bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying multilevel and multisectoral strategies to develop a Theory of Change for improving child and adolescent mental health services in a case-study district in South Africa
Authors: Babatunde Gbotemi B. , van Rensburg André Janse , Bhana Arvin , Petersen Inge 
Published: June 2022

Abstract
Background
The lack of child and adolescent mental health (CAMH) policies and implementation plans constitute major barriers to CAMH services in low resource settings. Engaging with on-the-ground stakeholders to identify possible contextually appropriate strategies for developing a CAMH collaborative system and inform CAMH plans and policies is important to ensure that resultant policies and plans are feasible and appropriate. Together with key stakeholders across multiple sectors, this study aims to (i) co-identify causal factors and potential strategies to overcome bottlenecks in one district in SA as a case study; and (ii) Co-develop a Theory of Change (ToC) for increasing access to CAMH services within the resource constraints of a remote resource-scarce district as a case study.

Methods
A participatory workshop was held with key stakeholders (n = 40) from the Departments of Health (DoH), Basic Education (DBE), and Social Development (DSD) and three community-based organisations offering CAMH services in the district. The stakeholders identified context-specific causal factors and possible strategies to address the bottlenecks in the workshop. All the factors identified in the workshop were compared and consolidated. A ToC map was developed based on the data obtained from the workshop. The ToC was further refined by conducting a follow-up virtual workshop with stakeholders (n = 15).

Results
Mapping out the strategies identified in the workshop facilitated the development of a ToC model for the resource-scarce context. Key multilevel and multisectoral task-sharing strategies emerged in support of the development of a collaborative system of care that includes the development of (i) community awareness programs and user-friendly CAMH psychoeducation and screening tools to strengthen mental health literacy and facilitate early identification at the community level; (ii) an intersectoral working group to facilitate intersectoral collaboration (iii) a functional district CAMH referral system, (iv) youth-friendly CAMH care packages.

Conclusions
In scarce-resource contexts, it is feasible to work collaboratively with key stakeholders across multiple sectors to identify feasible multilevel and multisectoral strategies that can be used to develop a ToC for improved access to CAMH services within a task-sharing approach.
Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial
Authors: Karakike Eleni , Scicluna Brendon P. , Roumpoutsou Maria , Mitrou Ioannis , Karampela Niki , Karageorgos Athanasios , Psaroulis Konstantinos , Massa Eleni , Pitsoulis Achillefs , Chaloulis Panagiotis , Pappa Evanthia , Schrijver Irene T. , Frantzeskaki Frantzeska , Lada Malvina , Dauby Nicolas , De Bels David , Floros Ioannis , Anisoglou Souzana , Antoniadou Eleni , Patrani Maria , Vlachogianni Glykeria , Mouloudi Eleni , Antoniadou Anastasia , Grimaldi David , Roger Thierry , Wiersinga W. Joost , Tsangaris Iraklis , Giamarellos-Bourboulis Evangelos J. 
Published: June 2022

Abstract
Background
Clarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome.

Methods
We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics.

Results
Fifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) − 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35–3.06]; P = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06–0.68]; P = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed.

Conclusions
Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration.
Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55.
Patient and health practitioner views and experiences of a cancer trial before and during COVID-19: qualitative study
Authors: Sherratt Frances C. , Fisher Peter , Mathieson Amy , Cherry Mary G. , Pettitt Andrew R. , Young Bridget 
Published: June 2022

Abstract
Background
Understanding patient and health practitioner perspectives on clinical trials can inform opportunities to enhance trial conduct and design, and therefore patient experience. Patients with haematological cancers have faced additional risk and uncertainty during the pandemic but it is unclear how they and practitioners have experienced cancer trials during this period. In the context of a haemato-oncology trial (PETReA), we compared patient and practitioner views and experiences of PETReA before and during COVID-19.

Methods
Qualitative study embedded within PETReA. Semi-structured interviews (N=41) with patients and practitioners from 16 NHS sites before (n=17) and during the first wave of COVID-19 (n=24). Analysis drew on the framework approach.

Results
Practitioners acknowledged the need for the trial to continue during the pandemic but their treatment preferences altered, becoming more pronounced for patients who had a favourable response to induction treatment, while staying unchanged for patients with a less favourable response. Practitioners commented that COVID-19 meant the evidence base for the trial arms was lacking or mixed, but that it likely increased the risks of maintenance treatment for patients with a favourable response to induction treatment. While only one participant interviewed withdrew from PETReA during the pandemic, others said they would consider withdrawing if information that they were at increased risk of severe illness from COVID-19 became available. During COVID-19, patients described less frequent contact with the trial team, which left some feeling less clear about their trial pathway. However, several described having in-depth, collaborative discussions with practitioners about the risks and benefits of randomisation in the context of COVID-19. Patients valued these discussions and were reassured by the emphasis practitioners placed on patients being free to withdraw if circumstances changed, and this helped patients feel comfortable about continuing in PETReA.

Conclusions
The findings point to ways trial communication can support patients to feel comfortable about continuing in a trial during uncertain times, including adopting a more in-depth, collaborative exploration of the risks and benefits of trial arms with patients and emphasising voluntariness. The results are relevant to trialists recruiting patients who are clinically extremely vulnerable or are at increased risk of poor COVID-19 outcomes despite being vaccinated.
Effect of negative pressure wound therapy after surgical removal of deep-seated high-malignant soft tissue sarcomas of the extremities and trunk wall—study protocol for a randomized controlled trial
Authors: Yilmaz Müjgan , Thorn Andrea , Sørensen Michala Skovlund , Jensen Claus Lindkær , Petersen Michael Mørk 
Published: June 2022

Abstract
Background
Sarcomas are a heterogeneous group of rare malignant tumors of mesenchymal origin in the musculoskeletal system. The main treatment is surgery often supplemented with pre-or postoperative radiotherapy.
A retrospective study by Bedi et al. indicated that negative pressure wound therapy (NPWT) reduced the risk of postoperative wound complications in patients treated with preoperative radiation followed by surgical tumor removal of lower extremity soft tissue sarcomas (STS), and the use of NPWT was not associated with an increased risk of local recurrence. Previous studies have shown that NPWT can reduce postoperative complications. STS surgeries are a high-risk procedure concerning wound complications.

Methods
Non-blinded single-center randomized controlled trial comparing NPWT versus conventional wound dressing and postoperative wound complications after surgical removal of deep-seated high-malignant STS of the extremities or trunk wall
Sample-size calculation: 154 STS patients (80% risk of avoiding type II error, 5% risk of type I error, and an 80% wound complication risk)
Block randomization of 8 into:
Group A: Conventional wound dressing
Group B: NPWT (PREVENA PLUS™ Incision Management System)
Inclusion criteria: Surgery for a deep-seated STS of an extremity or the trunk wall
Exclusion criteria: Age < 18 years, plastic surgery, low malignant/borderline STS, chemotherapy, preoperative radiotherapy, allergic/hypersensitive to acrylic adhesives or silver, unwilling/unable to provide informed consent, metastatic disease, and ischemic surgeries
Primary study endpoints were set as major wound complications defined by O’Sullivan et al. as a secondary surgery under anesthesia for wound repairs and wound management without secondary surgery within 4 months postoperatively.
Secondary study endpoints among others are Musculoskeletal Tumor Society Score (MSTS), Toronto Extremity Salvage Score (TESS), and European Quality of Life - 5 Dimensions (EQ-5D).
Approval from the Scientific Ethical Committee and the Data Protection Agency has been obtained, and the study is registered at clinicaltrial.gov.
This study did not apply for external funding.

Discussion
Many new medical devices and technical solutions are currently being introduced, and even though some documentation regarding the use of NPWT, e.g., in joint replacement surgery exist, it is also important to seek documentation for this treatment principle in STS surgery.

Trial registration
Registered at ClinicalTrials.gov NCT04960332 and approved on 11 July 2021
Enhanced production of hydroxy fatty acids in Arabidopsis seed through modification of multiple gene expression
Authors: Park Mid-Eum , Lee Kyeong-Ryeol , Chen Grace Q. , Kim Hyun Uk 
Published: June 2022

Abstract
Background
Castor (Ricinus communis L.) seeds contain unusual fatty acid, hydroxy fatty acid (HFA) used as a chemical feedstock for numerous industrial products. Castor cultivation is limited by the potent toxin ricin in its seeds and other poor agronomic traits, so it is advantageous to develop a suitable HFA-producing crop. Significant research efforts have been made to produce HFA in model Arabidopsis, but the level of HFA produced in transgenic Arabidopsis is much less than the level found in castor seeds which produce 90% HFA in seed oil.

Results
We designed a transformation construct that allowed co-expression of five essential castor genes (named pCam5) involved in HFA biosynthesis, including an oleate$$\Delta$$
Δ
12-hydroxylase (FAH12), diacylglycerol (DAG) acyltransferase 2 (DGAT2), phospholipid: DAG acyltransferase 1–2 (PDAT1-2), phosphatidylcholine (PC): DAG cholinephosphotransferase (PDCT) and Lyso-PC acyltransferase (LPCAT). Transgenic ArabidopsispCam5 lines produced HFA counting for 25% in seed oil. By knocking out ArabidopsisFatty acid elongase 1 (AtFAE1) in pCam5 using CRISPR/Cas9 technology, the resulted pCam5-atfae1 lines produced over 31% of HFA. Astonishingly, the pCam5-atfae1 line increased seed size, weight, and total oil per seed exceeding wild type by 40%. Seed germination, seedling growth and seed mucilage content of pCam5-atfae1 lines were not affected by the genetic modification.

Conclusions
Our results provide not only insights for future research uncovering mechanisms of HFA synthesis in seed, but also metabolic engineering strategies for generating safe HFA-producing crops.
Near-infrared light reduces β-amyloid-stimulated microglial toxicity and enhances survival of neurons: mechanisms of light therapy for Alzheimer’s disease
Authors: Stepanov Yurii V. , Golovynska Iuliia , Zhang Renlong , Golovynskyi Sergii , Stepanova Liudmyla I. , Gorbach Oleksandr , Dovbynchuk Taisa , Garmanchuk Liudmyla V. , Ohulchanskyy Tymish Y. , Qu Junle 
Published: June 2022

Abstract
Background
Low-intensity light can decelerate neurodegenerative disease progression and reduce amyloid β (Aβ) levels in the cortex, though the cellular and molecular mechanisms by which photobiomodulation (PBM) protects against neurodegeneration are still in the early stages. Microglia cells play a key role in the pathology of Alzheimer’s disease by causing chronic inflammation. We present new results concerning the PBM of both oxidative stress and microglia metabolism associated with the activation of metabolic processes by 808 nm near-infrared light.

Methods
The studies were carried out using healthy male mice to obtain the microglial cell suspension from the hippocampus. Oligomeric β-amyloid (1-42) was prepared and used to treat microglia cells. Light irradiation of cells was performed using diode lasers emitting at 808 nm (30 mW/cm2 for 5 min, resulting in a dose of 10 J/cm2). Mitochondrial membrane potential, ROS level studies, cell viability, apoptosis, and necrosis assays were performed using epifluorescence microscopy. Phagocytosis, nitric oxide and H2O2 production, arginase, and glucose 6-phosphate dehydrogenase activities were measured using standard assays. Cytokines, glucose, lactate, and ATP were measurements with ELISA. As our data were normally distributed, two-way ANOVA test was used.

Results
The light induces a metabolic shift from glycolysis to mitochondrial activity in pro-inflammatory microglia affected by oligomeric Aβ. Thereby, the level of anti-inflammatory microglia increases. This process is accompanied by a decrease in pro-inflammatory cytokines and an activation of phagocytosis. Light exposure decreases the Aβ-induced activity of glucose-6-phosphate dehydrogenase, an enzyme that regulates the rate of the pentose phosphate pathway, which activates nicotinamide adenine dinucleotide phosphate oxidases to further produce ROS. During co-cultivation of neurons with microglia, light prevents the death of neurons, which is caused by ROS produced by Aβ-altered microglia.

Conclusions
These original data clarify reasons for how PBM protects against neurodegeneration and support the use of light for therapeutic research in the treatment of Alzheimer’s disease.

Graphical Abstract
Drug-associated hyperammonaemia: a Bayesian analysis of the WHO Pharmacovigilance Database
Authors: Balcerac Alexander , Bihan Kevin , Lebrun-Vignes Bénédicte , Thabut Dominique , Salem Joe-Elie , Weiss Nicolas 
Published: June 2022

Abstract
Background
Hyperammonaemia is frequent in Intensive Care Unit patients. Some drugs have been described as associated with this condition, but there are no large-scale studies investigating this topic and most descriptions only consist of case-reports.

Methods
We performed a disproportionality analysis using VigiBase, the World Health Organization Pharmacovigilance Database, using the information component (IC). The IC compares observed and expected values to find associations between drugs and hyperammonaemia using disproportionate Bayesian reporting. An IC0.25 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. The main demographic and clinical features, confounding factors, and severity of cases have been recorded.

Results
We identified 71 drugs with a disproportionate reporting in 2924 cases of hyperammonaemia. Most of the suspected drugs could be categorised into 4 main therapeutic classes: oncologic drugs, anti-epileptic drugs, immunosuppressants and psychiatric drugs. The drugs most frequently involved were valproic acid, fluorouracil, topiramate, oxaliplatin and asparaginase. In addition to these molecules known to be responsible for hyperammonaemia, our study reported 60 drugs not previously identified as responsible for hyperammonaemia. These include recently marketed molecules including anti-epileptics such as cannabidiol, immunosuppressants such as basiliximab, and anti-angiogenics agents such as tyrosine kinase inhibitors (sunitinib, sorafenib, regorafenib, lenvatinib) and monoclonal antibodies (bevacizumab, ramucirumab). The severity of cases varies depending on the drug class involved and high mortality rates are present when hyperammonaemia occurs in patients receiving immunosuppressant and oncologic drugs.

Conclusions
This study constitutes the first large-scale study on drug-associated hyperammonaemia. This description may prove useful for clinicians in patients’ care as well as for trial design.

Graphical Abstract
DOA-guided source separation with direction-based initialization and time annotations using complex angular central Gaussian mixture models
Authors: Bohlender Alexander , Severen Lucas Van , Sterckx Jonathan , Madhu Nilesh 
Published: June 2022

AbstractBy means of spatial clustering and time-frequency masking, a mixture of multiple speakers and noise can be separated into the underlying signal components. The parameters of a model, such as a complex angular central Gaussian mixture model (cACGMM), can be determined based on the given signal mixture itself. Then, no misfit between training and testing conditions arises, as opposed to approaches that require labeled datasets to be trained. Whereas the separation can be performed in a completely unsupervised way, it may be beneficial to take advantage of a priori knowledge. The parameter estimation is sensitive to the initialization, and it is necessary to address the frequency permutation problem. In this paper, we therefore consider three techniques to overcome these limitations using direction of arrival (DOA) estimates. First, we propose an initialization with simple DOA-based masks. Secondly, we derive speaker specific time annotations from the same masks in order to constrain the cACGMM. Thirdly, we employ an approach where the mixture components are specific to each DOA instead of each speaker. We conduct experiments with sudden DOA changes, as well as a gradually moving speaker. The results demonstrate that particularly the DOA-based initialization is effective to overcome both of the described limitations. In this case, even methods based on normally unavailable oracle information are not observed to be more beneficial to the permutation resolution or the initialization. Lastly, we also show that the proposed DOA-guided source separation works quite robustly in the presence of adverse conditions and realistic DOA estimation errors.
Acupuncture mechanism studies employing task-based fMRI: a scoping review protocol
Authors: Yan Yan , Sheng Ru-ya , Wang Yu , Zhang Chun-hong 
Published: June 2022

Abstract
Background
Acupuncture is a widely used alternative and complementary therapy. Functional magnetic resonance imaging (fMRI) is an important technique to explore the underlying mechanism of acupuncture, and the task-based fMRI can reflect the instant effects or sustained effects of acupuncture in the brain. This scoping review aims to summarize the characteristics of acupuncture mechanism studies employing task-based fMRI and conclude a reference for future studies.

Methods/design
This review will follow the Guidance for Conducting Scoping Reviews. Eligible articles will be collected from 7 databases (PubMed, Embase, Cochrane, CNKI, WanFang, VIP, and CBM) with the related keywords such as “Acupuncture” and “fMRI”; those articles should be published from January 1, 2000, to December 31, 2021; and the language should be restricted in English or Chinese. Each research step will involve at least two reviewers. The PRISMA-ScR (Preferred Reporting Items for Systemic Reviews and Meta-Analysis Extension for Scoping Reviews) will be used to organize the review. Data will be extracted from the illegible articles, and findings will be presented in tables and narrative form. A descriptive qualitative approach to analysis will be conducted to form the scoping review.

Discussion
This review aims to clarify the extent of acupuncture mechanism studies employing task-based fMRI. It is supposed to make a critical evaluation or propose quality requirements for future studies by summarizing the objectives and designs of eligible studies. What is more, directional suggestions will be provided for further studies.

Scoping review registration
Open Science Framework https://osf.io/zjrdc/.
A mobile-based pregaming drinking prevention intervention for college students: study protocol for a randomized controlled trial
Authors: Pedersen Eric R. , Hummer Justin F. , Davis Jordan P. , Fitzke Reagan E. , Christie Nina C. , Witkiewitz Katie , Clapp John D. 
Published: June 2022

AbstractBackgroundPregaming is a high-drink context popular among college students that often leads to elevated blood alcohol levels and negative consequences. Over 15 years of research studies have demonstrated that pregaming represents one of the riskiest known behaviors among college students, yet no pregaming-specific interventions have been developed to help prevent this behavior. General brief interventions for students do not reduce pregaming behavior and may not be appropriate, as they do not help students develop skills unique to the pregaming context that could help them drink less. We developed a brief, mobile-based intervention that is proposed to prevent heavy drinking during pregaming for college students, with the ultimate goal that behavioral reductions in this risky practice will ultimately affect global drinking and prevent consequences.Methods/DesignThe intervention, Pregaming Awareness in College Environments (PACE), was developed by combining two innovations to facilitate behavior change: (1) a mobile-based application that increases accessibility, is easy and engaging to use, and broadens the reach of the intervention content and (2) personalized pregaming-specific intervention content with harm reduction and cognitive behavioral skills proven to be mechanisms preventing and reducing heavy drinking among college students. After a develop and beta-test phase, we propose to test the efficacy of PACE in a preliminary randomized controlled trial with 500 college students who pregame at least once per week. Pregaming, general drinking, and alcohol-related consequences outcomes will be examined in the immediate (2 weeks post-intervention) and short-terms (six and 14-week post-intervention). We will also evaluate moderator effects for age, sex, and heaviness of drinking to allow for more refined information for a planned larger test of the intervention to follow this initial trial of PACE.DiscussionThis pregaming intervention clinical trial, if found to be efficacious, will culminate with an easily-disseminated mobile-based intervention for college student drinkers. It has the potential to reach millions of college students, perhaps as a clinical tool used by college counseling centers as an adjunct to formal care or as a preventive tool for first-year students or other high-risk groups on campus.Trial registration: ClinicalTrials.gov Identifier NCT04016766.