bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of Radiation Pneumonitis With Machine Learning in Stage III Lung Cancer: A Pilot Study
Authors: Yakar Melek , Etiz Durmus , Metintas Muzaffer , Ak Guntulu , Celik Ozer
Published: May 2021

Background:

Radiation pneumonitis (RP) is a dose-limiting toxicity in lung cancer radiotherapy (RT). As risk factors in the development of RP, patient and tumor characteristics, dosimetric parameters, and treatment features are intertwined, and it is not always possible to associate RP with a single parameter. This study aimed to determine the algorithm that most accurately predicted RP development with machine learning.

Methods:

Of the 197 cases diagnosed with stage III lung cancer and underwent RT and chemotherapy between 2014 and 2020, 193 were evaluated. The CTCAE 5.0 grading system was used for the RP evaluation. Synthetic minority oversampling technique was used to create a balanced data set. Logistic regression, artificial neural networks, eXtreme Gradient Boosting (XGB), Support Vector Machines, Random Forest, Gaussian Naive Bayes and Light Gradient Boosting Machine algorithms were used. After the correlation analysis, a permutation-based method was utilized for as a variable selection.

Results:

RP was seen in 51 of the 193 cases. Parameters affecting RP were determined as, total(t)V5, ipsilateral lung Dmax, contralateral lung Dmax, total lung Dmax, gross tumor volume, number of chemotherapy cycles before RT, tumor size, lymph node localization and asbestos exposure. LGBM was found to be the algorithm that best predicted RP at 85% accuracy (confidence interval: 0.73-0.96), 97% sensitivity, and 50% specificity.

Conclusion:

When the clinical and dosimetric parameters were evaluated together, the LGBM algorithm had the highest accuracy in predicting RP. However, in order to use this algorithm in clinical practice, it is necessary to increase data diversity and the number of patients by sharing data between centers.
Dietary Modification for the Restoration of Gut Microbiome and Management of Symptoms in Irritable Bowel Syndrome
Authors: Thomas Andrew , Thomas Annie , Butler-Sanchez Madeline
Published: May 2021

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder leading to chronic debilitating issues. A healthy diet plays an integral role in maintaining the gut microbiota equilibrium, thus promoting digestive health. The structure and function of gut microbiota are affected by genetics and environmental factors, such as altered dietary habits, gastroenteritis, stress, increased use of alcohol and drugs, and medication use. Whereas there are various management approaches cited in the literature to manage symptoms of IBS, the purpose of this article is to focus on dietary options that will restore the gut microbiome and help in managing IBS symptoms. Some of the diets that are discussed in this article include a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, gluten-free/wheat-free diet, high-fiber diet, dietary and herbal supplements (psyllium, peppermint oil), and probiotics/prebiotics/synbiotics. The clinical practice guidelines recommended by the American College of Gastroenterology outlines evidence-based dietary recommendations for patients with IBS to manage symptoms. Recent advancements in the dietary management of IBS highlighting the use of a patient-centered, personalized nutrition approach along with lifestyle changes, pharmacological therapies, and psychosocial and behavioral interventions are also reviewed and discussed.
Treatment of carotid cavernous sinus fistulas with flow diverters. A case report and systematic review
Authors: Stamatopoulos Theodosios , Anagnostou Evangelos , Plakas Sotirios , Papachristou Konstantinos , Lagos Panagiotis , Samelis Apostolos , Derakhshani Shahram , Mitsos Aristotelis
Published: May 2021

Introduction

Carotid cavernous fistulas (CCFs) are rare, usually follow head trauma or aneurysmal rupture. Recent treatment options include endovascular techniques such as flow diversion devices (FDDs).

Objective

To present our case treated with FDD application with transarterial cavernous-sinus coiling and present a systematic review on the use and effectiveness of FDDs in CCF treatment.

Materials and methods

We present our case of CCF treatment with FDD. A search was also conducted in PubMed, EMBASE and Cochrane until November 2020. Reference lists were also cross-checked.

Results

Including our case, thirty-eight patients were identified with a CCF that was treated with FDDs in sixteen studies. Twenty-two patients were females, nine were males and the rest unidentified. The mean age was 52,6 years (range 17–86, SD± 19.28). Thirty-six patients suffered from direct and two from indirect CCFs. Single FDD was used in four cases, single FDD with embolic materials in eleven cases, multiple overlapping FDDs were used in six cases and multiple overlapping FDDs with embolic materials were used in seventeen cases. Thirty-five patients (92,1%) had clinical improvement, immediate angiographic occlusion was seen in 44,7% of the cases, while long-term occlusion rate was 100% but with variable follow-up periods. One patient (2,6%) presented with a neurological deficit related to FDD deployment.

Conclusion

Targeted treatment of CCFs with single or overlapping FDDs with or without adjunct embolic agents offers a high success rate, both clinically and long-term angiographically compared to other endovascular methods alone. However, further research with multi-center prospective trials is warranted.
Mingled bodies and voices: Maternal reflections on caregiver expertise and intellectual disability
Authors: MacGregor Laura
Published: May 2021

The risk of viral infection during the COVID-19 pandemic has caused many hospitals to prohibit all patient visitors, including family caregivers for people with intellectual disabilities. Drawing on a postmodern, intersubjective view of the body, as well as my experience as the mother of a young adult with profound disabilities, I argue that caregiver knowledge while unconventional within the medical paradigm must be viewed as essential expertise. People with profound intellectual disabilities often have concurrent, complex medical issues that are complicated by their inability to self-advocate. Optimal care rests upon the ongoing presence and expertise of their primary caregiver. Medical professionals risk patient care by excluding the essential expertise of family caregivers at any time, and specifically during COVID-19.
Replacing willow with bamboo in cricket bats
Authors: Tinkler-Davies Ben , Ramage Michael H , Shah Darshil U
Published: May 2021

Willow has been used for nearly 200 years as the main material in the blades of cricket bats, whilst the application of bamboo in sport has declined. In this work, laminated bamboo was characterised to assess if it could be a viable alternative to willow. Bamboo matures much more quickly than willow and is prevalent in countries, such as India, where there is a large interest in cricket. Using bamboo could lead to increased participation in cricket and new products focused around the low-cost production and increased sustainability of cricket bats. Alongside materials testing, finite element modelling was used to understand the properties of a full-scale cricket bat made of laminated bamboo. Working with Garrard & Flack, a cricket bat manufacturing company, a full-size bamboo bat prototype was fabricated. It was found that laminated bamboo could be a suitable alternative to willow due to its higher Modulus of Elasticity, higher coefficient of restitution and larger area of coverage of the ‘sweet-spot’, enabling increased energy transfer from the player to the ball. However, due to its higher density, shape optimisation is required to design a light-weight laminated bamboo bat.
Covid-19, capitalism and political elites: The real threat to humanity
Authors: Alexiou Constantinos
Published: May 2021

It has been more than a year since the Covid-19 outbreak in Wuhan, one of the largest cities in China. The global tsunami that followed took the bourgeois regimes across the globe by surprise heralding a new era of socioeconomic misery, suggesting that this multifaceted crisis could become the worst crisis in the history of capitalism. The inability of the current political system to deal with the Covid-19 pandemic became apparent from the very outset, hence exposing – in the most emphatic manner – the ills of the dominant market economy. In this opinion paper, we argue that society, as a global collective entity, has been reduced to an entity that obeys orders and dances to the rhythm set by international organizations. Furthermore, the severely restricted political and social rights might be a dress rehearsal of what the future holds for humanity.
Novel leukocyte-depleted platelet-rich plasma-based skin equivalent as an in vitro model of chronic wounds: a preliminary study
Authors: Seria Elisa , Galea George , Borg Joseph , Schembri Kevin , Grech Gabriella , Tagliaferro Sarah Samut , Felice Alexander
Published: May 2021

Background

Chronic leg ulcerations are associated with Haemoglobin disorders, Type2 Diabetes Mellitus, and long-term venous insufficiency, where poor perfusion and altered metabolism develop into a chronic inflammation that impairs wound closure. Skin equivalent organotypic cultures can be engineered in vitro to study skin biology and wound closure by modelling the specific cellular components of the skin. This study aimed to develop a novel bioactive platelet-rich plasma (PRP) leukocyte depleted scaffold to facilitate the study of common clinical skin wounds in patients with poor chronic skin perfusion and low leukocyte infiltration. A scratch assay was performed on the skin model to mimic two skin wound conditions, an untreated condition and a condition treated with recombinant tumour necrotic factor (rTNF) to imitate the stimulation of an inflammatory state. Gene expression of IL8 and TGFA was analysed in both conditions. Statistical analysis was done through ANOVA and paired student t-test. P < 0.05 was considered significant.

Results

A skin model that consisted of a leukocyte-depleted, platelet-rich plasma scaffold was setup with embedded fibroblasts as dermal equivalents and seeded keratinocytes as multi-layered epidermis. Gene expression levels of IL8 and TGFA were significantly different between the control and scratched conditions (p < 0.001 and p < 0.01 respectively), as well as between the control and treated conditions (p < 0.01 and p < 0.001 respectively). The scratch assay induced IL8 upregulation after 3 h (p < 0.05) which continued to increase up to day 1 (p < 0.05). On the other hand, the administration of TNF led to the downregulation of IL8 (p < 0.01), followed by an upregulation on day 2. IL8 gene expression decreased in the scratched condition after day 1 as the natural healing process took place and was lower than in the treated condition on day 8 (p < 0.05).

Both untreated and treated conditions showed a downregulation of TGFA 3 h after scratch when compared with the control condition (p < 0.01). Administration of rTNF showed significant downregulation of TGFA after 24 h when compared with the control (p < 0.01) and treated conditions (p < 0.05).

Conclusion

This study suggests that a leukocyte-depleted PRP-based skin equivalent can be a useful model for the in vitro study of chronic skin wounds related to poor skin perfusion.
Using random forests to model 90-day hometime in people with stroke
Authors: Holodinsky Jessalyn K. , Yu Amy Y. X. , Kapral Moira K. , Austin Peter C.
Published: May 2021

Background

Ninety-day hometime, the number of days a patient is living in the community in the first 90 after stroke, exhibits a non-normal bucket-shaped distribution, with lower and upper constraints making its analysis difficult. In this proof-of-concept study we evaluated the performance of random forests regression in the analysis of hometime.

Methods

Using administrative data we identified stroke hospitalizations between 2010 and 2017 in Ontario, Canada. We used random forests regression to predict 90-day hometime using 15 covariates. Model accuracy was determined using ther-squaredstatistic. Variable importance in prediction and the marginal effects of each covariate were explored.

Results

We identified 75,745 eligible patients. Median 90-day hometime was 59 days (Q1: 2, Q3: 83). Random forests predicted hometime with reasonable accuracy (adjusted r-squared 0.3462); no implausible values were predicted but extreme values were predicted with low accuracy. Frailty, stroke severity, and age exhibited inverse non-linear relationships with hometime and patients arriving by ambulance had less hometime than those who did not.

Conclusions

Random forests may be a useful method for analyzing 90-day hometime and capturing the complex non-linear relationships which exist between predictors and hometime. Future work should compare random forests to other models and focus on improving the accuracy of predictions of extreme values of hometime.
Effect of a figure-of-eight cerclage wire with two Kirschner wires on fixation strength for transverse metacarpal shaft fractures: an in vitro study with artificial bone
Authors: Chiu Yung-Cheng , Hsu Cheng-En , Ho Tsung-Yu , Ting Yen-Nien , Tsai Ming-Tzu , Hsu Jui-Ting
Published: May 2021

Background

Metacarpal shaft fractures are a common type of hand fracture. Despite providing strong fixation strength, plate fixation has numerous shortcomings. Concerning internal fixation with Kirschner wires (K-wires), although this approach is frequently used to treat metacarpal shaft fractures, the lack of functional stability may result in fixation failure.

Objective

To evaluate the effect of figure-of-eight cerclage wire on fixation for transverse metacarpal shaft fractures using two K-wires.

Materials and methods

We used a saw blade to create transverse metacarpal shaft fractures in 14 fourth-generation artificial third metacarpal bones (Sawbones, Vashon, WA, USA), which were assigned to groups undergoing fixation with two K-wires (KP) or with two K-wires and figure-of-eight cerclage wire (KP&F8). All specimens were subjected to material testing, specifically cantilever bending tests. The maximum fracture force and stiffness of the two fixation types were determined on the basis of the force–displacement data. The Mann–Whitney U test was used to compare between-group differences in maximum fracture force and stiffness.

Results

The maximum fracture force of the KP group (median ± interquartile range = 97.30 ± 29.70 N) was significantly lower than that of the KP&F8 group (153.2 ± 69.50 N, p < 0.05; Figure 5a), with the median of the KP&F8 group exceeding that of the KP group by 57.5%. Similarly, stiffness was significantly lower in the KP group (18.14 ± 9.84 N/mm) than in the KP&F8 group (38.25 ± 23.49 N/mm; p < 0.05; Figure 5b), with the median of the KP&F8 group exceeding that of the KP group by 110.9%.

Conclusion

The incorporation of a figure-of-eight cerclage wire increased the maximum fracture force and stiffness by 57.5 and 110.9%, respectively, compared with those achieved in standard two K-wire fixation. Therefore, hand surgeons are advised to consider the proposed approach to increase fixation strength.
Oral manifestations of patients with systemic sclerosis: a meta-analysis for case-controlled studies
Authors: Zhang Suhan , Zhu Junfei , Zhu Yanshan , Zhang Xiaochao , Wu Ruifang , Li Siying , Su Yuwen
Published: May 2021

Background

Systemic sclerosis (SSc) is a multisystem rheumatic disease. Orofacial manifestations are commonly in SSc but maybe usually ignored and overshadowed by other systemic complications. Multiple comparative studies have been conducted to investigate the possible links between SSc and oral manifestations. The present study aimed to investigate the oral health status in patients with SSc.

Methods

Pubmed, Embase, Web of Science, and Scopus were searched up to July 2020. Following outcomes were evaluated: Probing depth (PD), Attachment loss (AL), Bleeding on probing (BOP), Number or percentage of Sites with PD ≥ 4 mm, Prevalence of periodontitis, Number of teeth, Decayed Teeth, Missing teeth, Filled teeth, DMFT index, and the interincisal distance. Newcastle-Ottawa Scale (NOS) were applied for quality assessment. The statistical analysis was processed using the software STATA.

Results

11 eligible studies were included. The maximum interincisor distance was significantly restricted in SSc patients (SMD − 1.061; 95 %CI [− 1.546, − 0.576]; Z = 4.29, P = 0.000).The prevalence of Periodontitis (OR 7.007; 95 %CI [3.529, 13.915]; Z = 5.56, P = 0.000), PD (SMD 3.101; 95 %CI [1.374, 4.829]; Z = 3.52, P = 0.000), AL(SMD 2.584; 95 %CI [0.321, 4.846]; Z = 2.24, P = 0.025), sites with PD ≥ 4mm (SMD 2.071 ; 95 %CI [0.267, 3.875]; Z = 2.25, P = 0.024) and the number of decayed teeth (SMD, 0.186; 95 %CI [0.007, 0.365]; Z = 2.04, P = 0.041) were increased significantly in SSc population in comparison with the controls.

Conclusions

SSc patients have limited mouth opening, higher periodontitis prevalence, and worse periodontal status, as well as an increased number of decayed teeth. Routinely oral hygiene instruction and initial periodontal treatment is recommended for SSc patients.
Use and usability of the dr. Bart app and its relation with health care utilisation and clinical outcomes in people with knee and/or hip osteoarthritis
Authors: Pelle Tim , van der Palen Job , de Graaf Frank , van den Hoogen Frank H. J. , Bevers Karen , van den Ende Cornelia H. M.
Published: May 2021

Background

Self-management is of paramount importance in the non-surgical treatment of knee/hip osteoarthritis (OA). Modern technologies offer the possibility of 24/7 self-management support. We developed an e-self-management application (dr. Bart app) for people with knee/hip OA.

The aim of this study was to document the use and usability of the dr. Bart app and its relation with health care utilisation and clinical outcomes in people with knee/hip OA.

Methods

For this study we used backend data for the first 26 weeks of use by the intervention group (N = 214) of an RCT examining the effectiveness of the dr. Bart app. A central element of the dr. Bart app is that it proposes a selection of 72 preformulated goals for health behaviours based on the ‘tiny habits method’ (e.g. after lunch I rise 12 times from my chair to train my leg muscles). The usability of the app was measured using the System Usability Scale questionnaire (SUS), on a scale of 0–100. To assess the association between the intensity of use of the app and health care utilisation (i.e., consultations in primary or secondary health care) and clinical outcomes (i.e., self-management behaviour, physical activity, health-related quality of life, illness perceptions, symptoms, pain, activities of daily living) we calculated Spearman rank correlation coefficients.

Results

Of the 214 participants, 171 (80%) logged in at least once with 151 (71%) choosing at least one goal and 114 (53%) completing at least one goal during the 26 weeks. Of those who chose at least one goal, 56 participants (37%) continued to log in for up to 26 weeks, 12 (8%) continued to select new goals from the offered goals and 37 (25%) continued to complete goals. Preformulated goals in the themes of physical activity (e.g., performing an exercise from the exercises library in the app) and nutrition (e.g., ‘eat two pieces of fruit today’) were found to be most popular with users. The mean usability scores (standard deviation) at the three and six month follow-ups were 65.9 (16.9) and 64.5 (17.5), respectively. The vast majority of associations between the intensity of use of the dr. Bart app and target outcomes were weak at ρ < (−) 0.25.

Conclusions

More than one-third of people with knee/hip OA who started using the app, continued to use it up to 26 weeks, though usability could be improved. Patients appear to have preferences for goals related to physical activity and nutrition, rather than for goals related to vitality and education. We found weak/no associations between the intensity of use of the dr. Bart app and health care utilisation and clinical outcomes.

Trial registration

(21 September 2017): Dutch Trial Register (Trial Number NTR6693/NL6505)
Narratives of young black men on barriers to health care and poor health care seeking behaviours at a university setting: a qualitative study
Authors: Khumalo Sinakekelwe , Mabaso Musawenkosi , Makusha Tawanda , Taylor Myra
Published: May 2021

Background

Institutions of higher learning provide education, training, independence and life-long skills for young people. However, for students to achieve their optimal growth and intellectual development they need to be healthy psychologically, mentally and physically. This can be achieved through the development of effective health programs for all university students. This qualitative study was designed to explore Black male students’ perspectives and experiences regarding the utilization of on-campus health services at the University of KwaZulu-Natal.

Methods

The study population was selected using purposive sampling. Data were collected using four focus group discussions (FGDs) with 36 participants and three key informant interviews. Thematic analysis was conducted to identify the key patterns and themes that emerged from the data.

Results

Emerging themes included poor knowledge and awareness, negative perceptions and attitudes, fear and lack of privacy, and negative experiences leading to poor access and utilization of campus health services. The findings suggested a need for more advocacy and awareness campaigns especially among first year students, campaigns for normalization of sexual health, addressing HIV stigma and discrimination, providing youth friendly services to improve students’ use of sexual health services, and ultimately, their overall health and well-being.

Conclusions

The findings give valuable insights from male students on the barriers and potential solutions to campus health services and highlight where improvements can be directed to increase access and use of health services by the study population.
NMR structural analysis of the yeast cytochrome c oxidase subunit Cox13 and its interaction with ATP
Authors: Zhou Shu , Pettersson Pontus , Björck Markus L. , Dawitz Hannah , Brzezinski Peter , Mäler Lena , Ädelroth Pia
Published: May 2021

Background

Mitochondrial respiration is organized in a series of enzyme complexes in turn forming dynamic supercomplexes. In Saccharomyces cerevisiae (baker’s yeast), Cox13 (CoxVIa in mammals) is a conserved peripheral subunit of Complex IV (cytochrome c oxidase, CytcO), localized at the interface of dimeric bovine CytcO, which has been implicated in the regulation of the complex.

Results

Here, we report the solution NMR structure of Cox13, which forms a dimer in detergent micelles. Each Cox13 monomer has three short helices (SH), corresponding to disordered regions in X-ray or cryo-EM structures of homologous proteins. Dimer formation is mainly induced by hydrophobic interactions between the transmembrane (TM) helix of each monomer. Furthermore, an analysis of chemical shift changes upon addition of ATP revealed that ATP binds at a conserved region of the C terminus with considerable conformational flexibility.

Conclusions

Together with functional analysis of purified CytcO, we suggest that this ATP interaction is inhibitory of catalytic activity. Our results shed light on the structural flexibility of an important subunit of yeast CytcO and provide structure-based insight into how ATP could regulate mitochondrial respiration.
A novel nonsense mutation in ARMC5 causes primary bilateral macronodular adrenocortical hyperplasia
Authors: He Wen-Tao , Wang Xiong , Song Wen , Song Xiao-Dong , Lu Yan-Jun , Lv Yan-Kai , He Ting , Yu Xue-Feng , Hu Shu-Hong
Published: May 2021

Background

Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare form of adrenal Cushing’s syndrome. The slowly progressing expansion of bilateral adrenal tissues usually persists for dozens of years, leading to delayed onset with severe conditions due to chronic mild hypercortisolism. About 20–50% cases were found to be caused by inactivating mutation of armadillo repeat-containing protein 5 (ARMC5) gene.

Case presentation

A 51-year-old man was admitted for severe diabetes mellitus, resistant hypertension, centripedal obesity and edema. PBMAH was diagnosed after determination of adrenocorticotropic hormone and cortisol levels, dexamethasone suppression tests and abdominal contrast-enhanced CT scanning. The metabolic disorders of the patient remarkably improved after sequentially bilateral laparoscopic adrenalectomy combined with hormone replacement. Sanger sequencing showed germline nonsense mutation of ARMC5 c.967C>T (p.Gln323Ter). The second somatic missense mutation of ARMC5 was detected in one out of two resected nodules, reflecting the second-hit model of tumorigenesis. Routine genetic testing in his apparently healthy offspring showed one of two daughters and one son harbored the germline mutation.

Conclusions

In conclusion, our case report highlight the importance of genetic testing in the molecular diagnosis of PBMAH. Genetic screening in related family members will find out asymptomatic variant carriers to guide life-long follow-up.
Lung function trajectories in children with post-prematurity respiratory disease: identifying risk factors for abnormal growth
Authors: Levin Jonathan C. , Sheils Catherine A. , Gaffin Jonathan M. , Hersh Craig P. , Rhein Lawrence M. , Hayden Lystra P.
Published: May 2021

Background

Survivors of prematurity are at risk for abnormal childhood lung function. Few studies have addressed trajectories of lung function and risk factors for abnormal growth in childhood. This study aims to describe changes in lung function in a contemporary cohort of children born preterm followed longitudinally in pulmonary clinic for post-prematurity respiratory disease and to assess maternal and neonatal risk factors associated with decreased lung function trajectories.

Methods

Observational cohort of 164 children born preterm ≤ 32 weeks gestation followed in pulmonary clinic at Boston Children’s Hospital with pulmonary function testing. We collected demographics and neonatal history. We used multivariable linear regression to identify the impact of neonatal and maternal risk factors on lung function trajectories in childhood.

Results

We identified 264 studies from 82 subjects with acceptable longitudinal FEV1 data and 138 studies from 47 subjects with acceptable longitudinal FVC and FEV1/FVC data. FEV1% predicted and FEV1/FVC were reduced compared to childhood norms. Growth in FVC outpaced FEV1, resulting in an FEV1/FVC that declined over time. In multivariable analyses, longer duration of mechanical ventilation was associated with a lower rate of rise in FEV1% predicted and greater decline in FEV1/FVC, and postnatal steroid exposure in the NICU was associated with a lower rate of rise in FEV1 and FVC % predicted. Maternal atopy and asthma were associated with a lower rate of rise in FEV1% predicted.

Conclusions

Children with post-prematurity respiratory disease demonstrate worsening obstruction in lung function throughout childhood. Neonatal risk factors including exposure to mechanical ventilation and postnatal steroids, as well as maternal atopy and asthma, were associated with diminished rate of rise in lung function. These results may have implications for lung function trajectories into adulthood.
Adaptive laboratory evolution accelerated glutarate production by Corynebacterium glutamicum
Authors: Prell Carina , Busche Tobias , Rückert Christian , Nolte Lea , Brandenbusch Christoph , Wendisch Volker F.
Published: May 2021

Background

The demand for biobased polymers is increasing steadily worldwide. Microbial hosts for production of their monomeric precursors such as glutarate are developed. To meet the market demand, production hosts have to be improved constantly with respect to product titers and yields, but also shortening bioprocess duration is important.

Results

In this study, adaptive laboratory evolution was used to improve a C. glutamicum strain engineered for production of the C5-dicarboxylic acid glutarate by flux enforcement. Deletion of the l-glutamic acid dehydrogenase gene gdh coupled growth to glutarate production since two transaminases in the glutarate pathway are crucial for nitrogen assimilation. The hypothesis that strains selected for faster glutarate-coupled growth by adaptive laboratory evolution show improved glutarate production was tested. A serial dilution growth experiment allowed isolating faster growing mutants with growth rates increasing from 0.10 h−1 by the parental strain to 0.17 h−1 by the fastest mutant. Indeed, the fastest growing mutant produced glutarate with a twofold higher volumetric productivity of 0.18 g L−1 h−1 than the parental strain. Genome sequencing of the evolved strain revealed candidate mutations for improved production. Reverse genetic engineering revealed that an amino acid exchange in the large subunit of l-glutamic acid-2-oxoglutarate aminotransferase was causal for accelerated glutarate production and its beneficial effect was dependent on flux enforcement due to deletion of gdh. Performance of the evolved mutant was stable at the 2 L bioreactor-scale operated in batch and fed-batch mode in a mineral salts medium and reached a titer of 22.7 g L−1, a yield of 0.23 g g−1 and a volumetric productivity of 0.35 g L−1 h−1. Reactive extraction of glutarate directly from the fermentation broth was optimized leading to yields of 58% and 99% in the reactive extraction and reactive re-extraction step, respectively. The fermentation medium was adapted according to the downstream processing results.

Conclusion

Flux enforcement to couple growth to operation of a product biosynthesis pathway provides a basis to select strains growing and producing faster by adaptive laboratory evolution. After identifying candidate mutations by genome sequencing causal mutations can be identified by reverse genetics. As exemplified here for glutarate production by C. glutamicum, this approach allowed deducing rational metabolic engineering strategies.
Correction to: Climate-proofing a malaria eradication strategy
Authors: Nissan Hannah , Ukawuba Israel , Thomson Madeleine
Published: May 2021

An amendment to this paper has been published and can be accessed via the original article.
Correction to: Total saponin from Anemone flaccida Fr. Schmidt abrogates osteoclast differentiation and bone resorption via the inhibition of RANKL-induced NF-κB, JNK and p38 MAPKs activation
Authors: Kong Xiangying , Wu Wenbin , Yang Yue , Wan Hongye , Li Xiaomin , Zhong Michun , Zhao Hongyan , Su Xiaohui , Jia Shiwei , Ju Dahong , Lin Na
Published: May 2021

An amendment to this paper has been published and can be accessed via the original article.
Correction to: Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis
Authors: Riordan Neil H. , Morales Isabela , Fernández Giselle , Allen Nicole , Fearnot Neal E. , Leckrone Michael E. , Markovich Dedra Jones , Mansfield Darla , Avila Dorita , Patel Amit N. , Kesari Santosh , Rodriguez Jorge Paz
Published: May 2021

An amendment to this paper has been published and can be accessed via the original article.
Combined intake of blueberry juice and probiotics ameliorate mitochondrial dysfunction by activating SIRT1 in alcoholic fatty liver disease
Authors: Fan Houmin , Shen Yanyan , Ren Ya , Mou Qiuju , Lin Tao , Zhu Lili , Ren Tingting
Published: May 2021

Background

Mitochondrial dysfunction has been implicated as a significant factor in the liver disease process. Blueberry juice and probiotics (BP) synergistically improve liver function in alcoholic fatty liver disease (AFLD), although the mechanism for this effect was unclear. This study aims to investigate the effect and specific mechanisms of BP on AFLD.

Methods

C57/BL6 mice were randomly divided into seven groups: CG (control), MG (AFLD model), BJ (MG mice treated with blueberry), BJB (MG mice treated with BP), SI (AFLD mice treated with SIRT1 siRNA), BJSI (SI mice treated with blueberry), and BJBSI (SI mice treated with BP). The mice were fed an alcohol liquid diet for 10 days to establish the AFLD model, and subjected to BP and SIRT1 siRNA intervention for 10 days. Liver pathology was performed on day 11, and biochemical and molecular analyses of liver mitochondria were employed on day 12.

Results

BP significantly ameliorated hepatic mitochondrial injury, mitochondrial swelling, and hepatic necrosis in AFLD. BP alleviated hepatic mitochondrial dysfunction by increasing the expression of succinate dehydrogenase and cytochrome c oxidase, increasing respiratory control rate and the ADP/O ratio, and facilitating the synthesis of energy-related molecules. Besides, BP increased the expression of glutathione and superoxide dismutase, and inhibited malondialdehyde expression and reactive oxygen species activity. BP-induced sirtuin 1 (SIRT1), which activates peroxisome proliferator-activated receptor-gamma coactivator-1α, both of which mediate mitochondrial homeostasis. SIRT1 silencing suppressed the BP-induced changes in liver mitochondria, blunting its efficacy.

Conclusions

The ingredients of BP ameliorate hepatocyte mitochondrial dysfunction in AFLD mice.
Implementation and sustainability factors of two early-stage breast cancer conversation aids in diverse practices
Authors: Schubbe Danielle , Yen Renata W. , Saunders Catherine H. , Elwyn Glyn , Forcino Rachel C. , O’Malley A. James , Politi Mary C. , Margenthaler Julie , Volk Robert J. , Sepucha Karen , Ozanne Elissa , Percac-Lima Sanja , Bradley Ann , Goodwin Courtney , van den Muijsenbergh Maria , Aarts Johanna W. M. , Scalia Peter , Durand Marie-Anne
Published: May 2021

Background

Conversation aids can facilitate shared decision-making and improve patient-centered outcomes. However, few examples exist of sustained use of conversation aids in routine care due to numerous barriers at clinical and organizational levels. We explored factors that will promote the sustained use of two early-stage breast cancer conversation aids. We examined differences in opinions between the two conversation aids and across socioeconomic strata.

Methods

We nested this study within a randomized controlled trial that demonstrated the effectiveness of two early-stage breast cancer surgery conversation aids, one text-based and one picture-based. These conversation aids facilitated more shared decision-making and improved the decision process, among other outcomes, across four health systems with socioeconomically diverse patient populations. We conducted semi-structured interviews with a purposive sample of patient participants across conversation aid assignment and socioeconomic status (SES) and collected observations and field notes. We interviewed trial surgeons and other stakeholders. Two independent coders conducted framework analysis using the NOrmalization MeAsure Development through Normalization Process Theory. We also conducted an inductive analysis. We conducted additional sub-analyses based on conversation aid assignment and patient SES.

Results

We conducted 73 semi-structured interviews with 43 patients, 16 surgeons, and 14 stakeholders like nurses, cancer center directors, and electronic health record (EHR) experts. Patients and surgeons felt the conversation aids should be used in breast cancer care in the future and were open to various methods of giving and receiving the conversation aid (EHR, email, patient portal, before consultation). Patients of higher SES were more likely to note the conversation aids influenced their treatment discussion, while patients of lower SES noted more influence on their decision-making. Intervention surgeons reported using the conversation aids did not lengthen their typical consultation time. Most intervention surgeons felt using the conversation aids enhanced their usual care after using it a few times, and most patients felt it appeared part of their normal routine.

Conclusions

Key factors that will guide the future sustained implementation of the conversation aids include adapting to existing clinical workflows, flexibility of use, patient characteristics, and communication preferences.

Trial registration

ClinicalTrials.gov Identifier: NCT03136367, registered on May 2, 2017
Correction to: Assessing rare diseases prevalence using literature quantification
Authors: Shourick Jason , Wack Maxime , Jannot Anne-Sophie
Published: May 2021

An amendment to this paper has been published and can be accessed via the original article.
Release of the National Scheme's Aboriginal and Torres Strait Islander Health and Cultural Safety Strategy 2020‐2025; the impacts for podiatry in Australia: a commentary
Authors: Gerrard James M. , Godwin Shirley , Chuter Vivienne , Munteanu Shannon E. , West Matthew , Hawke Fiona
Published: May 2021

Background

Developing since colonisation, Australia's healthcare system has dismissed an ongoing and successful First Nations health paradigm in place for 60,000 years. From Captain James Cook documenting ‘very old’ First Nations Peoples being ‘far more happier than we Europeans' and Governor Arthur Phillip naming Manly in admiration of the physical health of Gadigal men of the Eora Nation, to anthropologist Daisy Bates' observation of First Nations Peoples living ‘into their eighties' and having a higher life expectancy than Europeans; our healthcare system's shameful cultural safety deficit has allowed for an Aboriginal and Torres Strait Islander child born in Australia today to expect to live 9 years less than a non‐Indigenous child. Disproportionately negative healthcare outcomes including early onset diabetes‐related foot disease and high rates of lower limb amputation in Aboriginal and Torres Strait Islander Peoples contribute to this gross inequity.

Main body

In 2020, the Australian Health Practitioner Regulation Authority released the National Scheme's Aboriginal and Torres Strait Islander Health and Cultural Safety Strategy 2020–2025 ‐ empowering all registered health practitioners within Australia to provide health care to Aboriginal and Torres Strait Islander Peoples that is inclusive, respectful and safe, as judged by the recipient of care. This recently released strategy is critically important to the podiatry profession in Australia. As clinicians, researchers and educators we have a collective responsibility to engage with this strategy of cultural safety. This commentary defines cultural safety for podiatry and outlines the components of the strategy in the context of our profession. Discussion considers the impact of the strategy on podiatry. It identifies mechanisms for podiatrists in all settings to facilitate safer practice, thereby advancing healthcare to produce more equitable outcomes.

Conclusion

Aboriginal and Torres Strait Islander Peoples access health services more frequently and have better health outcomes where provision of care is culturally safe. By engaging with the National Scheme's Aboriginal and Torres Strait Islander Health and Cultural Safety Strategy, all registered podiatrists in Australia can contribute to achieving equity in health outcomes for Aboriginal and Torres Strait Islander Peoples.
Long-read cDNA sequencing identifies functional pseudogenes in the human transcriptome
Authors: Troskie Robin-Lee , Jafrani Yohaann , Mercer Tim R. , Ewing Adam D. , Faulkner Geoffrey J. , Cheetham Seth W.
Published: May 2021

Pseudogenes are gene copies presumed to mainly be functionless relics of evolution due to acquired deleterious mutations or transcriptional silencing. Using deep full-length PacBio cDNA sequencing of normal human tissues and cancer cell lines, we identify here hundreds of novel transcribed pseudogenes expressed in tissue-specific patterns. Some pseudogene transcripts have intact open reading frames and are translated in cultured cells, representing unannotated protein-coding genes. To assess the biological impact of noncoding pseudogenes, we CRISPR-Cas9 delete the nucleus-enriched pseudogene PDCL3P4 and observe hundreds of perturbed genes. This study highlights pseudogenes as a complex and dynamic component of the human transcriptional landscape.
Whole School SEND (WSS) Review: study protocol for a two-arm pragmatic parallel cluster randomised controlled trial in 160 English secondary schools
Authors: Morris Stephen , Smith Andrew , Lewin Cathy , Hick Peter , Harrison Jordan
Published: May 2021

Background

The trial will study the effects of the Whole School SEND Review on secondary school pupils in English mainstream education, to understand the impact of the intervention on academic attainment, wellbeing, and school attendance. The Review is designed to facilitate whole-school change through providing enhanced, intensive and sustained support and training in inclusive education for school special educational needs coordinators and leadership teams. The trial will have a specific focus on pupils designated as having special educational needs or disabilities.

Methods

We recruited 160 English secondary schools (approx. 58,000 pupils across two cohorts) to a two-arm pragmatic parallel cluster randomised controlled trial, with allocation at the school level. Randomisation will be stratified by school region. The primary outcome is attainment in English language (using standardised national test results at 16 years) for pupils designated as having a special educational need (approx. 4000 pupils). Secondary outcomes will be measured for pupils both with and without a special educational need designation and include pupil wellbeing (measured using the Strengths and Difficulties Questionnaire), absences and exclusions, and attainment in Mathematics and English language at 16 years. The intervention will be implemented from July 2021 and analysis of outcomes (for the year 9 cohort) will take place in September 2023, with further analysis (for the year 8 cohort) in September 2024 if the evaluation shows that acceptable implementation fidelity has been achieved.

Discussion

Pupils with special educational needs represent a significant and often vulnerable part of the secondary school population, are disproportionately likely to be excluded from school, eligible for free school meals, or supported by children’s social care. Despite these multiple important areas of need, school leaders report substantial challenges in making additional provision for this group. Previous research has highlighted the development of inclusive school cultures (rather focusing primarily on targeted individualised approaches) as being important. This trial will investigate how an intervention designed to drive whole school change may lead to outcomes for pupils with and without a special educational needs designation. As such, this trial is expected to make an important contribution to research evidence and to UK educational policy.

Trial registration

ISRCTN registry ISRCTN11339306. Registered on 12 March 2020 (retrospectively registered).
Frozen vs. fresh cycles IVF outcomes: retrospective study from an Indonesian IVF centre
Authors: Permadi Wiryawan , Bayuaji Hartanto , Tjandraprawira Kevin Dominique , Tjahyadi Dian , Harlianto Harris , Achmad Yanni Melliandari , Astarto Nanang Winarto , Djuwantono Tono
Published: May 2021

Objective

To compare the live birth rates (LBR) and neonatal outcomes of frozen cycle in vitro fertilization (IVF) with fresh cycle IVF in the Indonesian population.

Results

This was retrospective study using secondary data of IVF patients at a private fertility centre. Study recruitment was between 3/8/2018 and 31/12/2019. Total sampling included all patients undergoing oocyte retrieval and embryo transfer within recruitment period. Patients undergoing fresh IVF cycles and frozen IVF cycles were compared. 351 patients were recruited: 68.1% (239/351) underwent fresh cycles and 31.9% (112/351) frozen cycles. AMH was significantly higher in frozen cycle group (p = 0.04). Ovulatory disorder was significantly higher in frozen cycle group (p = 0.001). Among patients aged ≤ 30, fresh cycle group had significantly higher LBR (p = 0.02). Among those with ovulatory disorder, LBR was significantly higher with frozen cycle. No significant LBR difference was noted with other infertility causes. When stratified according to pregnancy order, frozen cycle patients had significantly higher birth lengths (p = 0.03) but not length of gestation nor neonatal birthweights. There was no significant difference in the proportion of biochemical pregnancy resulting in LBR (p = 0.08). To conclude, frozen cycle provided higher LBR among patients with ovulatory disorder but fresh cycle was beneficial among patients aged ≤ 30.
Validation of amyloid PET positivity thresholds in centiloids: a multisite PET study approach
Authors:   for the Alzheimer’s Disease Neuroimaging Initiative, Royse Sarah K. , Minhas Davneet S. , Lopresti Brian J. , Murphy Alice , Ward Tyler , Koeppe Robert A. , Bullich Santiago , DeSanti Susan , Jagust William J. , Landau Susan M.
Published: May 2021

Background

Inconsistent positivity thresholds, image analysis pipelines, and quantitative outcomes are key challenges of multisite studies using more than one β-amyloid (Aβ) radiotracer in positron emission tomography (PET). Variability related to these factors contributes to disagreement and lack of replicability in research and clinical trials. To address these problems and promote Aβ PET harmonization, we used [18F]florbetaben (FBB) and [18F]florbetapir (FBP) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to derive (1) standardized Centiloid (CL) transformations and (2) internally consistent positivity thresholds based on separate young control samples.

Methods

We analyzed Aβ PET data using a native-space, automated image processing pipeline that is used for PET quantification in many large, multisite AD studies and trials and made available to the research community. With this pipeline, we derived SUVR-to-CL transformations using the Global Alzheimer’s Association Interactive Network data; we used reference regions for cross-sectional (whole cerebellum) and longitudinal (subcortical white matter, brain stem, whole cerebellum) analyses. Finally, we developed a FBB positivity threshold using an independent young control sample (N=62) with methods parallel to our existing FBP positivity threshold and validated the FBB threshold using a data-driven approach in ADNI participants (N=295).

Results

The FBB threshold based on the young sample (1.08; 18 CL) was consistent with that of the data-driven approach (1.10; 21 CL), and the existing FBP threshold converted to CL with the derived transformation (1.11; 20 CL). The following equations can be used to convert whole cerebellum- (cross-sectional) and composite- (longitudinal) normalized FBB and FBP data quantified with the native-space pipeline to CL units:

[18F]FBB: CLwhole cerebellum = 157.15 × SUVRFBB − 151.87; threshold=1.08, 18 CL

[18F]FBP: CLwhole cerebellum = 188.22 × SUVRFBP − 189.16; threshold=1.11, 20 CL

[18F]FBB: CLcomposite = 244.20 × SUVRFBB − 170.80

[18F]FBP: CLcomposite = 300.66 × SUVRFBP − 208.84

Conclusions

FBB and FBP positivity thresholds derived from independent young control samples and quantified using an automated, native-space approach result in similar CL values. These findings are applicable to thousands of available and anticipated outcomes analyzed using this pipeline and shared with the scientific community. This work demonstrates the feasibility of harmonized PET acquisition and analysis in multisite PET studies and internal consistency of positivity thresholds in standardized units.