bluuebunny/crossref_metadata_2025_split huggingface dataset:
From Wolf-Hirschhorn syndrome to NSD2 haploinsufficiency: a shifting paradigm through the description of a new case and a review of the literature
Authors: Wiel Luisa Cortellazzo , Bruno Irene , Barbi Egidio , Sirchia Fabio 
Published: May 2022

Abstract
Background
Wolf-Hirschhorn syndrome (WHS) is a well-defined disorder, whose core phenotype encompasses growth restriction, facial gestalt, intellectual disability and seizures. Nevertheless, great phenotypic variability exists due to the variable extent of the responsible 4p deletion. In addition, exome sequencing analyses, recently identified two genes, namely NSD2 and NELFA, whose loss-of-function variants contribute to a clinical spectrum consistent with atypical or partial WHS.
The observation of patients exhibiting clinical features resembling WHS, with only mild developmental delay and without the typical dysmorphic features, carrying microdeletions sparing NSD2, has lead to the hypothesis that NSD2 is responsible for the intellectual disability and the facial gestalt of WHS. While presenting some of the typical findings of WHS (intellectual disability, facial gestalt, microcephaly, growth restriction and congenital heart defects), NSD2-deleted children tend to display a milder spectrum of skeletal abnormalities, usually consisting of clinodactyly, and do not exhibit seizures.
We describe the clinical picture of a child with WHS due to a de novo mutation of NSD2 and discuss the clinical and diagnostic implications.

Case presentation
A 6-year-old boy was evaluated for a history of intrauterine growth restriction, low birth weight, neonatal hypotonia, and psychomotor delay. No episodes of seizure were reported. At physical examination, he displayed marphanoid habitus, muscle hypotrophy and facial dysmorphisms consisting in high frontal hairline, upslanting palpebral fissures and full lips with bifid ugula. Cryptorchidism, shawl scrotum, mild clinodactyly of the right little finger and bilateral syndactyly of the II and III toes with sandal gap were also noted. The radiographic essay demonstrated delayed bone age and echocardiography showed mild mitral prolapse. Whole genome sequencing analysis revealed a heterozygous de novo variant of NSD2 (c.2523delG).

Conclusions
Full WHS phenotype likely arises from the cumulative effect of the combined haploinsufficiency of several causative genes mapping within the 4p16.3 region, as a contiguous genes syndrome, with slightly different phenotypes depending on the specific genes involved in the deletion.
When evaluating children with pictures resembling WHS, in absence of seizures, clinicians should consider this differential diagnosis.
How much is the lack of retention evidence costing trial teams in Ireland and the UK?
Authors: Murphy Ellen , Shiely Frances , Treweek Shaun 
Published: May 2022

Abstract
Background
Evidence to support the use of many retention strategies in clinical trials is lacking. Despite this, trial teams still need to have some form of retention strategy in their trials to try and avoid high attrition rates. This study aimed to estimate how much this lack of retention evidence might be costing trials in Ireland and the UK.

Methods
We selected the top ten most routinely used retention strategies by Clinical Trial Units in the UK and made assumptions as to how each of these strategies was most likely to be implemented and the costs involved in doing this. We applied our costing model to a hypothetical trial scenario in both Ireland and the UK as well as to three published trial protocols. We developed the costing model and calculated the costs in Microsoft Excel.

Results
Retention strategies were often poorly specified, meaning we had to make assumptions about implementation and in some cases about the strategy itself. Based on our assumptions, some retention strategies can be extremely expensive; some of the costliest strategies included “data collection scheduled with routine care” (€900–€32,503.25), “a timeline of participant visits for sites”—with integrated participant reminder (€304.74–€14,803.70), and “routine site visits by CTU staff” and “investigator meetings face to face”, both costing (€777.67–€14,753.48). Others such as “telephone reminders for questionnaire response” (€34.58–€568.62), “a timeline of participant visits for sites”—site reminder alone (€79.18–€112.23), and “targeted recruitment of sites/GPs” (€30–€1620) were less costly compared to the other strategies.

Discussion
The resources invested in the use of some retention strategies may outweigh known or imagined benefits on retention. Where benefits are currently unknown, evaluation should be a priority.

Conclusion
More evaluation of the effectiveness and cost of trial retention strategies is needed to avoid widespread use of strategies that are both expensive and ineffective.
ACL Surgery Necessity in Non-Acute Patients (ACL SNNAP): a statistical analysis plan for a randomised controlled trial
Authors: Stokes Jamie R. , Beard David J. , Davies Loretta , Shirkey Beverly A. , Price Andrew , Cook Jonathan A. ,   The ACL SNNAP Study Group, Barker Karen , Carr Andrew , Cook Jonathan , Davies Loretta , Haddad Fares , Jackson William , Lamb Sallie , Leal Jose , Monk Paul , O’Leary Sean , Price Andrew , Wilson Chris 
Published: May 2022

Abstract
Background
Rupture of the anterior cruciate ligament (ACL) is a common injury, primarily affecting young, active individuals. Despite surgical intervention being the more common treatment for patients suffering ACL ruptures, current management is based on limited and generally low-quality evidence. We describe a statistical analysis plan (SAP) for the ACL SNNAP randomised controlled trial, which aims to investigate the necessity of surgical management in patients with ACL injuries.

Methods/design
ACL SNNAP is a pragmatic, multi-centre, superiority, parallel-group randomised controlled trial in participants with a symptomatic non-acute ACL deficient knee. Participants are allocated in a 1:1 ratio to either non-surgical management (rehabilitation) or surgical management (reconstruction) with the aim of assessing the efficacy and cost-effectiveness. The primary outcome of the study is the Knee Injury and Osteoarthritis Outcome Score (KOOS4) at 18 months post-randomisation. The KOOS4 score at 18 months will be evaluated using a linear regression model adjusting for recruitment centre and baseline KOOS4 scores, allowing for intra-centre correlation. A secondary analysis of the primary outcome will be carried out using an area under the curve (AUC) approach using treatment estimates obtained from a mixed model using baseline, 6 months, 12 months, and 18 months post-randomisation outcome data. Secondary outcomes will be measured at 18 months and will include return to activity/level of sport participation, intervention-related complications, the EQ-5D-5L questionnaire, all 5 individual subscales of the KOOS questionnaire, the ACL-QOL score, expectations of return to activity and cost-effectiveness of the interventions. Missing primary outcome data will be investigated through a sensitivity analysis. Full details of the planned methods for the statistical analysis of clinical outcomes are presented in this paper. The study protocol for the ACL SNNAP trial has been published previously.

Discussion
The methods of analysis for the ACL SNNAP trial have been described here to minimise the risk of data-driven results and reporting bias. Any deviations from the analysis methods described in this paper will be described in full and justified in the publications of the trial results.

Trial registration
ISRCTN ISRCTN10110685. Registered on 16 November 2016
Securing jugular central venous access devices with dressings fixed to a liquid adhesive in an intensive care unit population: a randomised controlled trial
Authors: Pearse India , Corley Amanda , Larsen Emily N. , Rickard Claire M. , Ware Robert S. , Campbell Jill , Coyer Fiona , Alexandrou Evan , O’Brien Catherine , Marsh Nicole 
Published: May 2022

Abstract
Background
Central venous access devices (CVADs) can have high rates of failure due to dressing-related complications. CVADs placed in the internal jugular vein are at particular risk of dressing failure-related complications, including catheter-associated bloodstream infection and medical adhesive-related skin injury. Application of Mastisol liquid adhesive (MLA) may reduce CVAD dressing failure and associated complications, by reducing the frequency of dressing changes. The aim of this study is to investigate whether, in an intensive care unit (ICU) population, standard dressing care with or without the addition of MLA, improves internal jugular CVAD dressing adherence.

Methods
This two-arm, parallel group randomised controlled trial will be conducted in three Australian ICUs. A total of 160 patients (80 per group) will be enrolled in accordance with study inclusion and exclusion criteria. Patients will be randomised to receive either (1) ‘standard’ (in accordance with local hospital policy) CVAD dressings (control) or (2) ‘standard’ dressings in addition to MLA (intervention). Patients will be followed from the time of CVAD insertion to 48 h after CVAD removal. The primary outcome is ‘dressing failure’ defined as requirement for initial CVAD dressing to be replaced prior to seven days (routine replacement).

Discussion
This study will be the first randomised controlled trial to evaluate the clinical effectiveness of MLA in the adult intensive care unit population and will also provide crucial data for patient-important outcomes such as infection and skin injury.

Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12621001012864. Registered on 2 August 2021
The effectiveness and cost-effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) for trauma patients with uncontrolled torso haemorrhage: study protocol for a randomised clinical trial (the UK-REBOA trial)
Authors: Jansen Jan O. , Cochran Claire , Boyers Dwayne , Gillies Katie , Lendrum Robbie , Sadek Sam , Lecky Fiona , MacLennan Graeme , Campbell Marion K. ,   the UK-REBOA Trial grantholders, Jansen Jan O. , Campbell Marion K. , Moran Chris , Brohi Karim , Lecky Fiona , Lendrum Robbie , MacLennan Graeme , Morrison Jonathan J. , Tai Nigel , Harris Tim , Norrie John , Boyers Dwayne , Paterson Alan , Welch Nick 
Published: May 2022

Abstract
Background
Haemorrhage is the most common cause of preventable death after injury. REBOA is a novel technique whereby a percutaneously inserted balloon is deployed in the aorta, providing a relatively quick means of temporarily controlling haemorrhage and augmenting cerebral and coronary perfusion, until definitive control of haemorrhage can be attained. The aim of the UK-REBOA trial is to establish the clinical and cost-effectiveness of a policy of standard major trauma centre treatment plus REBOA, as compared with standard major trauma centre treatment alone, for the management of uncontrolled torso haemorrhage caused by injury.

Methods
Pragmatic, Bayesian, group-sequential, randomised controlled trial, performed in 16 major trauma centres in England. We aim to randomise 120 injured patients with suspected exsanguinating haemorrhage to either standard major trauma centre care plus REBOA or standard major trauma centre care alone. The primary clinical outcome is 90-day mortality. Secondary clinical outcomes include 3-h, 6-h, and 24-h mortality; in-hospital mortality; 6-month mortality; length of stay (in hospital and intensive care unit); 24-h blood product use; need for haemorrhage control procedure (operation or angioembolisation); and time to commencement of haemorrhage control procedure (REBOA, operation, or angioembolisation). The primary economic outcome is lifetime incremental cost per QALY gained, from a health and personal social services perspective.

Discussion
This study, which is the first to randomly allocate patients to treatment with REBOA or standard care, will contribute high-level evidence on the clinical and cost-effectiveness of REBOA in the management of trauma patients with exsanguinating haemorrhage and will provide important data on the feasibility of implementation of REBOA into mainstream clinical practice.

Trial registration
ISRCTN16184981
Analysis of total phenolic contents, flavonoids, antioxidant and antibacterial activities of Croton macrostachyus root extracts
Authors: Ayele Dessie T. , Akele M. L. , Melese A. T. 
Published: May 2022

AbstractPlants are good sources of various bioactive substances and have significant importance for the discovery of new drugs. In this study, Croton macrostachyus plant roots from six different sites in the Central Gondar Zone, Ethiopia, were collected; and their phenolic and flavonoid contents, as well as antioxidant and antibacterial activities were investigated. Total phenolics and flavonoid contents of the root extracts were determined by the Folin–Ciocalteu and aluminum chloride methods, respectively. The antioxidant activity was determined by the DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging method. Moreover, the antibacterial activities were evaluated by disk diffusion method. Results revealed that total polyphenols and flavonoid contents were in the range of 802 ± 53–1557 ± 75 mg GAE/100 g and 342 ± 26–745 ± 32 mg CE/100 g, respectively. Root extracts of C. macrostachyus were found to have higher antioxidant activities ranging from 3.53 ± 0.38 to 6.38 ± 0.62 mg AAE/g sample. They also showed inhibition zones of 5.8, 6.2, 5.9 and 6.0 mm for Staphylococcus aurous, Staphylococcus pneumonia, Escherichia coli and Klebsiella pneumonia, and had equivalent potency with the reference Gentamicin antibiotic. Pearson correlation result indicated a strong relationship between total polyphenol contents and their respective antioxidant activities. This study articulates that the root extracts accumulated a substantial quantity of polyphenols and bears a considerable antioxidant activity.
Artifact reduction in contrast-enhanced mammography
Authors: Gennaro Gisella , Baldan Enrica , Bezzon Elisabetta , Caumo Francesca 
Published: May 2022

Abstract
Objective
To evaluate the effectiveness of a new algorithm developed to reduce artifacts in dual-energy subtraction (DES) contrast-enhanced mammography (CEM) images while preserving contrast enhancement of possible lesions.

Methods
A retrospective multi-reader paired study was performed by using 134 CEM studies obtained from the first 134 women enrolled in a prospective clinical study aiming to compare the clinical performance of CEM to those of breast MRI in screening of women at increased risk of breast cancer. Four experienced readers compared independently the standard (STD) DES images with those obtained by reprocessing the raw images by a new algorithm (NEW), expected to reduce the DES artifact intensity. The intensity of three types of artifacts (breast-in-breast, ripple, and skinfold enhancement) and the intensity of possible contrast uptake were assessed visually and rated using a categorical ordinal scale. Proportions of images rated by the majority of readers as “Absent”, “Weak”, “Medium”, “Strong” in each artifact intensity category were compared between the two algorithms. P-values lower than 0.05 were considered statistically significant.

Results
The NEW algorithm succeeded in eliminating 84.5% of breast-in-breast artifacts, 84.2% of ripple artifacts, and 56.9% of skinfold enhancement artifacts versus STD DES images, and reduced the artifact intensity in 12.1%, 13.0%, and 28.8% of the images, respectively. The visibility of lesion contrast uptake was the same with the STD and the NEW algorithms.

Conclusion
The new dual-energy subtraction algorithm demonstrated to be effective in reducing/eliminating CEM-related artifacts while preserving lesion contrast enhancement.
Considering sex and gender in Epidemiology: a challenge beyond terminology. From conceptual analysis to methodological strategies
Authors: Colineaux Hélène , Soulier Alexandra , Lepage Benoit , Kelly-Irving Michelle 
Published: May 2022

Abstract
Background
Epidemiologists need tools to measure effects of gender, a complex concept originating in the social sciences which is not easily operationalized in the discipline. Our aim is to clarify useful concepts, measures, paths, effects, and analytical strategies to explore mechanisms of health difference between men and women.

Methods
We reviewed concepts to clarify their definitions and limitations for their translation into usable measures in Epidemiology. Then we conducted methodological research using a causal framework to propose methodologically appropriate strategies for measuring sex and gender effects in health.

Results
(1) Concepts and measures. We define gender as a set of norms prescribed to individuals according to their attributed-at-birth sex. Gender pressure creates a systemic gap, at population level, in behaviors, activities, experiences, etc., between men and women. A pragmatic individual measure of gender would correspond to the level at which an individual complies with a set of elements constituting femininity or masculinity in a given population, place and time. (2) Main analytical strategy. Defining and measuring gender are not sufficient to distinguish the effects of sex and gender on a health outcome. We should also think in terms of mechanisms, i.e., how the variables are linked together, to define appropriate analytical strategies. A causal framework can help us to conceptualize “sex” as a “parent” of a gender or gendered variable. This implies that we cannot interpret sex effects as sexed mechanisms, and that we can explore gendered mechanisms of sex-differences by mediation analyses. (3) Alternative strategy. Gender could also be directly examined as a mechanism, rather than through a variable representing its realization in the individual, by approaching it as an interaction between sex and social environment.

Conclusions
Both analytical strategies have limitations relative to the impossibility of reducing a complex concept to a single or a few measures, and of capturing the entire effect of the phenomenon of gender. However, these strategies could lead to more accurate analyses of the mechanisms underlying health differences between men and women.
Interaural time difference individualization in HRTF by scaling through anthropometric parameters
Authors: Gutierrez-Parera Pablo , Lopez Jose J. , Mora-Merchan Javier M. , Larios Diego F. 
Published: May 2022

AbstractHead-related transfer function (HRTF) individualization can improve the perception of binaural sound. The interaural time difference (ITD) of the HRTF is a relevant cue for sound localization, especially in azimuth. Therefore, individualization of the ITD is likely to result in better sound spatial localization. A study of ITD has been conducted from a perceptual point of view using data from individual HRTF measurements and subjective perceptual tests. Two anthropometric dimensions have been demonstrated in relation to the ITD, predicting the subjective behavior of various subjects in a perceptual test. With this information, a method is proposed to individualize the ITD of a generic HRTF set by adapting it with a scale factor, which is obtained by a linear regression formula dependent on the two previous anthropometric dimensions. The method has been validated with both objective measures and another perceptual test. In addition, practical regression formula coefficients are provided for fitting the ITD of the generic HRTFs of the widely used Brüel & Kjær 4100 and Neumann KU100 binaural dummy heads.
Immune cells-derived exosomes function as a double-edged sword: role in disease progression and their therapeutic applications
Authors: Hazrati Ali , Soudi Sara , Malekpour Kosar , Mahmoudi Mohammad , Rahimi Arezou , Hashemi Seyed Mahmoud , Varma Rajender S. 
Published: May 2022

AbstractExosomes, ranging in size from 30 to 150 nm as identified initially via electron microscopy in 1946, are one of the extracellular vesicles (EVs) produced by many cells and have been the subject of many studies; initially, they were considered as cell wastes with the belief that cells produced exosomes to maintain homeostasis. Nowadays, it has been found that EVs secreted by different cells play a vital role in cellular communication and are usually secreted in both physiological and pathological conditions. Due to the presence of different markers and ligands on the surface of exosomes, they have paracrine, endocrine and autocrine effects in some cases. Immune cells, like other cells, can secrete exosomes that interact with surrounding cells via these vesicles. Immune system cells-derived exosomes (IEXs) induce different responses, such as increasing and decreasing the transcription of various genes and regulating cytokine production. This review deliberate the function of innate and acquired immune cells derived exosomes, their role in the pathogenesis of immune diseases, and their therapeutic appliances.
District-level religious composition and child health in India
Authors: Richards Bailey , Rao Krishna , Bishai David 
Published: May 2022

Abstract
Background
Community characteristics are a significant social determinant of child health. Little is known about the effects of social heterogeneity as a specific factor that might impact health. This paper aims to fill the void in research on the health effects of India’s district-level religious heterogeneity.

Methods
Weighted state fixed effects multivariate logistic regression was applied to India’s Third District Level Household Survey (2007–2008). The dependent variables were death of a child under five and indicators of healthcare utilization. The key independent variables were the proportions in the district who were Hindu, Muslim, Christian, Buddhist, and Sikh. The analysis controlled for generic community diversity, household religion, and socioeconomic status. Separate, sub-group analysis focused on Muslims only, Christians only, and Buddhists only.

Results
Multivariate fixed effects models show that a 1% point increase in the proportion of Muslim, Christian, or Buddhist households in a community is associated with respective odds ratios of child death of 1.008, 1.009, and 1.012 of experiencing the death of a child. The impact of a household’s own religious affiliation is statistically insignificant in these models. Higher proportions of Muslims and Christians in a community lower the odds of BCG (a vaccine for childhood tuberculosis) receipt and child healthcare-seeking.

Conclusions
Households residing where there are higher levels of religious minorities in India experience worse child survival. These effects are not mediated by the household’s own religious affiliation. There is evidence that health system performance and quality is systematically worse in communities with higher proportions of religious minorities. Our study can help policymakers identify communities where children may be at higher risk based on community heterogeneity and the potential for insufficient collective action. Policymakers might consider flagging these communities for special attention, because social heterogeneity is likely to be of long duration.