infected with the wAlbB strain using the shell-vial technique. The replication of dengue, West Nile and three strains of Zika (genus Flavivirus), and Ross River, Barmah Forest and Sindbis (genus Alphavirus) viruses was compared in wAlbB-infected cells with Wolbachia-free controls. Infectious virus titres were determined using either immunofocus or plaque assays. A general linear model was used to test for significant differences in replication between flaviviruses and alphaviruses.

Results

Titres of all viruses were significantly reduced in cell cultures infected with wAlbB versus Wolbachia-free controls. The magnitude of reduction in virus yields varied among virus species and, within species, also among the strains utilized.

Conclusion

Our results suggest that wAlbB infection of arthropods could be used to reduce transmission of a wide range of pathogenic RNA viruses.
Anthropometric, physiological characteristics and rugby-specific game skills of schoolboy players of different age categories and playing standards
Authors: Chiwaridzo Matthew , Ferguson Gillian D. , Smits-Engelsman Bouwien C. M.
Published: February 2020

Background

Rugby is increasingly gaining popularity among school-aged male junior players in countries hardly known for dominating international rugby, such as Zimbabwe. Given rugby combativeness, participating adolescents should possess qualities or skills commensurate with the physical demands of the sport for effective participation. This study investigated the independent and interactive effects of age category and playing standard on anthropometric, physiological characteristics and rugby-specific game skills among Zimbabwean athletes.

Methods

Two hundred and eight elite, sub-elite and non-rugby players competing at Under 16 and Under 19 age categories were assessed using the School Clinical Rugby Measure (SCRuM) test battery. Participants underwent height, sitting height, mass, skinfolds, speed, agility, upper-and-lower muscular strength and power, prolonged high-intensity intermittent running ability, tackling, passing and catching assessments in a cross-sectional experimental design.

Results

Age categories had significant main effect on all SCRuM test items except sum of seven skinfolds (p = 0.45, η2p = 0.003). Playing standard had significant main effects for all variables except height (p = 0.40, η2p = 0.01) and sum of seven skinfolds (p = 0.11, η2p = 0.02). Specifically, upper-and-lower muscular strength and power, prolonged high-intensity intermittent running ability, tackling, passing and catching improved with increasing playing standards. However, two-way analysis of variance only demonstrated significant interactions between the effects of age category and playing standards for vertical jump height (VJ) test, 2-kg medicine ball chest throw (2-kg MBCT) test, Yo-Yo intermittent recovery test level 1 (Yo-Yo IRT L1), and tackling and catching tests. Yo-Yo IRT L1, VJ, tackling and catching tests demonstrated greater discriminative ability among Under 16 s, whereas the 2-kg MBCT test showed better ability in Under 19 s.

Conclusion

All SCRuM variables except skinfolds improved with age, highlighting relative sensitivity in differentiating older from younger athletes. However, the discriminative ability by playing standards for VJ, 2-kg MBCT, Yo-Yo IRT L1, tackling and catching ability tests was age-dependent. These findings informs on general attribute development in junior rugby players with age and on specific players attributes in need of monitoring for attainment of elite status at U16 or U19 level.