bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the psychometric properties of the Sense of Coherence scale (SOC-13) in patients with cardiovascular risk factors: a study of the method effects associated with negatively worded items
Authors: Domínguez-Salas Sara , Andrés-Villas Montserrat , Riera-Sampol Aina , Tauler Pedro , Bennasar-Veny Miquel , Aguilo Antoni , Rivera Francisco
Published: January 2022

Purpose

The objectives of this study were to analyze the psychometric properties of the Sense of Coherence scale (SOC-13), determine the role of the method effect in the performance of the instrument, and identify the relationship with health perception, quality of life, and sleep quality in patients at cardiovascular risk.

Methods

The final sample consisted of 293 patients at cardiovascular risk, with a mean age of 61.9 years (SD = 8.8), 49.8% of whom were women. The SOC-13, the Patient Health Questionnaire (PHQ-9), and the Medical Outcomes Study-Sleep Scale (MOS-Sleep) were administered. In addition, the participant's self-perceived health and quality of life were also evaluated. All analyses were carried out with SPSS 26.0 and EQS 6.1 statistical software.

Results

The results showed adequate reliability for the SOC-13, with a Cronbach's alpha of .789. The fit of the structures was not adequate in any of the cases (.26 to .62 for one factor, .26 to.73 for three factors, .20 to .54 for one second-order factor, and .25, .42, and .54 for three first-order factors). The three structure models showed an improved fit when adding a latent factor resulting from the method effect (.6 to .85 for one factor, .11 to.90 for three factors, and .11 to .96 for one second-order factor). Moreover, positive correlations were found with health perception, perceived quality of life, and perceived sleep quality.

Conclusion

The SOC-13 is a suitable instrument for patients with cardiovascular risk in Spain, and it is also an indicator of health perception, quality of life, and perceived quality of sleep. Control of the method effect improves the fit of the instrument’s structure. As a future direction, it is recommended to conduct new studies in this and other samples and using different versions of the SOC.

Trial registration

International Standard Randomized Controlled Trial Number: ISRCTN76069254, 08/04/2015 retrospectively registered.
Hsa_circ_0020850 promotes the malignant behaviors of lung adenocarcinoma by regulating miR-326/BECN1 axis
Authors: Li Xiaoju , Su Shengtian , Ye Dan , Yu Zhigao , Lu Wenjing , Liu Liang
Published: January 2022

Background

Circular RNAs (circRNAs) are a novel type of endogenous RNAs and play vital roles in lung adenocarcinoma. However, the function and underlying mechanism of circ_0020850 in lung adenocarcinoma remain unknown.

Methods

The levels of circ_0020850, microRNA-326 (miR-326), and Beclin1 (BECN1) were analyzed by real-time quantitative polymerase chain reaction and western blot analyses. The migration and invasion were determined by wound healing and transwell assays, respectively. Colony formation assay was used to assess cell proliferation ability. The angiogenic ability was analyzed by Matrigel angiogenesis assay. The apoptosis rate was calculated by flow cytometry assay. Dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were conducted to confirm the interaction relationship among circ_0020850, miR-326, and BECN1. A xenograft mice model was established to assess the role of circ_0020850 in vivo.

Results

We found that circ_0020850 was obviously overexpressed in lung adenocarcinoma tissues and cells. Knockdown of circ_0020850 inhibited migration, invasion, proliferation, and angiogenesis but induced apoptosis in lung adenocarcinoma cells in vitro, as well as curbed tumor growth in vivo. MiR-326 was a target of circ_0020850, and knockdown of miR-326 abolished the suppression effect of circ_0020850 on the malignant behaviors of lung adenocarcinoma cells. Additionally, miR-326 could negatively regulate BECN1 expression, thereby regulating lung adenocarcinoma cell phenotypes. Importantly, circ_0020850 could directly bind to miR-326 and thus relieve miR-326-mediated inhibition on BECN1.

Conclusion

Circ_0020850 promoted the malignant development of lung adenocarcinoma by regulating miR-326/BECN1 axis, indicating that circ_0020850 might serve as a promising target for the diagnosis and treatment of lung adenocarcinoma patients.
A toolkit to rapidly modify root systems through single plant selection
Authors: Rambla Charlotte , Van Der Meer Sarah , Voss-Fels Kai P. , Makhoul Manar , Obermeier Christian , Snowdon Rod , Ober Eric S. , Watt Michelle , Alahmad Samir , Hickey Lee T.
Published: January 2022

Background

The incorporation of root traits into elite germplasm is typically a slow process. Thus, innovative approaches are required to accelerate research and pre-breeding programs targeting root traits to improve yield stability in different environments and soil types. Marker-assisted selection (MAS) can help to speed up the process by selecting key genes or quantitative trait loci (QTL) associated with root traits. However, this approach is limited due to the complex genetic control of root traits and the limited number of well-characterised large effect QTL. Coupling MAS with phenotyping could increase the reliability of selection. Here we present a useful framework to rapidly modify root traits in elite germplasm. In this wheat exemplar, a single plant selection (SPS) approach combined three main elements: phenotypic selection (in this case for seminal root angle); MAS using KASP markers (targeting a root biomass QTL); and speed breeding to accelerate each cycle.

Results

To develop a SPS approach that integrates non-destructive screening for seminal root angle and root biomass, two initial experiments were conducted. Firstly, we demonstrated that transplanting wheat seedlings from clear pots (for seminal root angle assessment) into sand pots (for root biomass assessment) did not impact the ability to differentiate genotypes with high and low root biomass. Secondly, we demonstrated that visual scores for root biomass were correlated with root dry weight (r = 0.72), indicating that single plants could be evaluated for root biomass in a non-destructive manner. To highlight the potential of the approach, we applied SPS in a backcrossing program which integrated MAS and speed breeding for the purpose of rapidly modifying the root system of elite bread wheat line Borlaug100. Bi-directional selection for root angle in segregating generations successfully shifted the mean root angle by 30° in the subsequent generation (P ≤ 0.05). Within 18 months, BC2F4:F5 introgression lines were developed that displayed a full range of root configurations, while retaining similar above-ground traits to the recurrent parent. Notably, the seminal root angle displayed by introgression lines varied more than 30° compared to the recurrent parent, resulting in lines with both narrow and wide root angles, and high and low root biomass phenotypes.

Conclusion

The SPS approach enables researchers and plant breeders to rapidly manipulate root traits of future crop varieties, which could help improve productivity in the face of increasing environmental fluctuations. The newly developed elite wheat lines with modified root traits provide valuable materials to study the value of different root systems to support yield in different environments and soil types.
Prognostic value of tumor measurement parameters and SCC-Ag changes in patients with locally-advanced cervical cancer
Authors: Chen Wenjuan , Xiu Siyi , Xie Xingyun , Guo Huiming , Xu Yuanji , Bai Penggang , Xia Xiaoyi
Published: January 2022

Objective

To investigate the prognostic relevance of specific measurement parameters such as tumor diameter, tumor volume, tumor volume reduction rate (TVRR), and changes in the squamous cell carcinoma antigen (SCC-Ag) level in patients with locally-advanced cervical cancer (LACC) undergoing concurrent radiotherapy and chemotherapy.

Methods

This was a retrospective study of 203 patients with stage IIA–IVA cervical squamous cell carcinoma who were newly diagnosed at our hospital between January 2011 and March 2015. Clinical data and pre-and post-treatment imaging information were collected and each parameter was calculated using 3DSlicer software. The pre/post-treatment tumor diameter (TDpre/post), tumor volume (TVpre/post), SCC-Ag (SCCpre/post), and TVRR, SCC-Ag reduction rate (SCCRR) were analyzed and their prognostic relevance evaluated.

Results

The median follow-up was 69 months. The 5-year overall survival (OS) and disease progression-free survival (PFS) rates were 69.5% and 64.5%, respectively. On univariate analysis, TDpre/post, TVpre/post, TVRR, SCCpre/post and SCCRR showed significant association with OS and PFS (P < 0.05). On multivariate analysis, TDpre [Hazard ratio (HR) = 0.373, P = 0.028], TDpost (HR = 0.376, P = 0.003) and SCCpost (HR = 0.374, P = 0.001) were independent predictors of OS. TVRR (HR = 2.998, P < 0.001), SCCpre (HR = 0.563, P = 0.041), and SCCpost (HR = 0.253, P < 0.001) were independent predictors of PFS. Tumor measurement parameters showed a positive correlation with SCC-Ag (P < 0.05).

Conclusion

TDpre/post, TVpre/post, TVRR, SCCpre/post, and SCCRR were prognostic factors in LACC. TDpre/post and SCCpost showed the most significant prognostic value. TVRR and SCCpre/post were closely related to disease progression. Further studies should investigate the correlation between measurement parameters of tumor and SCC-Ag.
Experienced fatigue in people with rare disorders: a scoping review on characteristics of existing research
Authors: Bathen Trine , Johansen Heidi , Strømme Hilde , Velvin Gry
Published: January 2022

Background

Experienced fatigue is an under-recognized and under-researched feature in persons with many different rare diseases. A better overview of the characteristics of existing research on experienced fatigue in children and adults with rare diseases is needed. The purpose of this review was to map and describe characteristics of existing research on experienced fatigue in a selection of rare diseases in rare developmental defects or anomalies during embryogenesis and rare genetic diseases. Furthermore, to identify research gaps and point to research agendas.

Methods

We applied a scoping review methodology, and performed a systematic search in March 2020 in bibliographic databases. References were sorted and evaluated for inclusion using EndNote and Rayyan. Data were extracted on the main research questions concerning characteristics of research on experienced fatigue (definition and focus on fatigue, study populations, research questions investigated and methods used).

Results

This review included 215 articles on ten different rare developmental defects/anomalies during embryogenesis and 35 rare genetic diseases. Of the 215 articles, 82 had investigation of experienced fatigue as primary aim or outcome. Included were 9 secondary research articles (reviews) and 206 primary research articles. A minority of articles included children. There were large differences in the number of studies in different diseases. Only 29 of 215 articles gave a description of how they defined the concept of experienced fatigue. The most common research-question reported on was prevalence and/ -or associations to fatigue. The least common was diagnostics (development or validation of fatigue assessment methods for a specific patient group). A large variety of methods were used to investigate experienced fatigue, impeding comparisons both within and across diagnoses.

Conclusion

This scoping review on the characteristics of fatigue research in rare diseases found a large variety of research on experienced fatigue. However, the minority of studies had investigation of experienced fatigue as a primary aim. There was large variation in how experienced fatigue was defined and also in how it was measured, both within and across diagnoses. More research on experienced fatigue is needed, both in children and adults with rare diseases. This review offers a basis for further research.
A novel H129-based anterograde monosynaptic tracer exhibits features of strong labeling intensity, high tracing efficiency, and reduced retrograde labeling
Authors: Yang Hong , Xiong Feng , Qin Hai-Bin , Yu Qun-Tao , Sun Jin-Yan , Zhao Hai-Wen , Li Dong , Zhou Youtong , Zhang Fu-Kun , Zhu Xiao-Wen , Wu Tong , Jiang Man , Xu Xiangmin , Lu Youming , Shen Hong-Jie , Zeng Wen-Bo , Zhao Fei , Luo Min-Hua
Published: January 2022

Background

Viral tracers are important tools for mapping brain connectomes. The feature of predominant anterograde transneuronal transmission offers herpes simplex virus-1 (HSV-1) strain H129 (HSV1-H129) as a promising candidate to be developed as anterograde viral tracers. In our earlier studies, we developed H129-derived anterograde polysynaptic tracers and TK deficient (H129-dTK) monosynaptic tracers. However, their broad application is limited by some intrinsic drawbacks of the H129-dTK tracers, such as low labeling intensity due to TK deficiency and potential retrograde labeling caused by axon terminal invasion. The glycoprotein K (gK) of HSV-1 plays important roles in virus entry, egress, and virus-induced cell fusion. Its deficiency severely disables virus egress and spread, while only slightly limits viral genome replication and expression of viral proteins. Therefore, we created a novel H129-derived anterograde monosynaptic tracer (H129-dgK) by targeting gK, which overcomes the limitations of H129-dTK.

Methods

Using our established platform and pipeline for developing viral tracers, we generated a novel tracer by deleting the gK gene from the H129-G4. The gK-deleted virus (H129-dgK-G4) was reconstituted and propagated in the Vero cell expressing wildtype H129 gK (gKwt) or the mutant gK (gKmut, A40V, C82S, M223I, L224V, V309M), respectively. Then the obtained viral tracers of gKmut pseudotyped and gKwt coated H129-dgK-G4 were tested in vitro and in vivo to characterize their tracing properties.

Results

H129-dgK-G4 expresses high levels of fluorescent proteins, eliminating the requirement of immunostaining for imaging detection. Compared to the TK deficient monosynaptic tracer H129-dTK-G4, H129-dgK-G4 labeled neurons with 1.76-fold stronger fluorescence intensity, and visualized 2.00-fold more postsynaptic neurons in the downstream brain regions. gKmut pseudotyping leads to a 77% decrease in retrograde labeling by reducing axon terminal invasion, and thus dramatically improves the anterograde-specific tracing of H129-dgK-G4. In addition, assisted by the AAV helper trans-complementarily expressing gKwt, H129-dgK-G4 allows for mapping monosynaptic connections and quantifying the circuit connectivity difference in the Alzheimer’s disease and control mouse brains.

Conclusions

gKmut pseudotyped H129-dgK-G4, a novel anterograde monosynaptic tracer, overcomes the limitations of H129-dTK tracers, and demonstrates desirable features of strong labeling intensity, high tracing efficiency, and improved anterograde specificity.
Edaravone activates the GDNF/RET neurotrophic signaling pathway and protects mRNA-induced motor neurons from iPS cells
Authors: Li Qian , Feng Yi , Xue Yingchao , Zhan Xiping , Fu Yi , Gui Gege , Zhou Weiqiang , Richard Jean-Philippe , Taga Arens , Li Pan , Mao Xiaobo , Maragakis Nicholas J. , Ying Mingyao
Published: January 2022

Background

Spinal cord motor neurons (MNs) from human iPS cells (iPSCs) have wide applications in disease modeling and therapeutic development for amyotrophic lateral sclerosis (ALS) and other MN-associated neurodegenerative diseases. We need highly efficient MN differentiation strategies for generating iPSC-derived disease models that closely recapitulate the genetic and phenotypic complexity of ALS. An important application of these models is to understand molecular mechanisms of action of FDA-approved ALS drugs that only show modest clinical efficacy. Novel mechanistic insights will help us design optimal therapeutic strategies together with predictive biomarkers to achieve better efficacy.

Methods

We induce efficient MN differentiation from iPSCs in 4 days using synthetic mRNAs coding two transcription factors (Ngn2 and Olig2) with phosphosite modification. These MNs after extensive characterization were applied in electrophysiological and neurotoxicity assays as well as transcriptomic analysis, to study the neuroprotective effect and molecular mechanisms of edaravone, an FDA-approved drug for ALS, for improving its clinical efficacy.

Results

We generate highly pure and functional mRNA-induced MNs (miMNs) from control and ALS iPSCs, as well as embryonic stem cells. Edaravone alleviates H2O2-induced neurotoxicity and electrophysiological dysfunction in miMNs, demonstrating its neuroprotective effect that was also found in the glutamate-induced miMN neurotoxicity model. Guided by the transcriptomic analysis, we show a previously unrecognized effect of edaravone to induce the GDNF receptor RET and the GDNF/RET neurotrophic signaling in vitro and in vivo, suggesting a clinically translatable strategy to activate this key neuroprotective signaling. Notably, edaravone can replace required neurotrophic factors (BDNF and GDNF) to support long-term miMN survival and maturation, further supporting the neurotrophic function of edaravone-activated signaling. Furthermore, we show that edaravone and GDNF combined treatment more effectively protects miMNs from H2O2-induced neurotoxicity than single treatment, suggesting a potential combination strategy for ALS treatment.

Conclusions

This study provides methodology to facilitate iPSC differentiation and disease modeling. Our discoveries will facilitate the development of optimal edaravone-based therapies for ALS and potentially other neurodegenerative diseases.

Graphical abstract
Mammalian tumor-like organs. 1. The role of tumor-like normal organs and atypical tumor organs in the evolution of development (carcino-evo-devo)
Authors: Kozlov A. P.
Published: January 2022

Background

Earlier I hypothesized that hereditary tumors might participate in the evolution of multicellular organisms. I formulated the hypothesis of evolution by tumor neofunctionalization, which suggested that the evolutionary role of hereditary tumors might consist in supplying evolving multicellular organisms with extra cell masses for the expression of evolutionarily novel genes and the origin of new cell types, tissues, and organs. A new theory—the carcino-evo-devo theory—has been developed based on this hypothesis.

Main text

My lab has confirmed several non-trivial predictions of this theory. Another non-trivial prediction is that evolutionarily new organs if they originated from hereditary tumors or tumor-like structures, should recapitulate some tumor features in their development. This paper reviews the tumor-like features of evolutionarily novel organs. It turns out that evolutionarily new organs such as the eutherian placenta, mammary gland, prostate, the infantile human brain, and hoods of goldfishes indeed have many features of tumors. I suggested calling normal organs, which have many tumor features, the tumor-like organs.

Conclusion

Tumor-like organs might originate from hereditary atypical tumor organs and represent the part of carcino-evo-devo relationships, i.e., coevolution of normal and neoplastic development. During subsequent evolution, tumor-like organs may lose the features of tumors and the high incidence of cancer and become normal organs without (or with almost no) tumor features.
NeuroTrace 500/525 identifies human induced pluripotent stem cell-derived brain pericyte-like cells
Authors: Kim Seo Young , Choi Jihye , Roh Junhee , Kim Chul Hoon
Published: January 2022

In the CNS, pericytes are important for maintaining the blood–brain barrier (BBB) and for controlling blood flow. Recently, several methods were suggested for the differentiation of human pluripotent stem cells (hPSCs) into brain mural cells, specifically pericytes or vascular smooth muscle cells (vSMCs). Unfortunately, identifying the pericytes from among such hPSC-derived mural cells has been challenging. This is due both to the lack of pericyte-specific markers and to the loss of defining anatomical information inherent to culture conditions. We therefore asked whether NeuroTrace 500/525, a newly developed dye that shows cell-specific uptake into pericytes in the mouse brain, can help identify human induced pluripotent stem cell (hiPSC)-derived brain pericyte-like cells. First, we found that NeuroTrace 500/525 specifically stains primary cultured human brain pericytes, confirming its specificity in vitro. Second, we found that NeuroTrace 500/525 specifically labels hiPSC-derived pericyte-like cells, but not endothelial cells or vSMCs derived from the same hiPSCs. Last, we found that neuroectoderm-derived vSMCs, which have pericyte-like features, also take up NeuroTrace 500/525. These data indicate NeuroTrace 500/525 is useful for identifying pericyte-like cells among hiPSC-derived brain mural cells.
The use of personal protection equipment does not negatively affect paramedics’ attention and dexterity: a prospective triple-cross over randomized controlled non-inferiority trial
Authors: Kienbacher Calvin Lukas , Grafeneder Jürgen , Tscherny Katharina , Krammel Mario , Fuhrmann Verena , Niederer Maximilian , Neudorfsky Sabine , Herbich Klaus , Schreiber Wolfgang , Herkner Harald , Roth Dominik
Published: January 2022

Background

The COVID-19 pandemic led to widespread use of personal protection equipment (PPE), including filtering face piece (FFP) masks, throughout the world. PPE. Previous studies indicate that PPE impairs neurocognitive performance in healthcare workers. Concerns for personnel safety have led to special recommendations regarding basic life support (BLS) in patients with a potential SARS-CoV-2 infection, including the use of PPE. Established instruments are available to assess attention and dexterity in BLS settings, respectively. We aimed to evaluate the influence of PPE with different types of FFP masks on these two neuropsychological components of EMS personnel during BLS.

Methods

This was a randomized controlled non-inferiority triple-crossover study. Teams of paramedics completed three 12-min long BLS scenarios on a manikin after having climbed three flights of stairs with equipment, each in three experimental conditions: (a) without pandemic PPE, (b) with PPE including a FFP2 mask with an expiration valve and (c) with PPE including an FFP2 mask without an expiration valve. The teams and intervention sequences were randomized. We measured the shift in concentration performance using the d2 test and dexterity using the nine-hole peg test (NHPT). We compared results between the three conditions. For the primary outcome, the non-inferiority margin was set at 20 points.

Results

Forty-eight paramedics participated. Concentration performance was significantly better after each scenario, with no differences noted between groups: d2 shift control versus with valve − 8.3 (95% CI − 19.4 to 2.7) points; control versus without valve − 8.5 (− 19.7 to 2.7) points; with valve versus without valve 0.1 (− 11.1 to 11.3) points. Similar results were found for the NHPT: + 0.3 (− 0.7 to 1.4), − 0.4 (− 1.4 to 0.7), 0.7 (− 0.4 to 1.8) s respectively.

Conclusion

Attention increases when performing BLS. Attention and dexterity are not inferior when wearing PPE, including FFP2 masks. PPE should be used on a low-threshold basis.
Infantile idiopathic intracranial hypertension: case report and review of the literature
Authors: Del Monte Francesco , Bucchino Laura , Versace Antonia , Tardivo Irene , Castagno Emanuele , Pieri Giovanni , Pilloni Giulia , Felici Enrico , Urbino Antonio Francesco
Published: January 2022

Background

Idiopathic intracranial hypertension is an infrequent condition of childhood, and is extremely rare in infants, with only 26 cases described. The etiology is still unknown. Typical clinical manifestations change with age, and symptoms are atypical in infants, thus the diagnosis could be late. This is based on increased opening pressure at lumbar puncture, papilloedema and normal cerebral MRI. The measurement of cerebrospinal fluid opening pressure in infants is an issue because many factors may affect it, and data about normal values are scanty. The mainstay of treatment is acetazolamide, which allows to relieve symptoms and to avoid permanent visual loss if promptly administered.

Case presentation

We report the case of an 8-month-old infant admitted because of vomit, loss of appetite and irritability; later, also bulging anterior fontanel was observed. Cerebral MRI and cerebrospinal fluid analysis resulted negative and after two lumbar punctures he experienced initial symptom relief. Once the diagnosis of idiopathic intracranial hypertension was made, he received oral acetazolamide, and corticosteroids, with progressive symptom resolution.

Conclusions

Infantile idiopathic intracranial hypertension is extremely rare, and not well described yet. Bulging anterior fontanel in otherwise healthy infants with normal neuroimaging should be always considered suggestive, but can be a late sign, while irritability and anorexia, especially if associated with vomiting, may represent an early sign. In such cases, lumbar puncture should be always done, hopefully with cerebrospinal fluid opening pressure measurement, which is among coded diagnostic criteria, but whose threshold is controversial in infants. Early diagnosis, timely treatment and strict follow-up help to prevent vision loss or death of affected infants.
Reasons in favour of universal vaccination campaign against COVID-19 in the pediatric population
Authors: Principi Nicola , Esposito Susanna
Published: January 2022

Background

Despite the growing evidence of the extreme efficacy of COVID-19 vaccines in adults and the elderly, the administration of the same prophylactic measures to pediatric subjects is debated by some parents and by a number of researchers. The aim of this manuscript is to explain the reasons for overcoming hesitancy towards COVID-19 vaccination in children and adolescents and to highlight the importance of universal COVID-19 vaccination in the pediatric population.

Main findings

Recent epidemiological data suggest that the risk that a child with COVID-19 is hospitalized or admitted to the pediatric intensive care unit is greater than initially thought. Children may also suffer from long COVID and school closure because of COVID-19 can cause relevant mental health problems in the pediatric population. Placebo-controlled, observer-blinded, clinical trials showed appropriate efficacy, safety and tolerability of authorized mRNA COVID-19 vaccines in children and adolescents 12–17 years old. Vaccination in children younger than 12 years of age will allow further benefits .

Conclusions

COVID-19 vaccine administration seems mandatory in all the children and adolescents because of COVID-19 related complications as well as the efficacy, safety and tolerability of COVID-19 vaccines in this population. Due to the recent approval of COVID-9 vaccines for children 5–10 years old, it is desirable that vaccine opponents can understand how important is the universal immunization against COVID-19 for the pediatric subjects.
Intranasal dexmedetomidine and intranasal ketamine association allows shorter induction time for pediatric sedation compared to intranasal dexmedetomidine and oral midazolam
Authors: Cossovel Francesca , Trombetta Andrea , Ramondo Augusto , Riccio Guglielmo , Ronfani Luca , Saccari Alessia , Cozzi Giorgio , Barbi Egidio
Published: January 2022

Background

Non-painful diagnostic procedures require an inactive state for a prolonged time, so that sedation is often needed in younger children to perform the procedures. Our standard of care in this setting consists of the association between oral midazolam (0.5 mg/kg) and intranasal dexmedetomidine (4 mcg/kg). One of the limits of this approach is that the onset of action is quite delayed (up to 55 min) and poorly predictable. We chose to compare this association with intranasal-ketamine and intranasal-dexmedetomidine.

Methods

This is a “pre-post” study. The study population included the first forty children receiving sedation with the “new” combination intranasal ketamine (3 mg/kg) and intranasal dexmedetomidine (4 mcg/kg) compared to a historical cohort including the last forty children receiving sedation with our standard of care combination of intranasal dexmedetomidine (4mcg/kg) and oral midazolam (0,5 mg/kg).

Results

The association intranasal dexmedetomidine and intranasal ketamine allowed for a significantly shorter sedation induction time than the combination intranasal dexmedetomidine and oral midazolam (13,5 min versus 35 min). Both group’s cumulative data showed a correlation between age and sedation effectiveness, with younger children presenting a higher success rate and shorter induction time (p 0,001). Conclusions: This study suggests that the ketamine and dexmedetomidine intranasal association may have a shorter onset of action when compared to intranasal dexmedetomidine and oral midazolam.
Altered microstructure of the splenium of corpus callosum is associated with neurodevelopmental impairment in preterm infants with necrotizing enterocolitis
Authors: Cha Jong Ho , Lim Jung-Sun , Jang Yong Hun , Hwang Jae Kyoon , Na Jae Yoon , Lee Jong-Min , Lee Hyun Ju , Ahn Ja-Hye
Published: January 2022

Background

Necrotizing enterocolitis (NEC) is a devastating disease in preterm infants with significant morbidities, including neurodevelopmental impairment (NDI). This study aimed to investigate whether NEC is associated with (1) brain volume expansion and white matter maturation using diffusion tensor imaging analysis and (2) NDI compared with preterm infants without NEC.

Methods

We included 86 preterm infants (20 with NEC and 66 without NEC) with no evidence of brain abnormalities on trans-fontanelle ultrasonography and magnetic resonance imaging at term-equivalent age (TEA). Regional brain volume analysis and white matter tractography were performed to study brain microstructure alterations. NDI was assessed using the Bayley Scales of Infant and Toddler Development-III (BSID-III) at 18 months of corrected age (CA).

Results

Preterm infants with NEC showed significantly high risk of motor impairment (odds ratio 58.26, 95% confidence interval 7.80–435.12, p < 0.001). We found significantly increased mean diffusivity (MD) in the splenium of corpus callosum (sCC) (p = 0.001) and the left corticospinal tract (p = 0.001) in preterm infants with NEC. The sCC with increased MD showed a negative association with the BSID-III language (p = 0.025) and motor scores (p = 0.002) at 18 months of CA, implying the relevance of sCC integrity with later NDI.

Conclusion

The white matter microstructure differed between preterm infants with and without NEC. The prognostic value of network parameters of sCC at TEA may provide better information for the early detection of NDI in preterm infants.
Impact of time to intubation on mortality and pulmonary sequelae in critically ill patients with COVID-19: a prospective cohort study
Authors: González Jessica , Benítez Iván D. , de Gonzalo-Calvo David , Torres Gerard , de Batlle Jordi , Gómez Silvia , Moncusí-Moix Anna , Carmona Paola , Santisteve Sally , Monge Aida , Gort-Paniello Clara , Zuil María , Cabo-Gambín Ramón , Manzano Senra Carlos , Vengoechea Aragoncillo José Javier , Vaca Rafaela , Minguez Olga , Aguilar María , Ferrer Ricard , Ceccato Adrián , Fernández Laia , Motos Ana , Riera Jordi , Menéndez Rosario , Garcia-Gasulla Darío , Peñuelas Oscar , Labarca Gonzalo , Caballero Jesús , Barberà Carme , Torres Antoni , Barbé Ferran ,   CIBERESUCICOVID Project (COV20/00110, ISCIII), Ferrer Ricard , Cecato Adrián , Fernández Laia , Motos Anna , Riera Jordi , Menéndez Rosario , García-Gasulla Dario , Peñuelas Oscar , Labarca Gonzalo , Caballero Jesus , Barberà Carme
Published: January 2022

Question

We evaluated whether the time between first respiratory support and intubation of patients receiving invasive mechanical ventilation (IMV) due to COVID-19 was associated with mortality or pulmonary sequelae.

Materials and methods

Prospective cohort of critical COVID-19 patients on IMV. Patients were classified as early intubation if they were intubated within the first 48 h from the first respiratory support or delayed intubation if they were intubated later. Surviving patients were evaluated after hospital discharge.

Results

We included 205 patients (140 with early IMV and 65 with delayed IMV). The median [p25;p75] age was 63 [56.0; 70.0] years, and 74.1% were male. The survival analysis showed a significant increase in the risk of mortality in the delayed group with an adjusted hazard ratio (HR) of 2.45 (95% CI 1.29–4.65). The continuous predictor time to IMV showed a nonlinear association with the risk of in-hospital mortality. A multivariate mortality model showed that delay of IMV was a factor associated with mortality (HR of 2.40; 95% CI 1.42–4.1). During follow-up, patients in the delayed group showed a worse DLCO (mean difference of − 10.77 (95% CI − 18.40 to − 3.15), with a greater number of affected lobes (+ 1.51 [95% CI 0.89–2.13]) and a greater TSS (+ 4.35 [95% CI 2.41–6.27]) in the chest CT scan.

Conclusions

Among critically ill patients with COVID-19 who required IMV, the delay in intubation from the first respiratory support was associated with an increase in hospital mortality and worse pulmonary sequelae during follow-up.
The genome of oil-Camellia and population genomics analysis provide insights into seed oil domestication
Authors: Lin Ping , Wang Kailiang , Wang Yupeng , Hu Zhikang , Yan Chao , Huang Hu , Ma Xianjin , Cao Yongqing , Long Wei , Liu Weixin , Li Xinlei , Fan Zhengqi , Li Jiyuan , Ye Ning , Ren Huadong , Yao Xiaohua , Yin Hengfu
Published: January 2022

Background

As a perennial crop, oil-Camellia possesses a long domestication history and produces high-quality seed oil that is beneficial to human health. Camellia oleifera Abel. is a sister species to the tea plant, which is extensively cultivated for edible oil production. However, the molecular mechanism of the domestication of oil-Camellia is still limited due to the lack of sufficient genomic information.

Results

To elucidate the genetic and genomic basis of evolution and domestication, here we report a chromosome-scale reference genome of wild oil-Camellia (2.95 Gb), together with transcriptome sequencing data of 221 cultivars. The oil-Camellia genome, assembled by an integrative approach of multiple sequencing technologies, consists of a large proportion of repetitive elements (76.1%) and high heterozygosity (2.52%). We construct a genetic map of high-density corrected markers by sequencing the controlled-pollination hybrids. Genome-wide association studies reveal a subset of artificially selected genes that are involved in the oil biosynthesis and phytohormone pathways. Particularly, we identify the elite alleles of genes encoding sugar-dependent triacylglycerol lipase 1, β-ketoacyl-acyl carrier protein synthase III, and stearoyl-acyl carrier protein desaturases; these alleles play important roles in enhancing the yield and quality of seed oil during oil-Camellia domestication.

Conclusions

We generate a chromosome-scale reference genome for oil-Camellia plants and demonstrate that the artificial selection of elite alleles of genes involved in oil biosynthesis contributes to oil-Camellia domestication.
Multiple secondary outcome analyses: precise interpretation is important
Authors: Parker Richard A. , Weir Christopher J.
Published: January 2022

Analysis of multiple secondary outcomes in a clinical trial leads to an increased probability of at least one false significant result among all secondary outcomes studied. In this paper, we question the notion that that if no multiplicity adjustment has been applied to multiple secondary outcome analyses in a clinical trial, then they must necessarily be regarded as exploratory. Instead, we argue that if individual secondary outcome results are interpreted carefully and precisely, there is no need to downgrade our interpretation to exploratory. This is because the probability of a false significant result for each comparison, the per-comparison wise error rate, does not increase with multiple testing. Strong effects on secondary outcomes should always be taken seriously and must not be dismissed purely on the basis of multiplicity concerns.
Nasal high-flow compared to non-invasive ventilation in treatment of acute acidotic hypercapnic exacerbation of chronic obstructive pulmonary disease—protocol for a randomized controlled noninferiority trial (ELVIS)
Authors: Bräunlich Jens , Köppe-Bauernfeind Nicole , Petroff David , Franke Annegret , Wirtz Hubert
Published: January 2022

Background

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) have a major negative impact on health status, rates of hospitalization, readmission, disease progression and mortality. Non-invasive ventilation (NIV) is the standard therapy for hypercapnic acidotic respiratory failure in AECOPD. Despite its beneficial effects, NIV is often poorly tolerated (11–34 % failure rate). An increasing number of studies have documented a beneficial effect of nasal high-flow (NHF) in acute hypercapnia. We designed a prospective, randomized, multi-centre, open label, non-inferiority trial to compare treatment failure in nasal NHF vs NIV in patients with acidotic hypercapnic AECOPD.

Methods

The study will be conducted in about 35 sites in Germany. Patients with hypercapnic AECOPD with respiratory acidosis (pH < 7.35) will be randomized 1:1 to NIV or NHF. The primary outcome is the combined endpoint of intubation, treatment failure or death at 72 h. The switch from one to the other device marks a device failure but acts as a rescue treatment in absence of intubation criteria. A sample size of 720 was calculated to have 80% power for showing that NHF is non-inferior to NIV with a margin of 8 percentage points. Linear regression will be used for the confirmatory analysis.

Discussion

If NHF is shown to be non-inferior to NIV in acidotic hypercapnic AECOPD, it could become an important alternative treatment.

Trial registration

ClinicalTrials.gov, NCT04881409, Registered on May 11, 2021
Comparison of outcomes and side effects for neoadjuvant chemotherapy with weekly cisplatin and paclitaxel followed by chemoradiation vs. chemoradiation alone in stage IIB–IVA cervical cancer: study protocol for a randomized controlled trial
Authors: Li Jing , Liu Hua , Li Ya , Li Jian , Shen Lifei , Long Wenqing , Yang Chenmin , Xu Haoping , Xi Wenqi , Cai Rong , Feng Weiwei
Published: January 2022

Background

Currently, the standard treatment for locally advanced cervical cancer is concurrent chemoradiation (CCRT). The effect of neoadjuvant chemotherapy in advanced cervical cancer is controversial. Studies have shown that the addition of a weekly regimen of neoadjuvant chemotherapy (NACT) followed by CCRT may be superior to a thrice-weekly regimen of NACT and CCRT. Among patients who had not received prior cisplatin, a cisplatin and paclitaxel (TP) regimen resulted in longer overall survival than other regimens. This study aims to investigate the feasibility, safety, and efficacy of NACT with weekly TP followed by CCRT.

Methods

This is a prospective, randomized, open-labeled, multicentered phase III study. Based on a 65% of 2-year disease-free survival (DFS) rate in the CCRT group and 80% of that in NACT followed by CCRT group, and on prerequisite conditions including an 8% loss to follow-up, a two-sided 5% of type I error probability, and an 80% of power, a total of 300 cases were required for enrollment. Patients with IIB–IVA cervical cancer will be randomly allocated in a 1:1 ratio to one of two intervention arms. In the study arm, patients will receive dose-dense cisplatin (40 mg/m2) and paclitaxel (60 mg/m2) weekly for 4 cycles followed by CCRT (45 Gy in 5 weeks concurrent with cisplatin 40 mg/m2 weekly) plus image-guided adaptive brachytherapy (IGBRT). In the control arm, patients will undergo CCRT treatment. The primary endpoint of the study is 2-year disease-free survival (DFS); the secondary endpoints are 5-year overall survival (OS) and disease-free survival (DFS), the response rate 3 months after treatment completion, grade III/IV adverse effects, and quality of life, and potential biomarkers for predicting treatment response will also be studied.

Discussion

The data gathered from the study will be used to determine whether NACT with weekly TP followed by CCRT may become an optimized treatment for locally advanced cervical cancer.

Trial registration

Chinese Clinical Trial Registry ChiCTR1900025327. Registered on 24 August 2019. medresman.org.cn ChiCTR1900025326
Patient-derived xenograft models capture genomic heterogeneity in endometrial cancer
Authors: Bonazzi Vanessa F. , Kondrashova Olga , Smith Deborah , Nones Katia , Sengal Asmerom T. , Ju Robert , Packer Leisl M. , Koufariotis Lambros T. , Kazakoff Stephen H. , Davidson Aimee L. , Ramarao-Milne Priya , Lakis Vanessa , Newell Felicity , Rogers Rebecca , Davies Claire , Nicklin James , Garrett Andrea , Chetty Naven , Perrin Lewis , Pearson John V. , Patch Ann-Marie , Waddell Nicola , Pollock Pamela M.
Published: January 2022

Background

Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models.

Methods

Here, we report whole exome or whole genome sequencing of 11 PDX models and their matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC.

Results

PDX models were successfully generated from grade 2/3 tumors, including three uterine carcinosarcomas. The models showed similar histomorphology to the primary tumors and represented all four molecular subtypes of EC, including five mismatch-repair deficient models. The different PDX lineages showed a wide range of inter-tumor and intra-tumor heterogeneity. However, for most PDX models, one arm recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease; however, all lacked the HR deficiency genomic signature.

Conclusions

EC PDX models represent the four molecular subtypes of disease and can capture intra-tumor heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi; however, deeper and more durable responses will likely require combination of PARPi with other agents.
Impact of lung function decline on time to hospitalisation events in systemic sclerosis-associated interstitial lung disease (SSc-ILD): a joint model analysis
Authors: Kreuter Michael , Del Galdo Francesco , Miede Corinna , Khanna Dinesh , Wuyts Wim A. , Hummers Laura K. , Alves Margarida , Schoof Nils , Stock Christian , Allanore Yannick
Published: January 2022

Background

Interstitial lung disease (ILD) is a common organ manifestation in systemic sclerosis (SSc) and is the leading cause of death in patients with SSc. A decline in forced vital capacity (FVC) is an indicator of ILD progression and is associated with mortality in patients with SSc-associated ILD (SSc-ILD). However, the relationship between FVC decline and hospitalisation events in patients with SSc-ILD is largely unknown. The objective of this post hoc analysis was to investigate the relationship between FVC decline and clinically important hospitalisation endpoints.

Methods

We used data from SENSCIS®, a phase III trial investigating the efficacy and safety of nintedanib in patients with SSc-ILD. Joint models for longitudinal and time-to-event data were used to assess the association between rate of decline in FVC% predicted and hospitalisation-related endpoints (including time to first all-cause hospitalisation or death; time to first SSc-related hospitalisation or death; and time to first admission to an emergency room [ER] or admission to hospital followed by admission to intensive care unit [ICU] or death) during the treatment period, over 52 weeks in patients with SSc-ILD.

Results

There was a statistically significant association between FVC decline and the risk of all-cause (n = 78) and SSc-related (n = 42) hospitalisations or death (both P < 0.0001). A decrease of 3% in FVC corresponded to a 1.43-fold increase in risk of all-cause hospitalisation or death (95% confidence interval [CI] 1.24, 1.65) and a 1.48-fold increase in risk of SSc-related hospitalisation or death (95% CI 1.23, 1.77). No statistically significant association was observed between FVC decline and admission to ER or to hospital followed by admission to ICU or death (n = 75; P = 0.15). The estimated slope difference for nintedanib versus placebo in the longitudinal sub-model was consistent with the primary analysis in SENSCIS®.

Conclusions

The association of lung function decline with an increased risk of hospitalisation suggests that slowing FVC decline in patients with SSc-ILD may prevent hospitalisations. Our findings also provide evidence that FVC decline may serve as a surrogate endpoint for clinically relevant hospitalisation-associated endpoints.

Trial registration

ClinicalTrials.govNCT02597933. Registered on 8 October 2015.
Inter-rater reliability of optic nerve sheath diameter measurement using real-time ultrasonography
Authors: Jennings Jason B. , Oliva Cynthia , Joyce Michael , Vitto Michael J. , Tozer Jordan , Taylor Lindsay A. , Evans David P.
Published: January 2022

Objectives

Ultrasound measurement of the optic nerve sheath diameter (ONSD) is a rapid, non-invasive means to indirectly assess intracranial pressure. Previous research has demonstrated the ability of emergency physicians to measure ONSD accurately with bedside ultrasound when compared to CT scan or MRI, however the reliability of this measurement between two or more operators has been called into question (Hassen et al. in J Emerg Med 48:450–457, 2015; Shirodkar et al. in Ind J Crit Care Med 19:466–470, 2015). Given the need for accurate and precise measurement to use this as a screening exam, we sought to determine the inter-rater reliability between ONSD measurements obtained in real time by fellowship-trained emergency ultrasound physicians.

Methods

Three ultrasound fellowship-trained emergency physicians measured bilateral ONSD of 10 healthy volunteers using a high-frequency linear transducer. The physicians were blinded to the other scanners’ measurements, and no instructions were given other than to obtain the ONSD. Each sonographer measured the ONSD in real time and it was recorded by a research coordinator. All measurements were recorded in millimeters. Intraclass correlation coefficients (ICCs) were calculated to estimate the inter-rater reliability.

Results

A total of 60 measurements of ONSD were obtained. The average measurement was 4.3 mm (3.83–4.77). Very little variation was found between the three physicians, with a calculated ICC of 0.82 (95% confidence interval 0.63–0.92).

Conclusions

ONSD measurement obtained by ultrasound fellowship-trained emergency medicine physicians is a reliable measurement with a high degree of correlation between scanners.