bluuebunny/crossref_metadata_2025 huggingface dataset:
Thirty-year clinical outcomes after haematopoietic stem cell transplantation in neuronopathic Gaucher disease
Authors: Donald Aimee , Björkvall Cecilia Kämpe , Vellodi Ashok ,   GAUCHERITE Consortium, Cox Timothy M. , Hughes Derralyn , Jones Simon A. , Wynn Robert , Machaczka Maciej
Published: June 2022

Background

Neuronopathic Gaucher Disease (nGD) describes the condition of a subgroup of patients with the Lysosomal Storage Disorder (LSD), Gaucher disease with involvement of the central nervous system (CNS) which results from inherited deficiency of β-glucosylceramidase. Although systemic manifestations of disease are now corrected by augmentation with macrophage-targeted therapeutic enzyme (enzyme replacement therapy, ERT), neurological disease progresses unpredictably as a result of failure of therapeutic enzyme to cross the blood–brain barrier (BBB). Without therapy, the systemic and neurological effects of the disease progress and shorten life: investigators, principally in Sweden and the UK, pioneered bone marrow transplantation (BMT; Haematopoietic Stem Cell Transplantation HSCT) to supply healthy marrow-derived macrophages and other cells, to correct the peripheral disease. Here we report the first long-term follow-up (over 20 years in all cases) of nine patients in the UK and Sweden who underwent HSCT in the 1970s and 1980s. This retrospective, multicentre observational study was undertaken to determine whether there are neurological features of Gaucher disease that can be corrected by HSCT and the extent to which deterioration continues after the procedure. Since intravenous administration of ERT is approved for patients with the neuronopathic disease and ameliorates many of the important systemic manifestations but fails to correct the neurological features, we also consider the current therapeutic positioning of HSCT in this disorder.

Results

In the nine patients here reported, neurological disease continued to progress after transplantation, manifesting as seizures, cerebellar disease and abnormalities of tone and reflexes.

Conclusions

Although neurological disease progressed in this cohort of patients, there may be a future role for HSCT in the treatment of nGD. The procedure has the unique advantage of providing a life-long source of normally functioning macrophages in the bone marrow, and possibly other sites, after a single administration. HSCT moreover, clearly ameliorates systemic disease and this may be advantageous—especially where sustained provision of high-cost ERT cannot be guaranteed. Given the remaining unmet needs of patients with neuronopathic Gaucher disease and the greatly improved safety profile of the transplant procedure, HSCT could be considered to provide permanent correction of systemic disease, including bone disease not ameliorated by ERT, when combined with emerging therapies directed at the neurological manifestations of disease; this could include ex-vivo gene therapy approaches.
A deep phenotyping experience: up to date in management and diagnosis of Malan syndrome in a single center surveillance report
Authors: Macchiaiolo Marina , Panfili Filippo M. , Vecchio Davide , Gonfiantini Michaela V. , Cortellessa Fabiana , Caciolo Cristina , Zollino Marcella , Accadia Maria , Seri Marco , Chinali Marcello , Mammì Corrado , Tartaglia Marco , Bartuli Andrea , Alfieri Paolo , Priolo Manuela
Published: June 2022

Background

Malan syndrome (MALNS) is a recently described ultrarare syndrome lacking guidelines for diagnosis, management and monitoring of evolutive complications. Less than 90 patients are reported in the literature and limited clinical information are available to assure a proper health surveillance.

Results

A multidisciplinary team with high expertise in MALNS has been launched at the “Ospedale Pediatrico Bambino Gesù”, Rome, Italy. Sixteen Italian MALNS individuals with molecular confirmed clinical diagnosis of MALNS were enrolled in the program. For all patients, 1-year surveillance in a dedicated outpatient Clinic was attained. The expert panel group enrolled 16 patients and performed a deep phenotyping analysis directed to clinically profiling the disorder and performing critical revision of previously reported individuals. Some evolutive complications were also assessed. Previously unappreciated features (e.g., high risk of bone fractures in childhood, neurological/neurovegetative symptoms, noise sensitivity and Chiari malformation type 1) requiring active surveillance were identified. A second case of neoplasm was recorded. No major cardiovascular anomalies were noticed. An accurate clinical description of 9 new MALNS cases was provided.

Conclusions

Deep phenotyping has provided a more accurate characterization of the main clinical features of MALNS and allows broadening the spectrum of disease. A minimal dataset of clinical evaluations and follow-up timeline has been proposed for proper management of patients affected by this ultrarare disorder.
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

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

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

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

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

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

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

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

By 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

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

Background

Pregaming 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/Design

The 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.

Discussion

This 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.
Active surveillance of carbapenem-resistant gram-negative bacteria to guide antibiotic therapy: a single-center prospective observational study
Authors: Liang Qiqiang , Chen Juan , Xu Yongshan , Chen Yibing , Huang Man
Published: June 2022

Background

Carbapenem-resistant gram-negative bacteria (CRGNB) have become a public health concern worldwide. The risk factors associated with CRGNB infection after colonization are unknown, nor is the optimal timing of antibiotic treatment, warranting further investigation.

Methods

A 4-year single-center prospective observational study was conducted. CRGNB-colonized patients were incorporated on admission into our observation cohort for an active surveillance culture program, and analysis of risk factors associated with infections after CRGNB colonization was performed. We divided patients into empirical antibiotic therapy groups and standard antibiotic therapy groups according to whether antibiotics were used before or after cultures yielded a result to explore the relationship between the timing of antibiotics and clinical efficacy.

Results

152 out of 451 CRGNB-colonized patients in the prospective observational cohort developed CRGNB infection. The risk factors associated with CRGNB infection after colonization included CRKP (P < 0.001, OR = 3.27) and CRPA (P < 0.001, OR = 2.97) colonization, history of carbapenems use (P < 0.001, OR = 5.48), and immunocompromise (P < 0.001, OR = 7.07). There were 88 infected patients in the empirical antibiotic therapy groups and 64 in standard antibiotic therapy groups. The mortality was lower in empirical therapy groups than standard therapy groups (17.0% vs. 37.5%, P = 0.004, OR = 0.32).

Conclusions

CRGNB colonized patients who are prone to infection have some high-risk factors included CRKP and CRPA colonization, immunocompromise, and prior carbapenems use. Once infection occurs in CRGNB-colonized patients, early use of effective antibiotics may be associated with reduced mortality, but more studies are needed.
Geographical distribution and genetic diversity of Bradyrhizobium spp. isolated from Korean soybean root nodules
Authors: Kim Ye-eun , Shin Hanseob , Yang Youri , Hur Hor-Gil
Published: June 2022

This study investigated the distribution and genetic diversity of the indigenous Bradyrhizobium spp. in the Korean agricultural field. A total of 254 Bradyrhizobium strains were isolated from 97 soybean samples (9 cultivars) collected in 14 regions. B. elkanii dominated in the southern regions, while B. diazoefficiens dominated in most central and northern regions. Through non-parametric multidimensional scaling (NMDS) analysis, we confirmed the possibility that environmental factors such as annual average temperature and soybean cultivars might affect the distribution of Bradyrhizobium spp. in some regions. The DNA fingerprint using repetitive DNA sequences showed the genetic diversity among the Bradyrhizobium strains isolated from the different regions. Clustering the strains based on the genetic diversity indicated that Bradyrhizobium spp. grouped into different clusters depending on geographic location. This study suggests that the Korean indigenous Bradyrhizobium spp. distribute differently according to the geographical feature, and the high genetic diversity of each strain attribute to the geographic location.
Patterns of human social contact and mask wearing in high-risk groups in China
Authors: Zheng Bo , Zhu Wenlong , Pan Jinhua , Wang Weibing
Published: June 2022

Background

The pandemic of coronavirus disease 2019 (COVID-19) has changed human behavior in areas such as contact patterns and mask-wearing frequency. Exploring human–human contact patterns and mask-wearing habits in high-risk groups is an essential step in fully understanding the transmission of respiratory infection-based diseases. This study had aims to quantify local human–human (H–H) contacts in high-risk groups in representative provinces of China and to explore the occupation-specific assortativity and heterogeneity of social contacts.

Methods

Delivery workers, medical workers, preschoolers, and students from Qinghai, Shanghai, and Zhejiang were recruited to complete an online questionnaire that queried general information, logged contacts, and assessed the willingness to wear a mask in different settings. The “group contact” was defined as contact with a group at least 20 individuals. The numbers of contacts across different characteristics were assessed and age-specific contact matrices were established. A generalized additive mixed model was used to analyze the associations between the number of individual contacts and several characteristics. The factors influencing the frequency of mask wearing were evaluated with a logistic regression model.

Results

A total of 611,287 contacts were reported by 15,635 participants. The frequency of daily individual contacts averaged 3.14 (95% confidence interval: 3.13–3.15) people per day, while that of group contacts was 37.90 (95% CI: 37.20–38.70). Skin-to-skin contact and long-duration contact were more likely to occur at home or among family members. Contact matrices of students were the most assortative (all contacts q-index = 0.899, 95% CI: 0.894–0.904). Participants with larger household sizes reported having more contacts. Higher household income per capita was significantly associated with a greater number of contacts among preschoolers (P50,000–99,999 = 0.033) and students (P10,000–29,999 = 0.017). In each of the public places, the frequency of mask wearing was highest for delivery workers. For preschoolers and students with more contacts, the proportion of those who reported always wearing masks was lower (P < 0.05) in schools/workplaces and public transportation than preschoolers and students with fewer contacts.

Conclusions

Contact screening efforts should be concentrated in the home, school, and workplace after an outbreak of an epidemic, as more than 75% of all contacts, on average, will be found in such places. Efforts should be made to improve the mask-wearing rate and age-specific health promotion measures aimed at reducing transmission for the younger demographic. Age-stratified and occupation-specific social contact research in high-risk groups could help inform policy-making decisions during the post-relaxation period of the COVID-19 pandemic.

Graphical Abstract
Promoting interactive skills and mind-mindedness among early childcare professionals: study protocol for a randomized wait-list controlled trial comparing the Circle of Security approach with care as usual in center-based childcare (the SECURE project)
Authors: Smith-Nielsen Johanne , Wendelboe Katrine Isabella , Mohr Julie Elisabeth Warberg , Væver Mette Skovgaard , Pontoppidan Maiken , Helmerhorst Katrien , Egmose Ida
Published: June 2022

Background

In countries where the majority of young children are enrolled in professional childcare, the childcare setting constitutes an important part of children’s caregiving environment. Research consistently shows that particularly the quality of the daily interactions and relationship between young children and their professional caregivers have long-term effects on a range of developmental child outcomes. Therefore, professional caregivers’ capacity for establishing high quality interactions with the children in their care is an important target of intervention.

Methods

A prospective, parallel, cluster-randomized wait-list controlled trial is used to test the efficacy of the attachment- and mentalization theory informed Circle of Security (COS) approach adapted to the childcare setting (COS-Classroom) on caregiver interactive skills and mind-mindedness. Participants are professional caregivers of children aged 0–2.9 years working in center-based childcare in Denmark. Approximately 31 childcare centers, corresponding to an estimated 113 caregivers, are expected to participate. The primary outcome is caregiver Sensitive responsiveness measured with the Caregiver Interactive Profile Scales (CIP-scales). Secondary outcomes include caregiver Mind-mindedness, the five remaining CIP-scales (Respect for autonomy, Structure and limit setting, Verbal communication, Developmental stimulation, and Fostering positive peer interactions), and caregivers’ resources to cope with work-related stress. Data on structural factors (e.g., staff stability, caregiver-child ratio, and level of pre-service education), caregiver attachment style, acceptability and feasibility of the COS-C together with qualitative data on how the participants experience the COS-C is additionally collected to investigate moderating and confounding effects.

Discussion

Examining the effectiveness of the COS-C in center-based childcare contributes to the knowledge of evidence-based intervention programs and can potentially improve the caregiver quality early childcare.

Trial registration: ClinicalTrials.gov: NCT04654533. Prospectively registered December 4, 2020, https://clinicaltrials.gov/ct2/show/NCT04654533.
Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations
Authors: Jitobaom Kunlakanya , Boonarkart Chompunuch , Manopwisedjaroen Suwimon , Punyadee Nuntaya , Borwornpinyo Suparerk , Thitithanyanont Arunee , Avirutnan Panisadee , Auewarakul Prasert
Published: June 2022

Background

COVID-19 pandemic has claimed millions of lives and devastated the health service system, livelihood, and economy in many countries worldwide. Despite the vaccination programs in many countries, the spread of the pandemic continues, and effective treatment is still urgently needed. Although some antiviral drugs have been shown to be effective, they are not widely available. Repurposing of anti-parasitic drugs with in vitro anti-SARS-CoV-2 activity is a promising approach being tested in many clinical trials. Combination of these drugs is a plausible way to enhance their effectiveness.

Methods

The in vitro anti-SARS-CoV-2 activity of combinations of niclosamide, ivermectin and chloroquine were evaluated in Vero E6 and lung epithelial cells, Calu-3.

Results

All the two-drug combinations showed higher potency resulting in up to 4-fold reduction in the half maximal inhibitory concentration (IC50) values compared to individual drugs. Among these combinations, niclosamide-ivermectin achieved the highest inhibitory level of over 99%. Combination synergy analysis showed niclosamide-ivermectin combination to have the best synergy score with a mean Loewe synergy score of 4.28 and a peak synergy score of 24.6 in Vero E6 cells and a mean Loewe synergy score of 3.82 and a peak synergy score of 10.86 in Calu-3 cells.

Conclusions

The present study demonstrated the benefit of drug combinations on anti-SARS-CoV-2 activity. Niclosamide and ivermectin showed the best synergistic profile and should be further tested in clinical trials.
Nonlinear triggering process of whistler-mode emissions in a homogeneous magnetic field
Authors: Fujiwara Yuya , Nogi Takeshi , Omura Yoshiharu
Published: June 2022

We perform an electromagnetic particle simulation of triggered emissions in a uniform magnetic field for understanding of nonlinear wave–particle interaction in the vicinity of the magnetic equator. A finite length of a whistler-mode triggering wave packet with a constant frequency is injected by oscillating an external current at the equator. We find that the first subpacket of triggered emissions is generated in the homogeneous magnetic field. By analyzing resonant currents and resonant electron dynamics in the simulation, we find that the formation of an electron hole in a velocity phase space results in resonant currents, and the currents cause wave amplification and frequency increase. We obtain the interaction time of counter-streaming resonant electrons in a triggering wave packet with a finite width. By changing the duration time of the triggering pulse, we evaluate the interaction time necessary for formation of an electron hole. We conduct 4 runs with different duration times of the triggering pulse, 980, 230, 105, 40 $$\Omega _e^{-1}$$

Ω
e

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1

, which correspond to cases with interaction times, 370%, 86%, 39%, and 15% of the nonlinear trapping period, respectively. We find generation of triggered emissions in the three cases of 370%, 86%, and 39%, which agrees with the conventional nonlinear model that the nonlinear transition time, which is necessary for formation of resonant currents, is about a quarter of the nonlinear trapping period.

Graphic Abstract
Screening and addressing social needs of children and families enrolled in a pediatric weight management program: a protocol for a pilot randomized controlled trial
Authors: Wahi Gita , Marjerrison Stacey , Gutierrez Carline , Krasevich Kimberley , Morrison Katherine M. , Thabane Lehana
Published: June 2022

Background

There is a paucity of evidence to support interventions that address the social needs of children and families with chronic medical conditions. The primary objective of this pilot randomized controlled trial (RCT) is to assess the feasibility of an intervention that screens for and addresses the social needs of children and families enrolled in a pediatric weight management clinic.

Method

We will conduct a single-center, pilot RCT of 40 families with children enrolled in a pediatric weight management program at a tertiary children’s hospital in Ontario, Canada. Families who are experiencing unmet social needs will be randomized to either a community navigator or self-navigation of community resources. The primary feasibility outcomes and criteria for success include the following: (1) recruitment rates, will be successful if 80% of our target sample is met in the 6 months of recruitment; (2) uptake of intervention, will be considered successful if > 80% of families complete the intervention; and (3) follow-up of participants, will be considered successful if > 90% of participants complete all the study visits. The secondary outcomes include estimating the preliminary effects on body mass index, body composition, and quality of life at 6 months. The analysis of feasibility outcomes will be based on descriptive statistics, and analysis of secondary clinical outcomes will be reported as estimates of effect. We will not perform tests of significance since these analyses are purely exploratory.

Discussion

This study is important because it will aim to improve the treatment of pediatric obesity by testing the feasibility of an intervention that addresses unmet social needs.

Trial registration

ClinicalTrias.gov: NCT04711707 (Registered January 13, 2021).
Constructional network at work in second language acquisition
Authors: Jiang Canzhong , Wen Xu
Published: June 2022

Second Language Acquisition (SLA) has benefited quite a lot from Construction Grammar. Most of the previous SLA researches adopting a constructionist approach have been primarily engaged in issues pertinent to the relevance of construction in SLA, the process of second language (L2) construction learning, and factors affecting L2 construction learning. This paper distinguishes itself from previous research by embarking on a new direction in the constructionist approach to SLA from the perspective of the constructional network. Specifically, it deals with how constructional network works in SLA and argues that L2 constructional network bears the imprint of and is reconstructed from L2 learners’ L1 constructional network. The constructional network works in SLA in at least two ways which are manifested in the motivating function of vertical links in L2 learners’ acquisition of schematic and complex constructions and the facilitative or inhibitive effect of horizontal links in L2 construction learning. Admittedly, our description of how the constructional network works in SLA is precursory and nonexclusive, and some general and specific issues are raised for future research.
Coumarin and fatty alcohol from root bark of strychnos innocua (delile): isolation, characterization and in silico molecular docking studies
Authors: Uttu Ahmed Jibrin , Sallau Muhammad Sani , Iyun Ogunkemi Risikat Agbeke , Ibrahim Hamisu
Published: June 2022

Background

Coumarin and fatty alcohol are abundant in nature, particularly in plants, and have been reported to have therapeutic uses. Strychnos innocua (Loganiaceae family) is commonly utilized for medicinal purposes in several African countries. Ethyl acetate extract of the plant (root bark) was subjected to chromatography separation, leading to the isolation of Umbelliferone (1) and 2,13-octadecadien-1-ol (2).

Results

Their structures were verified using mass spectrometry (MS) and nuclear magnetic resonance (NMR) and then compared with published data. This is the first time these compounds (1 and 2) have been isolated from S. innocua root bark. In the molecular docking analysis, the binding scores of the compounds (1 and 2) with the binding sites of Staphylococcus aureus pyruvate carboxylase (PDB: 3HO8) and Pseudomonas aeruginosa virulence factor regulator (PDB: 2OZ6) were − 5.6 and − 4.7 kcal/mol, and − 6.9 and − 5.7 kcal/mol, respectively. These were compared with ciprofloxacin (standard drug), which had docking scores of -6.6 and -8.7 kcal/mol, respectively.

Conclusions

In conclusion, this study established the rich presence of Umbelliferone and 2,13-octadecadien-1-ol in the plant root bark, and their docking studies revealed moderate binding potential with the binding sites of S. aureus and P. aeruginosa.

Graphical Abstract
Quantitative analysis of retained austenite in Nb added Fe-based alloy
Authors: Ko Kwang Kyu , Jang Jin Ho , Tiwari Saurabh , Bae Hyo Ju , Sung Hyo Kyung , Kim Jung Gi , Seol Jae Bok
Published: June 2022

The use of Pipelines for long-distance transportation of crude oil, natural gas and similar applications is increasing and has pivotal importance in recent times. High specific strength plays a crucial role in improving transport efficiency through increased pressure and improved laying efficiency through reduced diameter and weight of line pipes. TRIP-based high-strength and high-ductility alloys comprise a mixture of ferrite, bainite, and retained austenite that provide excellent mechanical properties such as dimensional stability, fatigue strength, and impact toughness. This study performs microstructure analysis using both Nital etching and LePera etching methods. At the time of Nital etching, it is difficult to distinctly observe second phase. However, using LePera etching conditions it is possible to distinctly measure the M/A phase and ferrite matrix. The fraction measurement was done using OM and SEM images which give similar results for the average volume fraction of the phases. Although it is possible to distinguish the M/A phase from the SEM image of the sample subjected to LePera etching. However, using Nital etching is nearly impossible. Nital etching is good at specific phase analysis than LePera etching when using SEM images.
Mixed connective tissue disease: presenting as trigeminal neuralgia
Authors: Jeemon Gladwin , Neha T. H.
Published: June 2022

Connective tissue diseases (autoimmune rheumatic diseases) are a group of disorders of unknown etiology. The term mixed connective tissue (MCTD) is used when two or more autoimmune diseases occur in the same individual simultaneously, for example, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis in various combinations. Here, we report a case of MCTD presenting as trigeminal neuralgia.