bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic significance of concurrent gene mutations in intensively treated patients withIDH-mutated AML: an ALFA study
Authors: Duchmann Matthieu , Micol Jean-Baptiste , Duployez Nicolas , Raffoux Emmanuel , Thomas Xavier , Marolleau Jean-Pierre , Braun Thorsten , Adès Lionel , Chantepie Sylvain , Lemasle Emilie , Berthon Céline , Malfuson Jean-Valère , Pautas Cécile , Lambert Juliette , Boissel Nicolas , Celli-Lebras Karine , Caillot Denis , Turlure Pascal , Vey Norbert , Pigneux Arnaud , Recher Christian , Terré Christine , Gardin Claude , Itzykson Raphaël , Preudhomme Claude , Dombret Hervé , de Botton Stéphane
Published: April 2021

In patients with isocitrate dehydrogenase (IDH)–mutated acute myeloid leukemia (AML) treated by intensive chemotherapy (IC), prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are of particular interest with the advent of IDH1/2 mutant inhibitors. We retrospectively analyzed 319 patients with newly diagnosed AML (127 with IDH1, 135 with IDH2R140, and 57 with IDH2R172 mutations) treated with IC in 3 Acute Leukemia French Association prospective trials. In each IDH subgroup, we analyzed the prognostic impact of clinical and genetic covariates, and the role of HSCT. In patients with IDH1 mutations, the presence of NPM1 mutations was the only variable predicting improved overall survival (OS) in multivariate analysis (P < .0001). In IDH2R140-mutated AML, normal karyotype (P = .008) and NPM1 mutations (P = .01) predicted better OS. NPM1 mutations were associated with better disease-free survival (DFS; P = .0009), whereas the presence of DNMT3A mutations was associated with shorter DFS (P = .0006). In IDH2R172-mutated AML, platelet count was the only variable retained in the multivariate model for OS (P = .002). Among nonfavorable European LeukemiaNet 2010–eligible patients, 71 (36%) underwent HSCT in first complete remission (CR1) and had longer OS (P = .03) and DFS (P = .02) than nontransplanted patients. Future clinical trials testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the primary prognostic factor in IDH1- or IDH2R140-mutated AML. HSCT improve OS of nonfavorable IDH1/2-mutated AML and should be fully integrated into the treatment strategy.
Characteristics and impact of exercise-induced laryngeal obstruction: an international perspective
Authors: Walsted Emil S. , Famokunwa Bamidele , Andersen Louise , Rubak Sune L. , Buchvald Frederik , Pedersen Lars , Dodd James , Backer Vibeke , Nielsen Kim G. , Getzin Andrew , Hull James H.
Published: April 2021

Background

Exercise-induced laryngeal obstruction (EILO) is a common cause of exertional breathlessness and wheeze yet is frequently misdiagnosed as asthma. Insight regarding the demographic characteristics, laryngeal abnormalities and impact of EILO is currently limited, with data only available from individual centre reports. The aim of this work was to provide a broader perspective from a collaboration between multiple international expert centres.

Methods

Five geographically distinct clinical paediatric and adult centres (3 Denmark, 1 UK, 1 USA) with an expertise in assessing unexplained exertional breathlessness completed database entry of key characteristic features for all cases referred with suspected EILO over a 5-year period. All included cases completed clinical asthma workup and continuous laryngoscopy during exercise (CLE) testing for EILO.

Results

Data were available for 1007 individuals (n=713 female (71%)) with a median (range) age of 24 (8–76) years, and of these 586 (58%) were diagnosed with EILO. In all centres, EILO was frequently misdiagnosed as asthma; on average there was a 2-year delay to diagnosis of EILO, and current asthma medication was discontinued in 20%. Collapse at the supraglottic level was seen in 60%, whereas vocal cord dysfunction (VCD) was only detected/visualised in 18%. Nearly half (45%) of individuals with EILO were active participants in recreational-level sports, suggesting that EILO is not simply confined to competitive/elite athletes.

Conclusion

Our findings indicate that key clinical characteristics and the impact of EILO/VCD are similar in globally distinct regions, facilitating improved awareness of this condition to enhance recognition and avoid erroneous asthma treatment.
GRAPES-DD: exploiting decision diagrams for index-driven search in biological graph databases
Authors: Licheri Nicola , Bonnici Vincenzo , Beccuti Marco , Giugno Rosalba
Published: April 2021

Background

Graphs are mathematical structures widely used for expressing relationships among elements when representing biomedical and biological information. On top of these representations, several analyses are performed. A common task is the search of one substructure within one graph, called target. The problem is referred to as one-to-one subgraph search, and it is known to be NP-complete. Heuristics and indexing techniques can be applied to facilitate the search. Indexing techniques are also exploited in the context of searching in a collection of target graphs, referred to as one-to-many subgraph problem. Filter-and-verification methods that use indexing approaches provide a fast pruning of target graphs or parts of them that do not contain the query. The expensive verification phase is then performed only on the subset of promising targets. Indexing strategies extract graph features at a sufficient granularity level for performing a powerful filtering step. Features are memorized in data structures allowing an efficient access. Indexing size, querying time and filtering power are key points for the development of efficient subgraph searching solutions.

Results

An existing approach, GRAPES, has been shown to have good performance in terms of speed-up for both one-to-one and one-to-many cases. However, it suffers in the size of the built index. For this reason, we propose GRAPES-DD, a modified version of GRAPES in which the indexing structure has been replaced with a Decision Diagram. Decision Diagrams are a broad class of data structures widely used to encode and manipulate functions efficiently. Experiments on biomedical structures and synthetic graphs have confirmed our expectation showing that GRAPES-DD has substantially reduced the memory utilization compared to GRAPES without worsening the searching time.

Conclusion

The use of Decision Diagrams for searching in biochemical and biological graphs is completely new and potentially promising thanks to their ability to encode compactly sets by exploiting their structure and regularity, and to manipulate entire sets of elements at once, instead of exploring each single element explicitly. Search strategies based on Decision Diagram makes the indexing for biochemical graphs, and not only, more affordable allowing us to potentially deal with huge and ever growing collections of biochemical and biological structures.
Gene coexpression networks reveal molecular interactions underlying cichlid jaw modularity
Authors: Singh Pooja , Ahi Ehsan Pashay , Sturmbauer Christian
Published: April 2021

Background

The oral and pharyngeal jaw of cichlid fishes are a classic example of evolutionary modularity as their functional decoupling boosted trophic diversification and contributed to the success of cichlid adaptive radiations. Most studies until now have focused on the functional, morphological, or genetic aspects of cichlid jaw modularity. Here we extend this concept to include transcriptional modularity by sequencing whole transcriptomes of the two jaws and comparing their gene coexpression networks.

Results

We show that transcriptional decoupling of gene expression underlies the functional decoupling of cichlid oral and pharyngeal jaw apparatus and the two units are evolving independently in recently diverged cichlid species from Lake Tanganyika. Oral and pharyngeal jaw coexpression networks reflect the common origin of the jaw regulatory program as there is high preservation of gene coexpression modules between the two sets of jaws. However, there is substantial rewiring of genetic architecture within those modules. We define a global jaw coexpression network and highlight jaw-specific and species-specific modules within it. Furthermore, we annotate a comprehensive in silico gene regulatory network linking the Wnt and AHR signalling pathways to jaw morphogenesis and response to environmental cues, respectively. Components of these pathways are significantly differentially expressed between the oral and pharyngeal jaw apparatus.

Conclusion

This study describes the concerted expression of many genes in cichlid oral and pharyngeal jaw apparatus at the onset of the independent life of cichlid fishes. Our findings suggest that – on the basis of an ancestral gill arch network—transcriptional rewiring may have driven the modular evolution of the oral and pharyngeal jaws, highlighting the evolutionary significance of gene network reuse. The gene coexpression and in silico regulatory networks presented here are intended as resource for future studies on the genetics of vertebrate jaw morphogenesis and trophic adaptation.
Chloroplast phylogenomic insights into the evolution of Distylium (Hamamelidaceae)
Authors: Dong Wenpan , Liu Yanlei , Xu Chao , Gao Yongwei , Yuan Qingjun , Suo Zhili , Zhang Zhixiang , Sun Jiahui
Published: April 2021

Background

MostDistyliumspecies are endangered.Distyliumspecies mostly display homoplasy in their flowers and fruits, and are classified primarily based on leaf morphology. However, leaf size, shape, and serration vary tremendously making it difficult to use those characters to identify most species and a significant challenge to address the taxonomy ofDistylium.To infer robust relationships and develop variable markers to identifyDistyliumspecies, we sequenced most of theDistyliumspecies chloroplast genomes.

Results

TheDistyliumchloroplast genome size was 159,041–159,127 bp and encoded 80 protein-coding, 30 transfer RNAs, and 4 ribosomal RNA genes. There was a conserved gene order and a typical quadripartite structure. Phylogenomic analysis based on whole chloroplast genome sequences yielded a highly resolved phylogenetic tree and formed a monophyletic group containing fourDistyliumclades. A dating analysis suggested thatDistyliumoriginated in the Oligocene (34.39 Ma) and diversified within approximately 1 Ma. The evidence shows thatDistyliumis a rapidly radiating group. Four highly variable markers,matK-trnK,ndhC-trnV,ycf1, andtrnT-trnL, and 74 polymorphic simple sequence repeats were discovered in theDistyliumplastomes.

Conclusions

The plastome sequences had sufficient polymorphic information to resolve phylogenetic relationships and identifyDistyliumspecies accurately.
The use of experimental vignette studies to identify drivers of variations in the delivery of health care: a scoping review
Authors: Sheringham Jessica , Kuhn Isla , Burt Jenni
Published: April 2021

Background

Identifying how unwarranted variations in healthcare delivery arise is challenging. Experimental vignette studies can help, by isolating and manipulating potential drivers of differences in care. There is a lack of methodological and practical guidance on how to design and conduct these studies robustly. The aim of this study was to locate, methodologically assess, and synthesise the contribution of experimental vignette studies to the identification of drivers of unwarranted variations in healthcare delivery.

Methods

We used a scoping review approach. We searched MEDLINE, Embase, Web of Science and CINAHL databases (2007–2019) using terms relating to vignettes and variations in healthcare. We screened title/abstracts and full text to identify studies using experimental vignettes to examine drivers of variations in healthcare delivery. Included papers were assessed against a methodological framework synthesised from vignette study design recommendations within and beyond healthcare.

Results

We located 21 eligible studies. Study participants were almost exclusively clinicians (18/21). Vignettes were delivered via text (n = 6), pictures (n = 6), video (n = 6) or interactively, using face-to-face, telephone or online simulated consultations (n = 3). Few studies evaluated the credibility of vignettes, and many had flaws in their wider study design. Ten were of good methodological quality. Studies contributed to understanding variations in care, most commonly by testing hypotheses that could not be examined directly using real patients.

Conclusions

Experimental vignette studies can be an important methodological tool for identifying how unwarranted variations in care can arise. Flaws in study design or conduct can limit their credibility or produce biased results. Their full potential has yet to be realised.
Acute surgical‐like abdomen as a gastrointestinal manifestation of COVID-19 infection: a case report in Colombia
Authors: Sierra-Arango Fernando , Vergara-Cabra Cathalina , Vásquez-Roldan Mariana , Pérez-Riveros Erika D.
Published: April 2021

Background

The SARS-CoV-2 pandemic is a considerable public health problem, which has caused a burden on health systems in many countries. Despite the existence of multiple studies on the different digestive symptoms and their relationship with this disease, it is still vital to highlight the severity of the different symptoms, the need to diagnose it properly and quickly. Currently in Colombia there are no writings that highlight the above.

Case presentation

This article reports the case of a 37-year-old female patient, with no important history, who consulted for 10 h of a generalized intense abdominal pain, of sudden onset, associated with multiple stools of diarrheal consistency, and no respiratory symptoms and no epidemiological exposure. Physical examination with intense pain in the colic frame with tenderness. It was decided to rule out surgical pathology and a CT scan was performed finding no evidence of acute intra-abdominal pathology, but with a peripheral alveolar, and ground-glass opacities at lung bases, classic COVID-19 radiological pattern, confirmed by a positive RT-PCR for SARS-CoV-2, leading to consider that the gastrointestinal symptoms were secondary to this infection. Symptomatic management was given with subsequent improvement.

Conclusions

It is extremely important to present this first case report of a young female COVID-19 patient with an acute abdominal pain as the main clinical manifestation, that almost culminates in a surgical procedure; demonstrating the scope of gastrointestinal symptoms secondary to SARS-CoV-2 infection.
Different renal manifestations associated with very early onset pediatric inflammatory bowel disease: case report and review of literature
Authors: Angeletti A. , Arrigo S. , Madeo A. , Molteni M. , Vietti E. , Arcuri L. , Coccia M. C. , Gandullia P. , Ghiggeri G. M.
Published: April 2021

Background

Inflammatory bowel diseases are characterized by chronic inflammation of the gastrointestinal tract. In particular, Crohn disease and ulcerative colitis represent the two most common types of clinical manifestations. Extraintestinal manifestations of inflammatory bowel diseases represent a common complications, probably reflecting the systemic inflammation. Renal involvement is reported in 4–23% of cases. However, available data are limited to few case series and retrospective analysis, therefore the real impact of renal involvement is not well defined.

Case presentation

We report the case of a 10-years old male affected by very early onset unclassified-Inflammatory bowel diseases since he was 1-year old, presenting with a flare of inflammatory bowel diseases associated with acute kidney injury due to granulomatous interstitial nephritis. Of interest, at 7-year-old, he was treated for IgA nephropathy.

To our knowledge, no previous reports have described a relapse of renal manifestation in inflammatory bowel diseases, characterized by two different clinical and histological phenotypes.

Conclusions

The link between the onset of kidney injuries with flares of intestinal inflammation suggest that nephritis maybe considered an extra-intestinal manifestation correlated with active inflammatory bowel disease. However, if granulomatous interstitial nephritis represents a cell-mediated hypersensitivity reaction than a true extraintestinal manifestation of inflammatory bowel diseases is still not clarified. We suggest as these renal manifestations here described may be interpreted as extraintestinal disorder and also considered as systemic signal of under treatment of the intestinal disease.
Barriers inhibiting effective detection and management of postpartum hemorrhage during facility-based births in Madagascar: findings from a qualitative study using a behavioral science lens
Authors: Flanagan Sara V. , Razafinamanana Tina , Warren Charlotte , Smith Jana
Published: April 2021

Background

Postpartum hemorrhage (PPH) is the leading cause of maternal mortality in low-income countries, and is the most common direct cause of maternal deaths in Madagascar. Studies in Madagascar and other low-income countries observe low provider adherence to recommended practices for PPH prevention and treatment. Our study addresses gaps in the literature by applying a behavioral science lens to identify barriers inhibiting facility-based providers’ consistent following of PPH best practices in Madagascar.

Methods

In June 2019, we undertook a cross-sectional qualitative research study in peri-urban and rural areas of the Vatovavy-Fitovinany region of Madagascar. We conducted 47 in-depth interviews in 19 facilities and five communities, with facility-based healthcare providers, postpartum women, medical supervisors, community health volunteers, and traditional birth attendants, and conducted thematic analysis of the transcripts.

Results

We identified seven key behavioral insights representing a range of factors that may contribute to delays in appropriate PPH management in these settings. Findings suggest providers’ perceived low risk of PPH may influence their compliance with best practices, subconsciously or explicitly, and lead them to undervalue the importance of PPH prevention and monitoring measures. Providers lack clear feedback on specific components of their performance, which ultimately inhibits continuous improvement of compliance with best practices. Providers demonstrate great resourcefulness while operating in a challenging context with limited equipment, supplies, and support; however, overcoming these challenges remains their foremost concern. This response to chronic scarcity is cognitively taxing and may ultimately affect clinical decision-making.

Conclusions

Our study reveals how perception of low risk of PPH, limited feedback on compliance with best practices and consequences of current practices, and a context of scarcity may negatively affect provider decision-making and clinical practices. Behaviorally informed interventions, designed for specific contexts that care providers operate in, can help improve quality of care and health outcomes for women in labor and childbirth.
Multivariate logistic regression analysis on the association between anthropometric indicators of under-five children in Nigeria: NDHS 2018
Authors: Tesfaw Lijalem Melie , Fenta Haile Mekonnen
Published: April 2021

Background

Child malnutrition is a huge health problem having multifaceted consequences for child survival and long-term well-being. Although, several studies investigated stunting, underweight, and wasting in low- and middle-income countries, in Nigeria, the link between them received little attention. The aim of this study is, therefore, to assess the association between anthropometric indicators of under-five children such as stunting, underweight and wasting given that of other characteristics of children and households.

Methods

The data for this study was obtained from Nigerian Demographic and health survey (NDHS) in 2018. A total of 11,314 under-five children were involved. Multivariate logistic regression model was used to determine the association between stunting, underweight and wasting given that of the estimated effect of other determinants.

Results

From 11,314 under-five children the study considered 36.2, 21.4 and 6.7% of them suffered from stunting, underweight and wasting, respectively. About half (50.7%) of the children were male, 24.1% was obtained from North West region of Nigeria, and 37.8% of them were from households having unimproved drinking water. The pairwise dependency between stunting and underweight; underweight and wasting was measured using odds ratio (OR) of 15.796, and 16.750 respectively. The estimated odds of children from richest household to become stunted, underweight, and wasted was respectively 0.392, 0.540, 0.786 times that of the estimated odds of children from poorest households.

Conclusion

The prevalence of under-five children with stunting, underweight and/or wasting in Nigeria was very high. The important determinants of stunting, underweight, and wasting for under five children were household wealth index, women body mass index, sex of the child, anemia, mothers’ age at first birth, and a diarrhea two weeks prior to the survey. Whereas, region, religion, multiple birth, women’s educational level significantly associated with both stunting and underweight. Both stunting and wasting significantly associated with underweight.
Atrophy patterns in isolated subscapularis lesions
Authors: Seppel Gernot , Voss Andreas , Henderson Daniel J. H. , Waldt Simone , Haller Bernhard , Forkel Philipp , Reuter Sven , Holzapfel Boris M. , Plath Johannes E. , Imhoff Andreas B.
Published: April 2021

Background

While supraspinatus atrophy can be described according to the system of Zanetti or Thomazeau there is still a lack of characterization of isolated subscapularis muscle atrophy. The aim of this study was to describe patterns of muscle atrophy following repair of isolated subscapularis (SSC) tendon.

Methods

Forty-nine control shoulder MRI scans, without rotator cuff pathology, atrophy or fatty infiltration, were prospectively evaluated and subscapularis diameters as well as cross sectional areas (complete and upper half) were assessed in a standardized oblique sagittal plane. Calculation of the ratio between the upper half of the cross sectional area (CSA) and the total CSA was performed. Eleven MRI scans of patients with subscapularis atrophy following isolated subscapularis tendon tears were analysed and cross sectional area ratio (upper half /total) determined. To guarantee reliable measurement of the CSA and its ratio, bony landmarks were also defined.

All parameters were statistically compared for inter-rater reliability, reproducibility and capacity to quantify subscapularis atrophy.

Results

The mean age in the control group was 49.7 years (± 15.0).

The mean cross sectional area (CSA) was 2367.0 mm2 (± 741.4) for the complete subscapularis muscle and 1048.2 mm2 (± 313.3) for the upper half, giving a mean ratio of 0.446 (± 0.046).

In the subscapularis repair group the mean age was 56.7 years (± 9.3). With a mean cross sectional area of 1554.7 mm2 (± 419.9) for the complete and of 422.9 mm2 (± 173.6) for the upper half of the subscapularis muscle, giving a mean CSA ratio of 0.269 (± 0.065) which was seen to be significantly lower than that of the control group (p < 0.05).

Conclusion

Analysis of typical atrophy patterns of the subscapularis muscle demonstrates that the CSA ratio represents a reliable and reproducible assessment tool in quantifying subscapularis atrophy. We propose the classification of subscapularis atrophy as Stage I (mild atrophy) in case of reduction of the cross sectional area ratio < 0.4, Stage II (moderate atrophy) in case of < 0.35 and Stage III (severe atrophy) if < 0.3.
A case of an injured calcaneus secundarius in a professional soccer player
Authors: Kepka Sabrina , Morel Marc , Garnier Franck , Pietra François , Marjanovic Nicolas , Zeller Pascal , Bilbault Pascal , Kremer Stéphane , Bierry Guillaume
Published: April 2021

Background

The calcaneus secundarius (CS) is an accessory ossicle of the anterior facet of the calcaneus and is usually asymptomatic. This accessory bone can be frequently mistaken for a fracture of the anterior process of the calcaneus. Few reports of symptomatic CS have been published, and physicians need to be familiar with imaging strategies when encountering chronic ankle pain or in case of suspicion of fracture of the anterior process of the calcaneus.

Case presentation

We describe the case of symptomatic CS in a professional soccer player injured during a match. First, computed tomography showed a large CS. Second, magnetic resonance imaging (MRI) demonstrated synchondrosis between the CS and the calcaneus, as well as edema (high MR T2 signal) within it, corresponding to posttraumatic edema. The patient was successfully treated with nonsteroidal anti-inflammatory drugs and physiotherapy; no surgical management was necessary. At the 4-week follow-up, he was pain-free and returned to activity.

Conclusion

This case illustrates the role of imaging for the diagnosis of CS in cases of acute pain of the foot. CT, as well as MRI, helped to confirm the diagnosis of CS traumatized synchondrosis, which can be mistaken for a fracture.
The diagnostic utility of diffusion weighted MRI imaging and ADC ratio to distinguish benign from malignant renal masses: sorting the kittens from the tigers
Authors: de Silva Suresh , Lockhart Kathleen Rebecca , Aslan Peter , Nash Peter , Hutton Anthony , Malouf David , Lee Dominic , Cozzi Paul , MacLean Fiona , Thompson James
Published: April 2021

Background

MRI is playing an increasing role in risk stratification and non-invasive diagnosis of the undifferentiated small renal mass. This study was designed to assess the reliability of MRI in diagnostic evaluation of renal masses, specifically characterising lesions with diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) values.

Methods

This is a retrospective analysis of patients undergoing MRI as part of their clinical workup for a renal mass suspicious for renal cell carcinoma (RCC) on CT or ultrasound followed by biopsy and/or surgical excision. All cases were conducted on 3 Tesla MRI, with conventional breath-held sequences, DWI and dynamic contrast enhanced phases. Tumour regions of interest were evaluated on ADC maps and compared with T2 weighted and post-contrast images.

Results

Of the 66 renal tumours included, 33 (50.0%) were Clear Cell RCC, 11 (16.7%) were Oncocytoma, nine (13.6%) were Angiomyolipoma (AML), nine (13.6%) were Papillary RCC and four (6.1%) were Chromophobe RCC. Oncocytoma had the largest ADC values, significantly larger than AMLs and all RCC subtypes (p < 0.001). The average ADC value was also significantly larger in Clear Cell RCCs compared to AMLs, and other RCC subtypes (p < 0.001).

Conclusions

MRI with DWI/ADC imaging may aid the differentiation of oncocytomas from RCCs and stratify RCC subtypes, Further studies are required to validate these findings.

Trial registration: Not applicable/retrospective study.
Pharmacokinetics of five phthalides in volatile oil of Ligusticum sinense Oliv.cv. Chaxiong, and comparison study on physicochemistry and pharmacokinetics after being formulated into solid dispersion and inclusion compound
Authors: Hu Peng-yi , Zhong Ying-huai , Feng Jian-fang , Li Dong-xun , Deng Ping , Zhang Wen-liu , Lei Zhi-qiang , Liu Xue-mei , Zhang Guo-song
Published: April 2021

Backgrounds

The dried rhizome ofLigusticum sinenseOliv.cv.Chaxionghas been used to treat cardiovascular and cerebrovascular diseases, atherosclerosis, anemia and stroke. A high purity extract from chaxiong (VOC, brownish yellow oil) was extracted and separated. Its main components were senkyunolide A (SA, 33.81%), N-butylphthalide (NBP, 1.38%), Neocnidilide (NOL, 16.53%), Z-ligustilide (ZL, 38.36%), and butenyl phthalide (BP, 2.48%), respectively. Little is known about the pharmacokinetics of these phthalides in Chaxiong, and different preparations to improve the physicochemistry and pharmacokinetics of VOC have not been investigated.

Methods

At different predetermined time points after oral administration or intravenous administration, the concentrations of SA, NBP, NOL, ZL and BP in the rat plasma were determined using LC-MS/MS, and the main PK parameters were investigated. VOC-P188 solid dispersion and VOC-β-CD inclusion compound were prepared by melting solvent method and grinding method, respectively. Moreover, the physicochemical properties, dissolution and pharmacokinetics of VOC-P188 solid dispersion and VOC-β-CD inclusion compound in rats were assessed in comparison to VOC.

Results

The absorptions of SA, NBP, NOL, ZL and BP in VOC were rapid after oral administration, and the absolute bioavailability was less than 25%. After the two preparations were prepared, dissolution rate was improved at pH 5.8 phosphate buffer solution. Comparing VOC and physical mixture with the solid dispersion and inclusion compound, it was observed differences occurred in the chemical composition, thermal stability, and morphology. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound had a significantly higher AUC and longer MRT in comparison with VOC.

Conclusion

SA, NBP, NOL, ZL and BP in VOC from chaxiong possessed poor absolute oral bioavailability. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound could be prospective means for improving oral bioavailability of SA, NBP, NOL, ZL and BP in VOC.
A qualitative study of physician perceptions and experiences of caring for critically ill patients in the context of resource strain during the first wave of the COVID-19 pandemic
Authors: Parsons Leigh Jeanna , Kemp Laryssa G. , de Grood Chloe , Brundin-Mather Rebecca , Stelfox Henry T. , Ng-Kamstra Josh S. , Fiest Kirsten M.
Published: April 2021

Background

The COVID-19 pandemic has led to global shortages in the resources required to care for critically ill patients and to protect frontline healthcare providers. This study investigated physicians’ perceptions and experiences of caring for critically ill patients in the context of actual or anticipated resource strain during the COVID-19 pandemic, and explored implications for the healthcare workforce and the delivery of patient care.

Methods

We recruited a diverse sample of critical care physicians from 13 Canadian Universities with adult critical care training programs. We conducted semi-structured telephone interviews between March 25–June 25, 2020 and used qualitative thematic analysis to derive primary themes and subthemes.

Results

Fifteen participants (eight female, seven male; median age = 40) from 14 different intensive care units described three overarching themes related to physicians’ perceptions and experiences of caring for critically ill patients during the pandemic: 1) Conditions contributing to resource strain (e.g., continuously evolving pandemic conditions); 2) Implications of resource strain on critical care physicians personally (e.g., safety concerns) and professionally (e.g. practice change); and 3) Enablers of resource sufficiency (e.g., adequate human resources).

Conclusions

The COVID-19 pandemic has required health systems and healthcare providers to continuously adapt to rapidly evolving circumstances. Participants’ uncertainty about whether their unit’s planning and resources would be sufficient to ensure the delivery of high quality patient care throughout the pandemic, coupled with fear and anxiety over personal and familial transmission, indicate the need for a unified systemic pandemic response plan for future infectious disease outbreaks.
Associations between dietary patterns and the incidence of total and fatal cardiovascular disease and all-cause mortality in 116,806 individuals from the UK Biobank: a prospective cohort study
Authors: Gao Min , Jebb Susan A. , Aveyard Paul , Ambrosini Gina L. , Perez-Cornago Aurora , Carter Jennifer , Sun Xinying , Piernas Carmen
Published: April 2021

Background

Traditionally, studies investigating diet and health associations have focused on single nutrients. However, key nutrients co-exist in many common foods, and studies focusing solely on individual nutrients may obscure their combined effects on cardiovascular disease (CVD) and all-cause mortality. We aimed to identify food-based dietary patterns which operate through excess energy intake and explain high variability in energy density, free sugars, saturated fat, and fiber intakes and to investigate their association with total and fatal CVD and all-cause mortality.

Methods

Detailed dietary data was collected using a 24-h online dietary assessment on two or more occasions (n = 116,806). We used reduced rank regression to derive dietary patterns explaining the maximum variance. Multivariable Cox-proportional hazards models were used to investigate prospective associations with all-cause mortality and fatal and non-fatal CVD.

Results

Over an average of 4.9 years of follow-up, 4245 cases of total CVD, 838 cases of fatal CVD, and 3629 cases of all-cause mortality occurred. Two dietary patterns were retained that jointly explained 63% of variation in energy density, free sugars, saturated fat, and fiber intakes in total. The main dietary pattern was characterized by high intakes of chocolate and confectionery, butter and low-fiber bread, and low intakes of fresh fruit and vegetables. There was a positive linear association between the dietary pattern and total CVD [hazard ratio (HR) per z-score 1.07, 95% confidence interval (CI) 1.04–1.09; HRtotal CVD 1.40, 95% CI 1.31–1.50, and HRall-cause mortality 1.37, 95% CI 1.27–1.47 in highest quintile]. A second dietary pattern was characterized by a higher intakes of sugar-sweetened beverages, fruit juice, and table sugar/preserves. There was a non-linear association with total CVD risk and all-cause mortality, with increased risk in the highest quintile [HRtotal CVD 1.14, 95% CI 1.07–1.22; HRall-cause mortality 1.11, 95% CI 1.03–1.19].

Conclusions

We identified dietary patterns which are associated with increased risk of CVD and all-cause mortality. These results help identify specific foods and beverages which are major contributors to unhealthy dietary patterns and provide evidence to underpin food-based dietary advice to reduce health risks.
Prognostic value of NT-proBNP in patients with chronic coronary syndrome and normal left ventricular systolic function according to glucose status: a prospective cohort study
Authors: Liu Hui-Hui , Cao Ye-Xuan , Jin Jing-Lu , Guo Yuan-Lin , Zhu Cheng-Gang , Wu Na-Qiong , Gao Ying , Zhang Yan , Xu Rui-Xia , Dong Qian , Li Jian-Jun
Published: April 2021

Background

The prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with coronary artery disease (CAD) with different glucose status has not been established. This study sought to evaluate the significance of NT-proBNP in predicting major adverse cardiovascular events (MACEs) in patients with chronic coronary syndrome (CCS) and normal left-ventricular systolic function (LVSF) according to different glucose status, especially in those with abnormal glucose metabolism.

Methods

A total of 8062 patients with CCS and normal LVSF were consecutively enrolled in this prospective study. Baseline plasma NT-proBNP levels were measured. The follow-up data of all patients were collected. Kaplan-Meier and Cox regression analyses were used to assess the risk of MACEs according to NT-proBNP tertiles stratified by glucose status.

Results

Over an average follow-up of 59.13 ± 18.23 months, 569 patients (7.1 %) suffered from MACEs, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Kaplan-Meier analysis showed that high NT-proBNP levels had a significant association with MACEs in subjects with prediabetes mellitus (pre-DM) or DM, but not in patients with normoglycemia. Multivariate Cox regression analysis revealed that NT-proBNP remained an independent predictor of MACEs in patients with pre-DM [hazard ratio (HR): 2.56, 95% confidence interval (CI): 1.34–4.91] or DM (HR: 2.34, 95% CI: 1.32–4.16). Moreover, adding NT-proBNP to the original Cox model including traditional risk factors significantly increased the C-statistic by 0.035 in pre-DM and DM, respectively.

Conclusions

The present study indicated that NT-proBNP could well predict worse outcomes in dysglycemic patients with CCS and normal LVSF, suggesting that NT-proBNP may help with risk stratification in this population.
Are there sex differences in the effect of type 2 diabetes in the incidence and outcomes of myocardial infarction? A matched-pair analysis using hospital discharge data
Authors: Lopez-de-Andres Ana , Jimenez-Garcia Rodrigo , Hernández-Barrera Valentin , de Miguel-Yanes Jose M. , Albaladejo-Vicente Romana , Villanueva-Orbaiz Rosa , Carabantes-Alarcon David , Zamorano-Leon Jose J. , Lopez-Herranz Marta , de Miguel-Diez Javier
Published: April 2021

Background

To analyze incidence, use of therapeutic procedures, and in-hospital outcomes in patients with ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI) according to the presence of type 2 diabetes (T2DM) in Spain (2016–2018) and to investigate sex differences.

Methods

Using the Spanish National Hospital Discharge Database, we estimated the incidence of myocardial infarctions (MI) in men and women with and without T2DM aged ≥ 40 years. We analyzed comorbidity, procedures, and outcomes. We matched each man and woman with T2DM with a non-T2DM man and woman of identical age, MI code, and year of hospitalization. Propensity score matching was used to compare men and women with T2DM.

Results

MI was coded in 109,759 men and 44,589 women (30.47% with T2DM). The adjusted incidence of STEMI (IRR 2.32; 95% CI 2.28–2.36) and NSTEMI (IRR 2.91; 95% CI 2.88–2.94) was higher in T2DM than non-T2DM patients, with higher IRRs for NSTEMI in both sexes. The incidence of STEMI and NSTEMI was higher in men with T2DM than in women with T2DM. After matching, percutaneous coronary intervention (PCI) was less frequent among T2DM men than non-T2DM men who had STEMI and NSTEMI. Women with T2DM and STEMI less frequently had a code for PCI that matched that of non-T2DM women. In-hospital mortality (IHM) was higher among T2DM women with STEMI and NSTEMI than in matched non-T2DM women. In men, IHM was higher only for NSTEMI. Propensity score matching showed higher use of PCI and coronary artery bypass graft and lower IHM among men with T2DM than women with T2DM for both STEMI and NSTEMI.

Conclusions

T2DM is associated with a higher incidence of STEMI and NSTEMI in both sexes. Men with T2DM had higher incidence rates of STEMI and NSTEMI than women with T2DM. Having T2DM increased the risk of IHM after STEMI and NSTEMI among women and among men only for NSTEMI. PCI appears to be less frequently used in T2DM patients After STEMI and NSTEMI, women with T2DM less frequently undergo revascularization procedures and have a higher mortality risk than T2DM men.
Stronger association of triglyceride glucose index than the HOMA-IR with arterial stiffness in patients with type 2 diabetes: a real-world single-centre study
Authors: Wang Shujie , Shi Juan , Peng Ying , Fang Qianhua , Mu Qian , Gu Weiqiong , Hong Jie , Zhang Yifei , Wang Weiqing
Published: April 2021

Background

The triglyceride-glucose index (TyG index) has been proposed as a simple and reliable alternative insulin resistance (IR) marker, while the homeostasis model assessment for IR (HOMA-IR) is the most frequently used index. Few studies have evaluated the role of IR assessed by the TyG index and HOMA-IR on arterial stiffness in a type 2 diabetes (T2D) population with a high risk of increased arterial stiffness. We aimed to investigate the association of the TyG index and HOMA-IR with arterial stiffness in patients with T2D.

Methods

We recruited 3185 patients with T2D, who underwent brachial-ankle pulse wave velocity (baPWV), an indicator of arterial stiffness, but without previous cardiovascular disease. Increased arterial stiffness was defined as a baPWV value greater than the 75th percentile (18.15 m/s) in the present study. The TyG index was determined as ln(fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2), and the HOMA-IR was calculated as (fasting insulin [μIU/mL] × fasting glucose [mmol/L])/22.5.

Results

The mean age of the study participants was 54.6 ± 12.0 years, and 1954 (61.4%) were men. Seemingly unrelated regression estimation analysis demonstrated that the TyG index had stronger associations with baPWV than the HOMA-IR (all P < 0.001). In the multivariable logistic analyses, each one-unit increase in the TyG index was associated with a 1.40-fold (95% CI 1.16–1.70, P < 0.001) higher prevalence of increased arterial stiffness, but the prominent association of the HOMA-IR with the prevalence of increased arterial stiffness was not observed. Subgroup analyses showed that a more significant association between the TyG index and the prevalence of increased arterial stiffness was detected in older patients with a longer duration of diabetes and poor glycaemic control (all P < 0.05).

Conclusions

Compared with the HOMA-IR, the TyG index is independently and more strongly associated with arterial stiffness in patients with T2D.
BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes
Authors: Wu Shuiyan , Jiang You , Hong Yi , Chu Xinran , Zhang Zimu , Tao Yanfang , Fan Ziwei , Bai Zhenjiang , Li Xiaolu , Chen Yanling , Li Zhiheng , Ding Xin , Lv Haitao , Du Xiaoli , Lim Su Lin , Zhang Yongping , Huang Saihu , Lu Jun , Pan Jian , Hu Shaoyan
Published: April 2021

Background

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL.

Methods

Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP).

Results

BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo.

Conclusions

BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.
Day-to-day progression of vital-sign circadian rhythms in the intensive care unit
Authors: Davidson Shaun , Villarroel Mauricio , Harford Mirae , Finnegan Eoin , Jorge João , Young Duncan , Watkinson Peter , Tarassenko Lionel
Published: April 2021

Background

Disrupted vital-sign circadian rhythms in the intensive care unit (ICU) are associated with complications such as immune system disruption, delirium and increased patient mortality. However, the prevalence and extent of this disruption is not well understood. Tools for its detection are currently limited.

Methods

This paper evaluated and compared vital-sign circadian rhythms in systolic blood pressure, heart rate, respiratory rate and temperature. Comparisons were made between the cohort of patients who recovered from the ICU and those who did not, across three large, publicly available clinical databases. This comparison included a qualitative assessment of rhythm profiles, as well as quantitative metrics such as peak–nadir excursions and correlation to a demographically matched ‘recovered’ profile.

Results

Circadian rhythms were present at the cohort level in all vital signs throughout an ICU stay. Peak–nadir excursions and correlation to a ‘recovered’ profile were typically greater throughout an ICU stay in the cohort of patients who recovered, compared to the cohort of patients who did not.

Conclusions

These results suggest that vital-sign circadian rhythms are typically present at the cohort level throughout an ICU stay and that quantitative assessment of these rhythms may provide information of prognostic use in the ICU.
Tuning a bi-enzymatic cascade reaction in Escherichia coli to facilitate NADPH regeneration for ε-caprolactone production
Authors: Xiong Jinghui , Chen Hefeng , Liu Ran , Yu Hao , Zhuo Min , Zhou Ting , Li Shuang
Published: April 2021

ε-Caprolactone is a monomer of poly(ε-caprolactone) which has been widely used in tissue engineering due to its biodegradability and biocompatibility. To meet the massive demand for this monomer, an efficient whole-cell biocatalytic approach was constructed to boost the ε-caprolactone production using cyclohexanol as substrate. Combining an alcohol dehydrogenase (ADH) with a cyclohexanone monooxygenase (CHMO) in Escherichia coli, a self-sufficient NADPH-cofactor regeneration system was obtained. Furthermore, some improved variants with the better substrate tolerance and higher catalytic ability to ε-caprolactone production were designed by regulating the ribosome binding sites. The best mutant strain exhibited an ε-caprolactone yield of 0.80 mol/mol using 60 mM cyclohexanol as substrate, while the starting strain only got a conversion of 0.38 mol/mol when 20 mM cyclohexanol was supplemented. The engineered whole-cell biocatalyst was used in four sequential batches to achieve a production of 126 mM ε-caprolactone with a high molar yield of 0.78 mol/mol.