bluuebunny/crossref_metadata_2025 huggingface dataset:
Determining association between blood glucose variability and postoperative delirium in acute aortic dissection patients: methodological issues
Authors: Li Cheng-Wen , Xue Fu-Shan , Hu Bin
Published: December 2021

The letter to the editor made several comments regarding possible methodological issues in the recent article by Lin et al. determining the association between blood glucose variability and postoperative delirium in patients undergoing acute aortic dissection surgery with cardiopulmonary bypass, which is published in Journal of Cardiothoracic Surgery. 2021; 16(1):82. Our concerns included the lack of some important perioperative factors associated with postoperative delirium, the process of establishing multivariate model and the method of using the receiver operating characteristic curve analysis to assess the predictive performance of the standard deviation of blood glucose for the development of POD. We would like to invite the authors to comment on these and believe that clarifying these issues would improve the transparency of this study and interpretation of findings.
Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening
Authors: Lin Yiming , Lin Bangbang , Chen Yanru , Zheng Zhenzhu , Fu Qingliu , Lin Weihua , Zhang Weifeng
Published: December 2021

Background

Primary carnitine deficiency (PCD) is an autosomal recessive disorder of carnitine transportation that leads to impaired fatty acid oxidation. Large-scale studies on newborn screening (NBS) for PCD are limited. This study aimed to investigate the biochemical and genetic characteristics of patients with PCD detected through NBS.

Results

A total of 548 247 newborns were screened for PCD between January 2014 and June 2021; 1714 newborns with low free carnitine (C0) levels were called back and 49 patients were diagnosed with PCD. The latest incidence rate in Quanzhou, China, was estimated to be 1 in 11 189 newborns. NBS results showed that the 49 patients had varying degrees of decreased C0 levels, whereas seven patients exhibited normal C0 levels during the recall review. All patients harbored biallelic pathogenic variants of theSLC22A5gene. Nineteen distinctSLC22A5variants were detected in these 49 patients, and most of the detected variants were clustered in exons 1, 4, and 7. The top eight variants had an allele frequency of 86.73%. The most common variant was c.760C > T (p.R254*) with an allele frequency of 31.63%, followed by c.51C > G (p.F17L) (17.35%) and c.1400C > G (p.S467C) (16.33%). The C0 level of patients with the N/N genotype was significantly lower than that of the M/M group. The C0 levels of patients with genotypes of R254*/R254* and R254*/F17L were far lower than those of patients with the R254*/S467C genotype.

Conclusions

This study presented more than 500,000 NBS data with the latest incidence of 1:11 189 in the Quanzhou area. TheSLC22A5variant spectrum in the selected southern Chinese population has been updated. Patients with null variants were associated with low C0 levels. Combining NBS with genetic testing is critical to improve screening efficiency because patients with PCD may have normal C0 levels during NBS and recall review.
Cardiovascular and connective tissue disorder features in FLNA-related PVNH patients: progress towards a refined delineation of this syndrome
Authors: Billon Clarisse , Adham Salma , Hernandez Poblete Natalia , Legrand Anne , Frank Michael , Chiche Laurent , Zuily Stephane , Benistan Karelle , Savale Laurent , Zaafrane-Khachnaoui Khaoula , Brehin Anne-Claire , Bal Laurence , Busa Tiffany , Fradin Mélanie , Quelin Chloé , Chesneau Bertrand , Wahl Denis , Fergelot Patricia , Goizet Cyril , Mirault Tristan , Jeunemaitre Xavier , Albuisson Juliette ,   Bordeaux-cohort collaborators, Dieux Anne , Labombarda Fabien , Rheims Sylvain , Boute Odile , Vincentelli André , Toutain Annick , Odent Sylvie , Lesca Gaetan , Vincent Marie , Piard Juliette , Favier Maud , Derambure Philippe , Edery Patrick , Thummler Susanne , Gérard Marion , Morice-Picard Fanny , Layet Valérie , Laroche Cécile , Pasquier Laurent , Sarrazin Elisabeth , Billette de Villemeur Thierry , Guyant-Marechal Lucie
Published: December 2021

Background

FLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowledged cause of seizures of various types. Neurological symptoms are inconstant, and cardiovascular (CV) defects or connective tissue disorders (CTD) have regularly been associated. We aimed at refining the description of CV and CTD features in patients with FLNA LoF and depicting the multisystemic nature of this condition.

Methods

We retrospectively evaluated FLNA variants and clinical presentations in FLNA LoF patient with at least one CV or CTD feature, from three cohorts: ten patients from the French Reference Center for Rare Vascular Diseases, 23 patients from the national reference diagnostic lab for filaminopathies-A, and 59 patients from literature review.

Results

Half of patients did not present neurological symptoms. Most patients presented a syndromic association combining CV and CTD features. CV anomalies, mostly aortic aneurysm and/or dilation were present in 75% of patients. CTD features were present in 75%. Variants analysis demonstrated an enrichment of coding variants in the CH1 domain of FLNA protein.

Conclusion

In FLNA LoF patients, the absence of seizures should not be overlooked. When considering a diagnosis of PVNH1, the assessment for CV and CTD anomalies is of major interest as they represent interlinked features. We recommend systematic study of FLNA within CTD genes panels, regardless of the presence of neurological symptoms.
Gastrointestinal nematodes and Fasciola hepatica in Norwegian cattle herds: a questionnaire to investigate farmers’ perceptions and control strategies
Authors: Opsal Tonje , Toftaker Ingrid , Nødtvedt Ane , Robertson Lucy Jane , Tysnes Kristoffer Relling , Woolsey Ian , Hektoen Lisbeth
Published: December 2021

Background

Pasture management influences the prevalence and impact of the pasture parasites (PP) in cattle herds, which cause production-limiting disease worldwide. Evaluating farmer management strategies is vital when considering sustainable PP control practices. The aim of this questionnaire-based study was to describe the pasture management and control strategies regarding PP in Norwegian beef cattle (BC) and dairy cattle (DC) production systems with a focus on gastrointestinal nematodes (GIN) andFasciola hepatica.

Results

A total of 745 responses from BC (return rate 20.5%) and 1347 responses from DC farmers (30.7%) were included. The mean total pasture time for DC was 4.2 months for first-season grazers and 4.3 months for second-season grazers and cows, while the corresponding finding in BC was 5.4 months. Home pasture was used for most of the pasture period, particularly for first-season grazer dairy heifers (81%), which were also commonly grazed on the same pasture every year (79%). For most farmers it was necessary for grazing areas to be used for cattle for more than one season (77% of BC farmers and 89% of DC farmers). However, changing the pasture during the season was common in both DC (67%) and BC (70%) herds. The majority of DC farmers (60%) stated that they did not consider that they had a problem with PP. Of the remaining 40%, few respondents could specify whether their herds had a problem due to infection by GIN (11%) or liver flukes (12%). Treatment for GIN was performed by 52% of DC and 34% of BC farmers. Diagnostic faecal samples were collected upon suspicion of parasitic disease by 5% of DC and 16% of BC farmers. Veterinarians were stated as a central source of information about parasite management and treatment.

Conclusions

Potential risks for exposure to PP were identified, such as use of the same pasture every year for first-season grazers and frequent use of home pasture. The perception of problems related to PP appeared low. Regular anthelmintic treatment without concurrent use of diagnostic faecal samples seems to be common practice.
Determinants of timely access to Specialized Mental Health Services and maintenance of a link with primary care: a cross-sectional study
Authors: dos Santos Treichel Carlos Alberto , Bakolis Ioannis , Onocko-Campos Rosana Teresa
Published: December 2021

Background

Although access to specialized services is one of the main components of the study of paths to mental health care worldwide, the factors related to the continuity of the patient’s link with Primary Care after admission to a Specialized Mental Health Services still need to be explored in greater depth. Thus, this study aimed to evaluate the determinants of timely access to Specialized Mental Health Services (outcome 1) and maintenance of a link with Primary Care after patients’ admission (outcome 2).

Methods

This is a cross-sectional study, conducted with 341 users of Specialized Mental Health Services at outpatient and community level in a medium-sized city in Brazil between August and November 2019. Associations between the outcomes and the other variables were explored with the use of Poisson regression models with robust variance estimators.

Results

Factors positively associated with timely access were the diagnosis of psychosis or psychoactive substance misuse. The inversely associated factors with this outcome were higher income, having their need for mental health care identified in an appointment for general complaints, having been referred to the current service by Primary Care, having attended the current service for up to 3 years and delay until the first appointment (in a previous service). Regarding the maintenance of a link with Primary Care, factors positively associated were being referred to the current service by Primary Care or private service and receiving visits from Community Health Agents. The inversely associated factors with this outcome were male sex, being employed, having a diagnosis of psychosis or psychoactive substance misuse, and a greater perception of social support.

Conclusions

In addition to individual factors, factors related to the organization of services and the referral between them stood out in influencing both the access and maintenance of the patients’ link with Primary Care. Thus, this study reinforces the idea that integration between Primary Care and Specialized Mental Health Services should be strengthened, both to reduce waiting times for between-service referrals and benefit of care continuity.
Comprehensive analysis of early pregnancy loss based on cytogenetic findings from a tertiary referral center
Authors: Wu Xiaoqing , Su Linjuan , Xie Xiaorui , He Deqin , Chen Xuemei , Wang Meiying , Wang Linshuo , Zheng Lin , Xu Liangpu
Published: December 2021

Background

Pregnancy loss is one of the most common complications during pregnancy. Clinical consultation based on etiology analysis are critical for reducing anxiety and distress. This study aimed to perform a comprehensive analysis for products of conception (POC) in miscarriage based on genetic etiology and clinical information.

Methods

A retrospective study was conducted according to cytogenetic findings of 1252 POC from spontaneous pregnancy loss over 11 years. The frequencies and profiles of chromosomal abnormalities were discussed according to the classification of women with different maternal ages, previous miscarriage history, normal live birth history, and different modes of conception.

Results

A total of 667 (53.2%) chromosomal abnormalities were observed, including 592 (47.3%) cases of numerical abnormalities, 38 (3.0%) cases of structural abnormalities, and 37 (3.0%) cases of mosaic aberrations. In women above 40 years of age, the rates of chromosomal abnormalities and viable autosomal trisomy were significantly higher than those in women with ≤ 29, 30–34, and 35–39 years of age (p < 0.05). The frequency of abnormal karyotype in women with normal live birth history was 61.1%, significantly higher than 52.5% in women without normal live birth history (p < 0.05). There was no significant differences among women without, with 1–2, and ≥ 3 previous miscarriages regarding the rate of abnormal karyotype (p > 0.05); viable autosomal trisomy was less common in women with ≥ 3 previous miscarriages than women with < 3 miscarriages. The frequency of chromosomal abnormalities was 49.0% and 55.0% in women with assisted conception and natural conception (p > 0.05), respectively; monosomy X was more frequently detected in women with natural conception than assisted conception.

Conclusion

The frequencies and profiles of chromosomal abnormalities in early miscarriages are strongly associated with clinical information including maternal age, previous miscarriage, live birth history, and mode of conception. Cytogenetic analysis of POC should be recommended to women with a first miscarriage and women with normal live birth history.
Identification of natural selection in genomic data with deep convolutional neural network
Authors: Nguembang Fadja Arnaud , Riguzzi Fabrizio , Bertorelle Giorgio , Trucchi Emiliano
Published: December 2021

Background

With the increase in the size of genomic datasets describing variability in populations, extracting relevant information becomes increasingly useful as well as complex. Recently, computational methodologies such as Supervised Machine Learning and specifically Convolutional Neural Networks have been proposed to make inferences on demographic and adaptive processes using genomic data. Even though it was already shown to be powerful and efficient in different fields of investigation, Supervised Machine Learning has still to be explored as to unfold its enormous potential in evolutionary genomics.

Results

The paper proposes a method based on Supervised Machine Learning for classifying genomic data, represented as windows of genomic sequences from a sample of individuals belonging to the same population. A Convolutional Neural Network is used to test whether a genomic window shows the signature of natural selection. Training performed on simulated data show that the proposed model can accurately predict neutral and selection processes on portions of genomes taken from real populations with almost 90% accuracy.
Novel approaches in cancer treatment: preclinical and clinical development of small non-coding RNA therapeutics
Authors: Cuciniello Rossana , Filosa Stefania , Crispi Stefania
Published: December 2021

Short or small interfering RNAs (siRNAs) and microRNA (miRNAs) are molecules similar in size and function able to inhibit gene expression based on their complementarity with mRNA sequences, inducing the degradation of the transcript or the inhibition of their translation.

siRNAs bind specifically to a single gene location by sequence complementarity and regulate gene expression by specifically targeting transcription units via posttranscriptional gene silencing. miRNAs can regulate the expression of different gene targets through their imperfect base pairing.

This process - known as RNA interference (RNAi) - modulates transcription in order to maintain a correct physiological environment, playing a role in almost the totality of the cellular pathways.

siRNAs have been evolutionary evolved for the protection of genome integrity in response to exogenous and invasive nucleic acids such as transgenes or transposons. Artificial siRNAs are widely used in molecular biology for transient silencing of genes of interest. This strategy allows to inhibit the expression of any target protein of known sequence and is currently used for the treatment of different human diseases including cancer.

Modifications and rearrangements in gene regions encoding for miRNAs have been found in cancer cells, and specific miRNA expression profiles characterize the developmental lineage and the differentiation state of the tumor. miRNAs with different expression patterns in tumors have been reported as oncogenes (oncomirs) or tumor-suppressors (anti-oncomirs). RNA modulation has become important in cancer research not only for development of early and easy diagnosis tools but also as a promising novel therapeutic approach.

Despite the emerging discoveries supporting the role of miRNAs in carcinogenesis and their and siRNAs possible use in therapy, a series of concerns regarding their development, delivery and side effects have arisen.

In this review we report the biology of miRNAs and siRNAs in relation to cancer summarizing the recent methods described to use them as novel therapeutic drugs and methods to specifically deliver them to cancer cells and overcome the limitations in the use of these molecules.
Complications associated with pre-hospital open thoracostomies: a rapid review
Authors: Mohrsen Stian , McMahon Niall , Corfield Alasdair , McKee Sinéad
Published: December 2021

Background

Open thoracostomies have become the standard of care in pre-hospital critical care in patients with chest injuries receiving positive pressure ventilation. The procedure has embedded itself as a rapid method to decompress air or fluid in the chest cavity since its original description in 1995, with a complication rate equal to or better than the out-of-hospital insertion of indwelling pleural catheters. A literature review was performed to explore potential negative implications of open thoracostomies and discuss its role in mechanically ventilated patients without clinical features of pneumothorax.

Main findings

A rapid review of key healthcare databases showed a significant rate of complications associated with pre-hospital open thoracostomies. Of 352 thoracostomies included in the final analysis, 10.6% (n = 38) led to complications of which most were related to operator error or infection (n = 26). Pneumothoraces were missed in 2.2% (n = 8) of all cases.

Conclusion

There is an appreciable complication rate associated with pre-hospital open thoracostomy. Based on a risk/benefit decision for individual patients, it may be appropriate to withhold intervention in the absence of clinical features, but consideration must be given to the environment where the patient will be monitored during care and transfer. Chest ultrasound can be an effective assessment adjunct to rule in pneumothorax, and may have a role in mitigating the rate of missed cases.
Examining non-technical skills for ad hoc resuscitation teams: a scoping review and taxonomy of team-related concepts
Authors: Evans J. Colin , Evans M. Blair , Slack Meagan , Peddle Michael , Lingard Lorelei
Published: December 2021

Background

Non-technical skills (NTS) concepts from high-risk industries such as aviation have been enthusiastically applied to medical teams for decades. Yet it remains unclear whether—and how—these concepts impact resuscitation team performance. In the context of ad hoc teams in prehospital, emergency department, and trauma domains, even less is known about their relevance and impact.

Methods

This scoping review, guided by PRISMA-ScR and Arksey & O’Malley’s framework, included a systematic search across five databases, followed by article selection and extracting and synthesizing data. Articles were eligible for inclusion if they pertained to NTS for resuscitation teams performing in prehospital, emergency department, or trauma settings. Articles were subjected to descriptive analysis, coherence analysis, and citation network analysis.

Results

Sixty-one articles were included. Descriptive analysis identified fourteen unique non-technical skills. Coherence analysis revealed inconsistencies in both definition and measurement of various NTS constructs, while citation network analysis suggests parallel, disconnected scholarly conversations that foster discordance in their operationalization across domains. To reconcile these inconsistencies, we offer a taxonomy of non-technical skills for ad hoc resuscitation teams.

Conclusion

This scoping review presents a vigorous investigation into the literature pertaining to how NTS influence optimal resuscitation performance for ad hoc prehospital, emergency department, and trauma teams. Our proposed taxonomy offers a coherent foundation and shared vocabulary for future research and education efforts. Finally, we identify important limitations regarding the traditional measurement of NTS, which constrain our understanding of how and why these concepts support optimal performance in team resuscitation.

Graphical abstract
Changes in carbon dioxide production and oxygen uptake evaluated using indirect calorimetry in mechanically ventilated patients with sepsis
Authors: Hirayama Ichiro , Asada Toshifumi , Yamamoto Miyuki , Hayase Naoki , Hiruma Takahiro , Doi Kent
Published: December 2021

Background

Several clinical guidelines recommend monitoring blood lactate levels and central venous oxygen saturation for hemodynamic management of patients with sepsis. We hypothesized that carbon dioxide production (VCO2) and oxygen extraction (VO2) evaluated using indirect calorimetry (IC) might provide additional information to understand the dynamic metabolic changes in sepsis.

Methods

Adult patients with sepsis who required mechanical ventilation in the intensive care unit (ICU) of our hospital between September 2019 and March 2020 were prospectively enrolled. Sepsis was diagnosed according to Sepsis-3. Continuous measurement of VCO2 and VO2 using IC for 2 h was conducted within 24 h after tracheal intubation, and the changes in VCO2 and VO2 over 2 h were calculated as the slopes by linear regression analysis. Furthermore, temporal lactate changes were evaluated. The primary outcome was 28-day survival.

Results

Thirty-four patients with sepsis were enrolled, 26 of whom survived 76%. Significant differences in the slope of VCO2 (− 1.412 vs. − 0.446) (p = 0.012) and VO2 (− 2.098 vs. − 0.851) (p = 0.023) changes were observed between non-survivors and survivors. Of note, all eight non-survivors and 17 of the 26 survivors showed negative slopes of VCO2 and VO2 changes. For these patients, 17 survivors had a median lactate of − 2.4% changes per hour (%/h), whereas non-survivors had a median lactate of 2.6%/hr (p = 0.023).

Conclusions

The non-survivors in this study showed temporal decreases in both VCO2 and VO2 along with lactate elevation. Monitoring the temporal changes in VCO2 and VO2 along with blood lactate levels may be useful in predicting the prognosis of sepsis.
Study on the mechanism of LOXL1-AS1/miR-3614-5p/YY1 signal axis in the malignant phenotype regulation of hepatocellular carcinoma
Authors: Feng ZhenYu , Ye ZhenYu , Xie JiaMing , Chen Wei , Li Wei , Xing ChunGen
Published: December 2021

Background

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high mortality worldwide. Accumulating researches have indicated that long non‑coding RNAs (lncRNAs) are involved in varies human cancers, including HCC. Nevertheless, the specific molecular mechanism of lncRNA lysyl oxidase like 1 antisense RNA 1 (LOXL1-AS1) in HCC is still unclear.

Methods

LOXL1-AS1 expression was tested via qRT-PCR in HCC cells. Functional and mechanism assays were respectively done to evaluate the biological functions of HCC cells and the potential interaction of LOXL1-AS1 and other factors.

Results

We discovered that LOXL1-AS1 was high expressed in HCC cells. Inhibition of LOXL1-AS1 repressed cell proliferation, migration and invasion, but enhanced cell apoptosis in HCC. Further, miR-3614-5p was proven to be sponged by LOXL1-AS1. Additionally, Yin Yang 1 (YY1) was proven as the target gene of miR-3614-5p, and YY1 depletion could repress HCC cell malignant behaviors. YY1 could also transcriptionally activate LOXL1-AS1 expression. In rescue assays, we confirmed that overexpression of YY1 or miR-3614-5p inhibition could reverse the suppressive effects of LOXL1-AS1 silence on the malignant behaviors of HCC cells.

Conclusion

In short, LOXL1-AS1/miR-3614-5p/YY1 forms a positive loop in modulating HCC cell malignant behaviors.
Impact of perinatal environmental health education intervention on exposure to endocrine disruptors during pregnancy—PREVED study: study protocol for a randomized controlled trial
Authors: Ouazzani Houria El. , Rouillon Steeve , Venisse Nicolas , Sifer-Rivière Lynda , Dupuis Antoine , Cambien Guillaume , Ayraud-Thevenot Sarah , Gourgues Anne-Sophie , Pierre-Eugène Pascale , Pierre Fabrice , Rabouan Sylvie ,   DisProSE Group, Migeot Virginie , Albouy-Llaty Marion
Published: December 2021

Background

The suspected or actual effects on health of endocrine-disrupting chemicals (EDC) and their ubiquitous presence in everyday life justify the implementation of health promotion interventions. These interventions should ideally be applied during critical windows like pregnancy. Perinatal environmental health education interventions may help to reduce EDC exposure during pregnancy.

Methods/design

PREVED (Pregnancy, PreVention, Endocrine Disruptors) is an open-label randomized controlled trial assessing the impact of environmental health education intervention on EDC exposure during pregnancy. Inclusion, consent, and randomization take place during the first trimester. The participants are randomly allocated into three groups: (i) control group (information leaflet on EDCs), (ii) intervention group in neutral location (information leaflet and workshops in a meeting room), and (iii) intervention group in contextualized location (information leaflet and workshops in a real apartment). Workshops are organized between the second and third trimesters of pregnancy. Main outcome is the percentage of participants who reported consuming manufactured/industrial food. Secondary outcomes are as follows: (i) psycho-social dimensions, (ii) EDC concentrations in urine, (iii) EDC concentration in colostrum, and (iv) percentage of participants who reported consuming paraben-free personal care products.

Discussion

PREVED is a ground-breaking intervention research project dedicated to perinatal environmental health education that aims to identify pollutant sources in daily life and to offer accessible and realistic alternative solutions, by promoting the sharing of know-how and experience in a positive and non-alarmist approach.

Trial registration

ClinicalTrials.gov: NCT03233984 (current status: ongoing). Retrospectively registered on 31 July 2017 (https://clinicaltrials.gov/ct2/show/NCT03233984) because when the first participant was enrolled in this non-drug intervention, ClinicalTrials.gov was centered in therapeutic trials.

The World Health Organization Trial Registration Data Set is in Additional file 1.
What do parents think of using informational videos to support recruitment for parenting trials? A qualitative study
Authors: Pontoppidan Maiken , Blower Sarah , Solvang Julie Nygaard , Bywater Tracey
Published: December 2021

Background

Lower than expected recruitment and retention rates are common challenges in parenting trials—particularly for community-based trials targeting parents of young children that rely on face-to-face recruitment by frontline workers. Recruitment requires parental informed consent, yet information sheets have been criticized for being lengthy and complex, and particularly challenging for parents with low literacy. Recent innovations include ‘talking head’ information videos. This paper aims to explore parent perceptions of using a ‘talking head’ video to support informed consent, recruitment, and retention procedures in parenting trials.

Methods

We conducted semi-structured interviews with a sample of 24 mothers recruited after their final follow-ups in two different parenting trials in Denmark. Before consenting to participate in the trials, parents were invited to view a video of a member of the study team giving information about the study, and again before the interviews for the current study. The audio data was transcribed and thematic analysis was conducted.

Results

We identified three overarching themes: (1) general impression of the video, (2) thoughts on participation in research, and (3) recruitment and retention. Participants were generally positive in their appraisal of the two talking head informational videos. We found that participants felt that a mix of paper-based and video-based sources of information would enable them to make an informed choice about whether to participate in a research study. We also found that a professionally produced video featuring a key member of the study team produced a feeling of commitment to the study that could impact retention rates.

Conclusions

Informational videos are acceptable to parents; however, co-production or participant/patient involvement in the development of such videos is recommended. Informational videos may not increase recruitment but have the potential for improving retention. Key design recommendations are to ensure a ‘professional’ look to the video, to supplement videos with paper-based information, to keep the length to < 3 min, and for the ‘talking head’ part to feature a key member of the study team.
Study protocol for a randomized clinical trial to evaluate the effect of the use of Xylitol gum in the prevention of caries lesions in children living in Ladakh—the Caries Prevention Xylitol in Children (CaPreXCh) trial
Authors: Cagetti Maria Grazia , Cocco Fabio , Calzavara Ezio , Augello Davide , Zangpoo Phunchok , Campus Guglielmo
Published: December 2021

Background

Xylitol use is reported to be able to reduce dental plaque amount and cariogenic bacteria and, as a consequence, the caries increment. Only few data on the oral health of Ladakh’s population are available. The aim of the present protocol will be to record the caries prevalence of primary and permanent molars of schoolchildren living in Ladakh and to implement a school-based Xylitol programme, named the Caries Prevention Xylitol in Children (CaPreXCh) trial, using chewing gums.

Methods

The protocol is designed as a triple-blind randomized, controlled, parallel-group clinical trial in children aged 5–14 years. The study should have been carried out from August 2021 to August 2024 in Zanskar Valley (Ladakh), but the COVID-19 pandemic does not allow today to make predictions on the exact start. Participants will be randomly allocated into two groups: subjects who will receive a chewing gum with Xylitol (70% w/v) as only sweetener, and those who will receive a sugared chewing gum containing Maltitol (23% w/v). The subjects will be instructed to chew a total of 6 pellets for 5 min divided into 3 intakes a day (2 in the morning, 2 after the midday meal and 2 in the afternoon) for one school year. Clinical examination will comprise an oral examination in which caries index (ICDAS scores), bleeding on probing and plaque pH evaluation after sucrose challenge will be recorded at baseline (t0); the clinical examination will be repeated after 12 months since the beginning of the chewing gum administration period (t1), after another 12-month period (t2) and finally after further 12 months (t3) (24 months from the end of the chewing gum use). The primary outcome will be the caries increment measured both at enamel and dentinal levels on primary and permanent molars. Data analysis will be conducted through Kaplan-Meyer graphs to evaluate caries increment. A comparison of the methods will be carried out with Cox regression with shared frailty. The net caries increment for initial, moderate and severe caries levels, using ICDAS (Δ-initial, Δ-moderate and Δ-severe), will be calculated.

Discussion

This trial will be the first trial conducted in India assessing the efficacy of a school-based caries preventive programme through the use of chewing gum containing only Xylitol as a sweetener. The findings could help strengthen the evidence for the efficacy of Xylitol use in community-based caries prevention programmes in children.

Trial registration

Clinical trials.govNCT04420780. Registered on June 9, 2020
Safety and efficacy of C1-inhibitor in traumatic brain injury (CIAO@TBI): study protocol for a randomized, placebo-controlled, multi-center trial
Authors: van Erp Inge A. M. , van Essen Thomas A. , Fluiter Kees , van Zwet Erik , van Vliet Peter , Baas Frank , Haitsma Iain , Verbaan Dagmar , Coert Bert , de Ruiter Godard C. W. , Moojen Wouter A. , van der Jagt Mathieu , Peul Wilco C.
Published: December 2021

Background

Traumatic brain injury (TBI) is a major cause of death and disability across all ages. After the primary impact, the pathophysiologic process of secondary brain injury consists of a neuroinflammation response that critically leads to irreversible brain damage in the first days after the trauma. A key catalyst in this inflammatory process is the complement system. Inhibiting the complement system could therefore be a therapeutic target in TBI.

Objective

To study the safety and efficacy of C1-inhibitor (C1-INH) compared to placebo in patients with TBI. By temporarily blocking the complement system, we hypothesize a decrease in the posttraumatic neuroinflammatory response resulting in a less unfavorable clinical outcome for TBI patients.

Methods

CIAO@TBI is a multicenter, randomized, blinded, phase II placebo-controlled trial. Adult TBI patients with GCS < 13 requiring intracranial pressure (ICP) monitoring will be randomized, using block randomization, within 12 h after trauma to one dose 6000 IU C1-INH or placebo. A total of 106 patients will be included, and follow-up will occur up to 12 months. The primary endpoints are (1) Therapy Intensity Level (TIL) Scale, (2) Glasgow Outcome Scale-Extended (GOSE) at 6 months, and (3) complication rate during hospitalization. Outcomes will be determined by a trial nurse blinded for the treatment allocation. Analyses will be conducted in an intention-to-treat analysis.

Discussion

We expect that C1-INH administration will be safe and potentially effective to improve clinical outcomes by reducing neuroinflammation in TBI patients.

Trial registration

ClinicalTrials.govNCT04489160. Registered on 27 July 2020. EudraCT 2020-000140-58
Effectiveness and safety of Bushen Huoxue granules in treatment of premature ovarian insufficiency: study protocol for a randomized, double-blinded, placebo-controlled, and multicenter clinical trial
Authors: Cao Ying , Peijuan-Wang  , Lu Yan , Chen Yue , Chen Si , Weibo-Zhao
Published: December 2021

Introduction

Premature ovarian insufficiency (POI) seriously affects the quality of life, endocrine function, and fertility of women of childbearing age. Currently, hormone replacement therapy for POI has some limitations, either with low efficacies or high side effects. Bushen Huoxue (BSHX) plays an important role in alleviating clinical symptoms and improving health status of POI patients. This placebo-controlled, randomized, double-blind, and multicenter clinical trial protocol aims to evaluate the effectiveness and safety of BSHX in women with POI.

Methods and design

We plan to recruit 150 women with POI from four participating hospitals in China. Participants will be randomized in a 1:1 to receive oral BSHX or BSHX placebo. All participants will be treated for 3 months and will be followed up for another 3 month. The primary outcome is questionnaire scores based on the changes in the total symptoms, which is the Chinese version of the Menopause-Specific Quality of Life (CMS) (Nie G, Yang H, Liu J, Zhao C, Wang X, Menopause 24(5):546–554, 2017). CMS will be measured before the intervention, at 3 months and 6 months after randomization for all participants. The other measurements include serum sex hormone levels, anti-Müllerian hormone (AMH) levels, ovarian peak systolic velocity (PSV; cm/s), and antral follicle count (AFC). In this study, the regulatory effects of traditional Chinese medicine on hormones were evaluated by the changes of serum sex hormone levels, which include serum estradiol (E2), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). These indicators will be measured before intervention and at 3 months after randomization.

Ethics and dissemination

This study was approved by the Research Ethics Committee of Jiangsu Province Hospital on Integration of Chinese and Western Medicine (2019LWKY014). All participants will provide written informed consent prior to randomization. The results of this research will be presented to academic conferences and peer-reviewed journals.

Trial registration

ChiCTR1900028451. Registered on 22 December 2019, https://www.chictr.org.cn/index.aspx.
Vibration therapy as an intervention for enhancing trochanteric hip fracture healing in elderly patients: a randomized double-blinded, placebo-controlled clinical trial
Authors: Wong Ronald Man Yeung , Chow Simon Kwoon Ho , Tang Ning , Chung Yik Lok , Griffith James , Liu Wing Hong , Ng Raymond Wai Kit , Tso Chi Yin , Cheung Wing Hoi
Published: December 2021

Background

There are more than 300,000 hip fractures yearly in the USA with mortality rates of 20% within 1 year. The treatment of osteoporotic fractures is a major challenge as bone quality is poor, and healing is expected to delay due to the impaired healing properties with respect to bone formation, angiogenesis, and mineralization. Enhancement of osteoporotic fracture healing and function is therefore critical as a major goal in modern fracture management. Previous pre-clinical studies have shown that low-magnitude high-frequency vibration (LMHFV) accelerates osteoporotic fracture healing. The objective of this study is to investigate the effect of LMHFV on accelerating trochanteric hip fracture healing and functional recovery.

Methods

This is a randomized, double-blinded, placebo-controlled clinical trial to evaluate the effect of LMHFV in accelerating trochanteric hip fracture healing. All fractures undergo cephalomedullary nail fixation. The primary outcome of this study is time to fracture healing by X-ray. Computed tomography (CT) and dual-energy X-ray absorptiometry (DXA) will also be performed. Blood circulation at the fracture site will be assessed by dynamic perfusion magnetic resonance (MR). Clinical results include functional recovery by muscle strength, timed up and go test (TUG), quality of life questionnaire (SF-36), balancing, falls, and mortality.

Discussion

Previous animal studies have demonstrated LMHFV to improve both normal and osteoporotic fracture healing by accelerating callus formation and mineralization. The mechanical stimulation stimulates angiogenesis by significantly enhancing vascular volume and blood flow velocity. This is the first study to translate LMHFV to enhancing hip fracture healing clinically. Positive results would provide a huge impact in the recovery of hip fracture patients and save healthcare costs.

Trial registration

Clinicaltrials.gov NCT04063891. Registered on August 21, 2019
Promoting inclusion in clinical trials—a rapid review of the literature and recommendations for action
Authors: Bodicoat Danielle H. , Routen Ash C. , Willis Andrew , Ekezie Winifred , Gillies Clare , Lawson Claire , Yates Thomas , Zaccardi Francesco , Davies Melanie J. , Khunti Kamlesh
Published: December 2021

Background

Without inclusion of diverse research participants, it is challenging to understand how study findings will translate into the real world. Despite this, a lack of inclusion of those from under-served groups in research is a prevailing problem due to multi-faceted barriers acting at multiple levels. Therefore, we rapidly reviewed international published literature, in relation to clinical trials, on barriers relating to inclusion, and evidence of approaches that are effective in overcoming these.

Methods

A rapid literature review was conducted searching PubMed for peer-reviewed articles that discussed barriers to inclusion or strategies to improve inclusion in clinical trial research published between 2010 and 2021. Grey literature articles were excluded.

Results

Seventy-two eligible articles were included. The main barriers identified were language and communication, lack of trust, access to trials, eligibility criteria, attitudes and beliefs, lack of knowledge around clinical trials, and logistical and practical issues. In relation to evidence-based strategies and enablers, two key themes arose: [1] a multi-faceted approach is essential [2]; no single strategy was universally effective either within or between trials. The key evidence-based strategies identified were cultural competency training, community partnerships, personalised approach, multilingual materials and staff, communication-specific strategies, increasing understanding and trust, and tackling logistical barriers.

Conclusions

Many of the barriers relating to inclusion are the same as those that impact trial design and healthcare delivery generally. However, the presentation of these barriers among different under-served groups may be unique to each population’s particular circumstances, background, and needs. Based on the literature, we make 15 recommendations that, if implemented, may help improve inclusion within clinical trials and clinical research more generally. The three main recommendations include improving cultural competency and sensitivity of all clinical trial staff through training and ongoing personal development, the need to establish a diverse community advisory panel for ongoing input into the research process, and increasing recruitment of staff from under-served groups. Implementation of these recommendations may help improve representation of under-served groups in clinical trials which would improve the external validity of associated findings.
Optimising recruitment to a late-phase tuberculosis clinical trial: a qualitative study exploring patient and practitioner experiences in Uzbekistan
Authors: Wharton-Smith Alexandra , Horter Shona , Douch Emma , Gray Nell , James Nicola , Nyang’wa Bern-Thomas , Singh Jatinder , Nusratovna Parpieva Nargiza , Tigay Zinaida , Kazounis Emil , Allanazarova Gulayim , Stringer Beverley
Published: December 2021

Background

Addressing the global burden of multidrug-resistant tuberculosis (MDR-TB) requires identification of shorter, less toxic treatment regimens. Médecins Sans Frontières (MSF) is currently conducting a phase II/III randomised controlled clinical trial, to find more effective, shorter and tolerable treatments for people with MDR-TB. Recruitment to the trial in Uzbekistan has been slower than expected; we aimed to study patient and health worker experiences of the trial, examining potential factors perceived to impede and facilitate trial recruitment, as well as general perceptions of clinical research in this context.

Methods

We conducted a qualitative study using maximum variation, purposive sampling of participants. We carried out in-depth interviews (IDIs) and focus group discussions (FGDs) guided by semi-structured topic guides. In December 2019 and January 2020, 26 interviews were conducted with patients, Ministry of Health (MoH) and MSF staff and trial health workers, to explore challenges and barriers to patient recruitment as well as perceptions of the trial and research in general. Preliminary findings from the interviews informed three subsequent focus group discussions held with patients, nurses and counsellors. Focus groups adopted a person-centred design, brainstorming potential solutions to problems and barriers. Interviews and FGDs were audio recorded, translated and transcribed verbatim. Thematic analysis, drawing on constant comparison, was used to analyse the data.

Results

Health system contexts may compete with new approaches especially when legislative health regulations or policy around treatment is ingrained in staff beliefs, perceptions and practice, which can undermine clinical trial recruitment. Trust plays a significant role in how patients engage with the trial. Decision-making processes are dynamic and associated with relationship to diagnosis, assimilation of information, previous knowledge or experience and influence of peers and close relations.

Conclusions

This qualitative analysis highlights ways in which insights developed together with patients and healthcare workers might inform approaches towards improved recruitment into trials, with the overall objective of delivering evidence for better treatments.
Construction of a tunable promoter library to optimize gene expression in Methylomonas sp. DH-1, a methanotroph, and its application to cadaverine production
Authors: Lee Hyang-Mi , Ren Jun , Yu Myeong-Sang , Kim Hyunjoo , Kim Woo Young , Shen Junhao , Yoo Seung Min , Eyun Seong-il , Na Dokyun
Published: December 2021

Background

As methane is 84 times more potent than carbon dioxide in exacerbating the greenhouse effect, there is an increasing interest in the utilization of methanotrophic bacteria that can convert harmful methane into various value-added compounds. A recently isolated methanotroph, Methylomonas sp. DH-1, is a promising biofactory platform because of its relatively fast growth. However, the lack of genetic engineering tools hampers its wide use in the bioindustry.

Results

Through three different approaches, we constructed a tunable promoter library comprising 33 promoters that can be used for the metabolic engineering of Methylomonas sp. DH-1. The library had an expression level of 0.24–410% when compared with the strength of the lac promoter. For practical application of the promoter library, we fine-tuned the expressions of cadA and cadB genes, required for cadaverine synthesis and export, respectively. The strain with PrpmB-cadA and PDnaA-cadB produced the highest cadaverine titre (18.12 ± 1.06 mg/L) in Methylomonas sp. DH-1, which was up to 2.8-fold higher than that obtained from a non-optimized strain. In addition, cell growth and lysine (a precursor of cadaverine) production assays suggested that gene expression optimization through transcription tuning can afford a balance between the growth and precursor supply.

Conclusions

The tunable promoter library provides standard and tunable components for gene expression, thereby facilitating the use of methanotrophs, specifically Methylomonas sp. DH-1, as a sustainable cell factory.

Graphical Abstract