bluuebunny/crossref_metadata_2025 huggingface dataset:
Mortality Benefit From the Passive Leg Raise Maneuver in Guiding Resuscitation of Septic Shock Patients: A Systematic Review and Meta-Analysis of Randomized Trials
Authors: Azadian Moosa , Win Suyee , Abdipour Amir , Kim Carolyn Krystal , Nguyen H. Bryant
Published: June 2021

Background:

Fluid therapy plays a major role in the management of critically ill patients. Yet assessment of intravascular volume in these patients is challenging. Different invasive and non-invasive methods have been used with variable results. The passive leg raise (PLR) maneuver has been recommended by international guidelines as a means to determine appropriate fluid resuscitation. We performed this systematic review and meta-analysis to determine if using this method of volume assessment has an impact on mortality outcome in patients with septic shock.

Methods:

This study is a systematic review and meta-analysis. We searched available data in the MEDLINE, CINAHL, EMBASE, and CENTRAL databases from inception until October 2020 for prospective, randomized, controlled trials that compared PLR-guided fluid resuscitation to standard care in adult patients with septic shock. Our primary outcome was mortality at the longest duration of follow-up.

Results:

We screened 1,425 article titles and abstracts. Of the 23 full-text articles reviewed, 5 studies with 462 patients met our eligibility criteria. Odds ratios (ORs) and associated 95% confidence intervals (CIs) for mortality at the longest reported time interval were calculated for each study. Using random effects modeling, the pooled OR (95% CI) for mortality with a PLR-guided resuscitation strategy was 0.82 (0.52 -1.30). The included studies were not blinded and they ranged from having low to high risk of bias using the Cochrane Risk of Bias Tool.

Conclusion:

Our analysis showed there was no statistically significant difference in mortality among septic shock patients treated with PLR-guided resuscitation vs. those with standard care.
Study on flow field and aerodynamic noise of electric vehicle rearview mirror
Authors: Hao Xiaowei , Yang Zhigang , Li Qiliang
Published: June 2021

With the development of new energy and intelligent vehicles, aerodynamic noise problem of pure electric vehicles at high speed has become increasingly prominent. The characteristics of the flow field and aerodynamic noise of the rearview mirror region were investigated by large eddy simulation, acoustic perturbation equations and reduction order analysis. By comparing the pressure coefficients of the coarse, medium and dense grids with wind tunnel test results, the pressure distribution, and numerical accuracy of the medium grid on the body are clarified. It is shown from the flow field proper orthogonal decomposition of the mid-section that the sum of the energy of the first three modes accounts for more than 16%. Based on spectral proper orthogonal decomposition, the peak frequencies of the first-order mode are 19 and 97 Hz. As for the turbulent pressure of side window, the first mode accounts for approximately 11.3% of the total energy, and its peak appears at 39 and 117 Hz. While the first mode of sound pressure accounts for about 41.7%, and the energy peaks occur at 410 and 546 Hz. Compared with traditional vehicle, less total turbulent pressure level and total sound pressure level are found at current electric vehicle because of the limited interaction between the rearview mirror and A-pillar.
Human Readiness Levels Promote Effective System Integration
Authors: Schwartz Benjamin , Dodson Joan E.
Published: June 2021

The purpose of a Human Readiness Level (HRL) scale is to indicate a developing system’s readiness for use by humans, that is, the maturity of human engineering efforts. We explore the factors driving the development of the HRL scale, how the scale enhances systems engineering and program execution, and potential shortcomings. We focus on the American National Standards Institute and Human Factors and Ergonomics Society (ANSI/HFES) 400-2021 standard, which includes an HRL scale and implementation guidance. Utilizing HRLs improves the integration of human systems considerations in the engineering process and results in improved system performance and life cycle concept realization.
DNA Mini-Barcodes, a Potential Weapon for Conservation and Combating Illegal Trade of Pangolin
Authors: Xie Xuena , Ye Haoting , Cai Xuan , Li Chan , Li Fang , Tian Enwei , Chao Zhi
Published: June 2021

Background

Smuggling and illegal trade of pangolins and their scales has drastically reduced the wild population of pangolins. Accurate species identification is currently in urgent need as a powerful weapon for combating pangolin smuggling and trade and conserving the already endangered pangolin species.

Aim of the study

To develop an efficient method based on DNA mini-barcodes for accurate pangolin species identification and authentication of processed pangolin scales against the non-target species.

Materials and methods

The primers for amplifying the DNA mini-barcodes were designed based on cytochrome C oxidase subunit I (COI) gene fragments. The mini-barcodes were compared with the two universal barcodes (COI and Cytb) for performance in pangolin species identification by calculating the Kimura-2-parameter (K2P) distance, assessing the clustering dendrogram, and analyzing the BLAST similarity and barcoding gap. The accuracy of the three barcodes was also compared for authentication of pangolin scales against non-target species.

Results

Comparison of the three barcodes showed that the mini-barcode form COI had the highest amplification success rate (100%) and high variable sites (40.0%), with the ratio of mean inter- to intraspecific distance ratio was 25 and a distinct DNA barcoding gap. In the neighbor-joining (NJ) tree constructed based on the mini-barcode regions, each species of the pangolin family formed an obvious clade respectively, and the clades were all separated from those of the non-target species, indicating that the genetic information in the mini-barcode was sufficient for species identification.

Conclusion

The DNA mini-barcodes based on COI gene fragments provide an effective and accurate method for identification of pangolin species and authentication of pangolin scale products.
Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double‐blind placebo‐controlled study
Authors: Ivy Dunbar , Bonnet Damien , Berger Rolf , Meyer Gisela M.B. , Baygani Simin , Li Baohui ,   the LVHV Study Group
Published: June 2021

This study evaluated the efficacy and safety of tadalafil in pediatric patients with pulmonary arterial hypertension. This phase‐3, international, randomized, multicenter (24 weeks double‐blind placebo‐controlled period; two‐year, open‐labeled extension period), add‐on (patient’s current endothelin receptor antagonist therapy) study included pediatric patients aged <18 years with pulmonary arterial hypertension. Patients received tadalafil 20 mg or 40 mg based on their weight (heavy‐weight: ≥40 kg; middle‐weight: ≥25 to <40 kg) or placebo orally once daily for 24 weeks. Primary endpoint was change from baseline in six‐minute walk distance in patients aged ≥6 years at Week 24. Sample size was amended from 134 to ≥34 patients, due to serious recruitment challenges. Therefore, statistical significance testing was not performed between treatment groups. Results showed that patient demographics and baseline characteristics (N = 35; tadalafil = 17; placebo = 18) were comparable between treatment groups; median age was 14.2 years (6.2–17.9 years) and majority (71.4%, n = 25) of patients were in the heavy‐weight cohort. Least square mean (standard error) changes from baseline in six‐minute walk distance at Week 24 was numerically greater with tadalafil versus placebo (60.48 (20.41) vs 36.60 (20.78) meters; placebo‐adjusted mean difference (standard deviation) 23.88 (29.11)). Safety of tadalafil treatment was as expected without any new safety concerns. During study Period 1, two patients (one in each group) discontinued due to investigator’s reported clinical worsening, and no deaths were reported. In conclusion, the statistical significance testing was not performed between the treatment groups due to low sample size; however, the study results show positive trend in improvement in non‐invasive measurements, commonly utilized by clinicians to evaluate the disease status for children with pulmonary arterial hypertension. Safety of tadalafil treatment was as expected without any new safety signals.
Vascular cell‐specific roles of mineralocorticoid receptors in pulmonary hypertension
Authors: Menon Divya P. , Qi Guanming , Kim Seung K. , Moss M. Elizabeth , Penumatsa Krishna C. , Warburton Rod R. , Toksoz Deniz , Wilson Jamie , Hill Nicholas S. , Jaffe Iris Z. , Preston Ioana R.
Published: June 2021

Abnormalities that characterize pulmonary arterial hypertension include impairment in the structure and function of pulmonary vascular endothelial and smooth muscle cells. Aldosterone levels are elevated in human pulmonary arterial hypertension and in experimental pulmonary hypertension, while inhibition of the aldosterone‐binding mineralocorticoid receptor attenuates pulmonary hypertension in multiple animal models. We explored the role of mineralocorticoid receptor in endothelial and smooth muscle cells in using cell‐specific mineralocorticoid receptor knockout mice exposed to sugen/hypoxia‐induced pulmonary hypertension. Treatment with the mineralocorticoid receptor inhibitor spironolactone significantly reduced right ventricular systolic pressure. However, this is not reproduced by selective mineralocorticoid receptor deletion in smooth muscle cells or endothelial cells. Similarly, spironolactone attenuated the increase in right ventricular cardiomyocyte area independent of vascular mineralocorticoid receptor with no effect on right ventricular weight or interstitial fibrosis. Right ventricular perivascular fibrosis was significantly decreased by spironolactone and this was reproduced by specific deletion of mineralocorticoid receptor from endothelial cells. Endothelial cell‐mineralocorticoid receptor deletion attenuated the sugen/hypoxia‐induced increase in the leukocyte‐adhesion molecule, E‐selectin, and collagen IIIA1 in the right ventricle. Spironolactone also significantly reduced pulmonary arteriolar muscularization, independent of endothelial cell‐mineralocorticoid receptor or smooth muscle cell‐mineralocorticoid receptor. Finally, the degree of pulmonary perivascular inflammation was attenuated by mineralocorticoid receptor antagonism and was fully reproduced by smooth muscle cell‐specific mineralocorticoid receptor deletion. These studies demonstrate that in the sugen/hypoxia pulmonary hypertension model, systemic‐mineralocorticoid receptor blockade significantly attenuates the disease and that mineralocorticoid receptor has cell‐specific effects, with endothelial cell‐mineralocorticoid receptor contributing to right ventricular perivascular fibrosis and smooth muscle cell‐mineralocorticoid receptor participating in pulmonary vascular inflammation. As mineralocorticoid receptor antagonists are being investigated to treat pulmonary arterial hypertension, these findings support novel mechanisms and potential mineralocorticoid receptor targets that mediate therapeutic benefits in patients.
Sandwich compression of sugi (Cryptomeria japonica) and hinoki (Chamaecyparis obtusa) wood: density distribution, surface hardness and their controllability
Authors: Huang Rongfeng , Fujimoto Noboru , Sakagami Hiroki , Feng Shanghuan
Published: June 2021

The sapwood and heartwood of plantation sugi wood (Cryptomeria japonica), and plantation hinoki (Chamaecyparis obtusa) wood were flat-sawn into timbers, then kiln-dried to a MC level below 12%. These timbers were further processed into specific sizes and wetted on the surfaces, preheated at 150 °C and radially compressed into sandwich compressed timbers. Density distribution, compressed layer(s) position and thickness, surface hardness were investigated. It was demonstrated that sugi and hinoki timbers were both applicable for sandwich compression. By controlling the preheating time, sugi heartwood timber, sugi sapwood timber and hinoki timber can be all sandwich compressed, which resulted in surfaces compressed timbers, interior compressed timbers and center compressed timbers. When sugi timbers were sandwich compressed, density only tremendously increased in the earlywood. The increased density of the compressed sugi earlywood was independent of compressed layer(s) position, compressing distance or annual growth width, while for hinoki timbers compression, density increased both in earlywood and latewood. Surface hardness of the uncompressed sugi sapwood was almost twice of that of the uncompressed sugi heartwood. Surface compression sharply increased the surface hardness of sugi heartwood and sugi sapwood. Interior compression and center compression also contributed to increased surface hardness for the compressed timbers, but to smaller extents. Surface hardness change due to the surface compression was consistent with the surface average density change of timbers. Compression layer(s) position exerted statistically significant effects on the surface hardness, while surface hardness of the compressed wood was almost unrelated to the original density of the used wood or average density of the sandwich compressed wood. However, bigger compressing distance led to bigger surface hardness for the surface compressed wood.
Methods to study organogenesis in decapod crustacean larvae II: analysing cells and tissues
Authors: Melzer R. R. , Spitzner F. , Šargač Z. , Hörnig M. K. , Krieger J. , Haug C. , Haug J. T. , Kirchhoff T. , Meth R. , Torres G. , Harzsch S.
Published: June 2021

Cells and tissues form the bewildering diversity of crustacean larval organ systems which are necessary for these organisms to autonomously survive in the plankton. For the developmental biologist, decapod crustaceans provide the fascinating opportunity to analyse how the adult organism unfolds from organ Anlagen compressed into a miniature larva in the sub-millimetre range. This publication is the second part of our survey of methods to study organogenesis in decapod crustacean larvae. In a companion paper, we have already described the techniques for culturing larvae in the laboratory and dissecting and chemically fixing their tissues for histological analyses. Here, we review various classical and more modern imaging techniques suitable for analyses of eidonomy, anatomy, and morphogenetic changes within decapod larval development, and protocols including many tips and tricks for successful research are provided. The methods cover reflected-light-based methods, autofluorescence-based imaging, scanning electron microscopy, usage of specific fluorescence markers, classical histology (paraffin, semithin and ultrathin sectioning combined with light and electron microscopy), X-ray microscopy (µCT), immunohistochemistry and usage of in vivo markers. For each method, we report our personal experience and give estimations of the method’s research possibilities, the effort needed, costs and provide an outlook for future directions of research.
Non-elective and revision arthroplasty are independently associated with hip and knee prosthetic joint infection caused by Acinetobacter baumannii: a Brazilian single center observational cohort study of 98 patients
Authors: da Silva Raquel Bandeira , Araujo Rodrigo Otavio , Salles Mauro José
Published: June 2021

Background

Prosthetic joint infection (PJI) caused by Acinetobacter baumannii (Ab) has become a growing concern due to its overwhelming ability to express resistance to antibiotics and produce biofilm.

Aim

This study aimed to identify independent risk factors (RFs) associated with Ab-associated PJI and their role in the treatment outcome.

Methods

This was a single-centre, retrospective cohort study of PJI patients diagnosed between January 2014 and July 2018. A PJI diagnosis was made based upon the MSIS 2018 criteria. To estimate RFs associated with Ab-associated PJI, multivariate analyses with a level of significance of p < 0.05 were performed. To evaluate treatment failure, Kaplan–Meier analysis and log-rank test were performed.

Results

Overall, 98 PJI cases were assessed, including 33 with Ab-associated PJI and 65 with PJI involving other microorganisms (non–Ab-associated PJI). Independent RFs associated with Ab-associated PJI were revision arthroplasty [odds ratio (OR) = 3.01; 95% confidence interval (CI) = 1.15–7.90; p = 0.025] and nonelective arthroplasty (OR = 2.65; 95% CI = 1.01–7.01; p = 0.049). Ab-associated PJI was also more likely than non–Ab-associated PJI to be classified as a chronic late infection (OR = 5.81; 95% CI = 2.1–16.07; p = 0.001). Ab-associated PJI was not associated with treatment failure (p = 0.557).

Conclusions

Late chronic infections, surgical revision and nonelective arthroplasty are well-known predictors of PJI but were also independently associated with Ab-associated PJI. Infections caused by Ab and surgical treatment with debridement, antibiotics and implant retention were not associated with PJI treatment failure.

Trial registration

Study data supporting our results were registered with the Brazilian Registry of Clinical Trials (https://www.ensaiosclinicos.gov.br/rg/RBR-6ft5yb/), an open-access virtual platform for the registration of studies on humans performed in Brazil.

Registration no.RBR-6ft5yb.
Diversity of tsetse flies and trypanosome species circulating in the area of Lake Iro in southeastern Chad
Authors: Signaboubo Djoukzoumka , Payne Vincent Khan , Moussa Ibrahim Mahamat Alhadj , Hassane Hassane Mahamat , Berger Petra , Kelm Soerge , Simo Gustave
Published: June 2021

Background

African trypanosomiases are vector-borne diseases that affect humans and livestock in sub-Saharan Africa. Although data have been collected on tsetse fauna as well as trypanosome infections in tsetse flies and mammals in foci of sleeping sickness in Chad, the situation of tsetse fly-transmitted trypanosomes remains unknown in several tsetse-infested areas of Chad. This study was designed to fill this epidemiological knowledge gap by determining the tsetse fauna as well as the trypanosomes infecting tsetse flies in the area of Lake Iro in southeastern Chad.

Methods

Tsetse flies were trapped along the Salamat River using biconical traps. The proboscis and tsetse body were removed from each fly. DNA was extracted from the proboscis using proteinase K and phosphate buffer and from the tsetse body using Chelex 5%. Tsetse flies were identified by amplifying and sequencing the cytochrome c oxydase I gene of each tsetse fly. Trypanosome species were detected by amplifying and sequencing the internal transcribed spacer 1 of infecting trypanosomes.

Results

A total of 617 tsetse flies were trapped; the apparent density of flies per trap per day was 2. 6. Of the trapped flies, 359 were randomly selected for the molecular identification and for the detection of infecting trypanosomes. Glossina morsitans submorsitans (96.1%) was the dominant tsetse fly species followed by G. fuscipes fuscipes (3.1%) and G. tachinoides (0.8%). Four trypanosome species, including Trypanosoma vivax, T. simiae, T. godfreyi and T. congolense savannah, were detected. Both single infection (56.7%) and mixed infections of trypanosomes (4.6%) were detected in G. m. submorsitans. The single infection included T. simiae (20.5%), T. congolense savannah (16.43%), T. vivax (11.7%) and T. godfreyi (9.8%). The trypanosome infection rate was 61.4% in G. m. submorsitans, 72.7% in G. f. fuscipes and 66.6% in G. tachinoides. Trypanosome infections were more prevalent in tsetse bodies (40.6%) than in the proboscis (16.3%).

Conclusion

This study revealed the presence of different tsetse species and a diversity of trypanosomes pathogenic to livestock in the area of Lake Iro. The results highlight the risks and constraints that animal African trypanosomiasis pose to livestock breeding and the importance of assessing trypanosome infections in livestock in this area.

Graphical Abstract
Personalized paths for physical activity: developing a person-centered quantitative function to determine a customized amount of exercise and enhancing individual commitment
Authors: Iolascon Giovanni , Gimigliano Francesca , Di Pietro Gioconda , Moretti Antimo , Paoletta Marco , Rivezzi Matteo , Distante Alessandro , Piscitelli Prisco
Published: June 2021

Background

Non-Communicable Diseases (NCDs) are leading causes of mortality. These conditions are also known as chronic diseases of long duration and generally slow progression. Physical activity (PA) is a main factor to delay symptoms and consequences of NCDs. In last decades, reduced physical exercise has been observed across all ages. Despite educational campaigns aimed at modifying unhealthy habits, it is difficult to promote healthy lifestyles in general population. Poor interest, lack of motivation, as well as career and family commitments hinder people’s participation in regular PA programs. In this study we propose a theoretical person-centred approach to actively involve general population in enhancing their opportunity to perform PA based on personalized needs and targets.

Methods

We defined four profiles of baseline PA levels (inactive, moderately inactive, moderately active, and active people) by referring to Metabolic equivalents (METs) based on individual answers to General Practice Physical Activity Questionnaire (GPPAQ).

Results

Based on the answers to the GPPAQ and by computing the related METs for each profile of baseline exercise levels, we developed an innovative person-centered web-based algorithm/function for enhancing and measuring PA participation in community settings. This function can compute evidence-based standardized profiles of participants, personalized goals of PA being functional to the purpose of maintaining or gaining health benefits, as well as the type and duration of PA needed to reach these goals.

Conclusion

It might be speculated that this approach would be a reliable method for increasing people’s self-efficacy and population adherence to recommended levels of PA. However, this theoretical proposal requires to be implemented in further research.
Compression socks enhance sensory feedback to improve standing balance reactions and reflex control of walking
Authors: Sun Yao , Munro Bridget , Zehr E. Paul
Published: June 2021

Background

Compression garments are generally used for their potential benefits in exercise performance and post-exercise recovery. Previous studies show that compression sleeves worn at the elbow change neuromuscular control and improve performance during reaching movement. Cutaneous stimulation of the foot skin produces location-specific reflexes in the lower limb that guide foot placement during locomotion. However, it is not clear whether enhancement of sensory feedback with compression socks can alter the neuromuscular excitability of muscles in the leg and amplify balance performance and walking. The current project aimed to determine whether enhanced sensory input from wearing compression socks could affect: 1) spinal cord excitability (as measured by cutaneous reflexes from stimulation at the top or bottom of the foot during locomotion); 2) static balance performance; and, 3) dynamic balance performance following virtual perturbations.

Methods

Twelve participants completed walking and balance tasks wearing four types of garments: 1) non-compression (control) socks; 2) ankle compression socks; 3) calf-compression socks; and, 4) customized ankle sleeves. During walking, electrical stimulations were delivered to three discrete locations on the dorsal (ankle crease, forefoot medial) and plantar (forefoot medial) surfaces of the foot in separate trials with each garment. Electromyography of ankle dorsiflexor tibialis anterior, plantarflexor medial gastrocnemius and evertor peroneus longus were measured bilaterally along with kinematic data from knee and ankle and kinetics under the right (stimulated) foot.

Results

Compared to control socks, altered cutaneous reflexes and biomechanical responses were observed in all the conditions during walking. In dynamic balance tests, time and integrated EMG for recovering from virtual perturbation were significantly reduced when wearing calf compression socks and the ankle sleeve.

Conclusions

Our findings suggest sensory enhancement from compression garments modifies spinal cord excitability during walking and improves performance in balance recovery after virtual perturbation.
The impacts of health systems financing fragmentation in low- and middle-income countries: a systematic review protocol
Authors: Siqueira Marina , Coube Maíra , Millett Christopher , Rocha Rudi , Hone Thomas
Published: June 2021

Background

Health systems are often fragmented in low- and middle-income countries (LMICs). This can increase inefficiencies and restrict progress towards universal health coverage. The objective of the systematic review described in this protocol will be to evaluate and synthesize the evidence concerning the impacts of health systems financing fragmentation in LMICs.

Methods

Literature searches will be conducted in multiple electronic databases, from their inception onwards, including MEDLINE, EMBASE, LILACS, CINAHL, Scopus, ScienceDirect, Scielo, Cochrane Library, EconLit, and JSTOR. Gray literature will be also targeted through searching OpenSIGLE, Google Scholar, and institutional websites (e.g., HMIC, The World Bank, WHO, PAHO, OECD). The search strings will include keywords related to LMICs, health system financing fragmentation, and health system goals. Experimental, quasi-experimental, and observational studies conducted in LMICs and examining health financing fragmentation across any relevant metric (e.g., the presence of different health funders/insurers, risk pooling mechanisms, eligibility categories, benefits packages, premiums) will be included. Studies will be eligible if they compare financing fragmentation in alternative settings or at least two-time points. The primary outcomes will be health system-related goals such as health outcomes (e.g., mortality, morbidity, patient-reported outcome measures) and indicators of access, services utilization, equity, and financial risk protection. Additional outcomes will include intermediate health system objectives (e.g., indicators of efficiency and quality). Two reviewers will independently screen all citations, abstract data, and full-text articles. Potential conflicts will be resolved through discussion and, when necessary, resolved by a third reviewer. The methodological quality (or risk of bias) of selected studies will be appraised using established checklists. Data extraction categories will include the studies’ objective and design, the fragmentation measurement and domains, and health outcomes linked to the fragmentation. A narrative synthesis will be used to describe the results and characteristics of all included studies and to explore relationships and findings both within and between the studies.

Discussion

Evidence on the impacts of health system fragmentation in LMICs is key for identifying evidence gaps and priority areas for intervention. This knowledge will be valuable to health system policymakers aiming to strengthen health systems in LMICs.

Systematic review registration

PROSPERO CRD42020201467
Weaning-associated feed deprivation stress causes microbiota disruptions in a novel mucin-containing in vitro model of the piglet colon (MPigut-IVM)
Authors: Gresse Raphaële , Chaucheyras-Durand Frédérique , Denis Sylvain , Beaumont Martin , Van de Wiele Tom , Forano Evelyne , Blanquet-Diot Stéphanie
Published: June 2021

Background

Risk factors for the etiology of post-weaning diarrhea, a major problem in swine industry associated with enormous economic losses, remain to be fully elucidated. In concordance with the ethical concerns raised by animal experiments, we developed a new in vitro model of the weaning piglet colon (MPigut-IVM) including a mucin bead compartment to reproduce the mucus surface from the gut to which gut microbes can adhere.

Results

Our results indicated that the MPigut-IVM is able to establish a representative piglet archaeal and bacterial colon microbiota in terms of taxonomic composition and function. The MPigut-IVM was consequently used to investigate the potential effects of feed deprivation, a common consequence of weaning in piglets, on the microbiota. The lack of nutrients in the MPigut-IVM led to an increased abundance of Prevotellaceae and Escherichia-Shigella and a decrease in Bacteroidiaceae and confirms previous in vivo findings. On top of a strong increase in redox potential, the feed deprivation stress induced modifications of microbial metabolite production such as a decrease in acetate and an increase in proportional valerate, isovalerate and isobutyrate production.

Conclusions

The MPigut-IVM is able to simulate luminal and mucosal piglet microbiota and represent an innovative tool for comparative studies to investigate the impact of weaning stressors on piglet microbiota. Besides, weaning-associated feed deprivation in piglets provokes disruptions of MPigut-IVM microbiota composition and functionality and could be implicated in the onset of post-weaning dysbiosis in piglets.
Promoting recovery in daily life: study protocol for a randomized controlled trial
Authors: Reis Dorota , Hart Alexander , Lehr Dirk , Friese Malte
Published: June 2021

Background

Work-related stress shows steadily increasing prevalence rates and has tangible consequences for individual workers, their organizations, and society as a whole. One mechanism that may help offset the negative outcomes of work-related stress on employees’ well-being is recovery. Recovery refers to the experience of unwinding from one's job when not at work. However, employees who experience high levels of work-related stress and are thus particularly in need of recovery tend to struggle to switch-off. Due to the detrimental effects of this prolonged and sustained mental representation of job stressors, interventions promoting recovery may contribute to improvements in employees' mental health.

Methods

In this randomized, waitlist controlled trial, we will investigate the effectiveness of two 6-week online training programs (cognitive behavioral and mindfulness-based). The sample will include employees working at least part-time during regular work hours. Besides the pre-post-follow-up assessments, the trial will include measurement bursts with the goal of examining the underlying mechanisms. We expect that both interventions will reduce work-related perseverative thinking (PT) compared with the waitlist control groups (primary outcome). Also, we expect that both interventions will result in similar improvements, but the underlying mechanisms will differ (process outcomes). In the cognitive-behavioral intervention group, we expect that the main mechanism responsible for lower PT levels will be an increase in recovery experiences across time. In the mindfulness-based group, we expect that the main mechanism responsible for lower PT levels will be an increase in facets of mindfulness across time.

Discussion

In the present study, we will investigate mechanisms underlying assumed changes in work-related PT in great detail. Besides evaluating the overall effectiveness of the two interventions in terms of pre-post-follow-up changes, we will look at the underlying processes at different levels—that is, within days, within weeks, across weeks, and between individuals. Accordingly, our study will offer a fine-grained approach to investigating potential determinants, mediators, and moderators of the processes that may, in the end, be responsible for work-related strain. From a public health perspective, if effective, the online training programs may offer valuable, low-threshold, and low-intensity interventions for a broad range of occupations.

Trial registrationGerman Clinical Trials Registration: DRKS00024933. Registered prospectively 7 April 2021.https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024933
Single cell transcriptome revealed tumor associated antigen (TAA) profile in lung adenocarcinoma (LUAD)
Authors: Lv Fang , Wu Xueying , Song Jin , Wang Pan , Ren Shucheng , Guo Wei , Xue Qi , Zhang Henghui , Zhao Jun
Published: June 2021

It has been suggested that the heterogeneity of TAAs in lung cancer may affect the therapeutic response and disease progression. Up to now, several tumor-associated antigen (TAA)-based cancer vaccines have been investigated in lung adenocarcinoma (LUAD); however, most of them have failed at the stage of clinical trials. The present study suggests that inter-tumoral heterogeneity of TAAs is large at single-cell resolution, while the communication between tumor cells and infiltrating T cells is closely related to the expression profile of TAAs.
Migrating architectures: Palladio’s legacy from Calcutta to New Delhi
Authors: Guerrieri Pilar Maria
Published: June 2021

Palladianism, which originated in Italy, is a style of architecture which spread widely across the world and has been extensively studied. It is known that it migrated to the UK during the eighteenth century at the same time as it did to Germany through Georg Knobelsdorff, to Russia through the work of Charles Cameron and Giacomo Quarenghi, to the US through Thomas Jefferson between the eighteenth and nineteenth centuries, and was adopted in Poland, Sweden, and elsewhere. Palladianism became a tool of politicians and a status symbol for the elites to differentiate themselves from the common man. There are a few studies on the migration and adoption of Palladianism in India, primarily in relation to Calcutta’s architecture between the eighteenth and nineteenth centuries. In particular, there is specific research focusing on Lord Wellesley’s Palladian building programme, frequently highlighting the relationship between Government House, Calcutta and Kedleston Hall in Derbyshire. This essay focuses on the subject of the migration of Palladian architecture and, in particular, on its adoption by the capitals of India, Calcutta and Delhi, on the basis of primary archival material.
Questionnaire for the assessment of adherence barriers of intravitreal therapy: the ABQ-IVT
Authors: Müller Sabrina , Junker Sophia , Wilke Thomas , Lommatzsch Albrecht , Schuster Alexander K. , Kaymak Hakan , Ehlken Christoph , Ziemssen Focke
Published: June 2021

Objective

To develop and validate a questionnaire for the investigation of non-adherence (NA) barriers in patients receiving intravitreal injection (IVT).

Design

Questionnaire development and cross-sectional patient survey combined with a retrospective medical chart review.

Participants

German patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) receiving anti-vascular endothelial growth factor (anti-VEGF) treatment via IVT.

Methods

The previously validated (indications: atrial fibrillation, human immunodeficiency virus, chronic inflammatory lung disease) Adherence Barriers Questionnaire (ABQ) was revised according to specifications of IVT, within the framework of an expert panel. The ABQ-IVT, which initially consisted of 24 items formulated as statements (4-point-Likert-scale ranging from “strongly agree” to “strongly disagree”), was applied in a cross-sectional survey. Evaluation of the questionnaire included an assessment of internal consistency and factor analysis. The occurrence of potential barriers in the patient sample was evaluated using descriptive statistics. To identify patient subpopulations, hierarchical cluster analysis was performed using ABQ-IVT answers as predictors. Due to difficulties in capturing NA as an external criterion, the evaluation of the questionnaire was limited to its internal validity and reliability.

Main outcome measures

Patients’ answers to the ABQ-IVT questionnaire and interviews.

Results

Of 253 patients, 234 (92%) were able to complete the ABQ-IVT questionnaire. Within the reliability analysis, the ABQ-IVT was reduced to 17 items. The condensed questionnaire demonstrated good internal consistency (Cronbach’s alpha = 0.78), and factor analysis showed no evidence for subscales of the questionnaire. Nearly half of the patients (49%) reported being affected by at least three different barriers. On average, a patient was affected by 3.1 barriers. The most frequently reported barriers were “Challenge due to time commitment of physician visits” (45% of the patients), “Depression” (29%) and “Travel and opportunity costs” (27%). Cluster analysis identified six patient subpopulations, each affected by different sets of barriers and differed regarding their patient characteristics.

Conclusions

The ABQ-IVT is a practical and reliable instrument for identifying patient-specific barriers to IVT treatment adherence. In practice, the questionnaire may be useful in assessing whether individual patients are at higher risk of NA due to specific adherence barriers. Aside from better awareness, this allows earlier interventions, though these still need to be validated. Patient subpopulations face different barriers and may, therefore, need distinct preventative care.
The external metastasis of the central nerve system germ cell tumors: case report and review of the literature
Authors: Wang Peng , Li Yanong , Qiu Xiaoguang
Published: June 2021

Background

Central nervous system germ cell tumors (CNS GCTs) represent a class of rare tumors that exhibit region-specific prevalence in some Asian areas (15.3%), higher than that in North America (3.6%), and age-specific prevalence in children and adolescents. According to the 2016 World Health Organization (WHO) classification, CNS GCTs can be categorized into germinomas and non-germinomatous GCTs (NGGCTs). Owing to the compression of the interventricular foramen by enlarged GCTs in the pineal gland, the resultant obstructive hydrocephalus may result in high intracranial pressure (HIP) at an alarming pace, which urgently requires a ventriculoperitoneal shunt for the relief of severe HIP. Although CNS GCT cells tend to migrate through the cerebrospinal fluid (CSF) starting from the subependymal lining, metastasis along the ventriculoperitoneal shunt tube is extremely rare.

Case presentation

In this study, we reported two cases of iGCTs with intraperitoneal metastasis. Both patients underwent ventriculoperitoneal shunt placement to alleviate HIP, and both received standard radiotherapy and chemotherapy, but they still developed abdominal metastasis, and all the abdominal masses were pathologically confirmed to be iGCTs.

Conclusions

We performed a literature study and found that from 1979 to 2020, a total of 18 cases of iGCTs were metastasized outside the nervous system. We also found a shift of the median of 13.5 months and that the most common primary site was the pineal region (83.3%); moreover, nearly half of the patients (44%) died within 1 year of metastasis, indicating a poor prognosis after celiac metastasis.
Randomized Phase II Study of PET Response–Adapted Combined Modality Therapy for Esophageal Cancer: Mature Results of the CALGB 80803 (Alliance) Trial
Authors: Goodman Karyn A. , Ou Fang-Shu , Hall Nathan C. , Bekaii-Saab Tanios , Fruth Briant , Twohy Erin , Meyers Michael O. , Boffa Daniel J. , Mitchell Kisha , Frankel Wendy L. , Niedzwiecki Donna , Noonan Anne , Janjigian Yelena Y. , Thurmes Paul J. , Venook Alan P. , Meyerhardt Jeffrey A. , O'Reilly Eileen M. , Ilson David H.
Published: June 2021

PURPOSE

To evaluate the use of early assessment of chemotherapy responsiveness by positron emission tomography (PET) imaging to tailor therapy in patients with esophageal and esophagogastric junction adenocarcinoma.

METHODS

After baseline PET, patients were randomly assigned to an induction chemotherapy regimen: modified oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel (CP). Repeat PET was performed after induction; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders (< 35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions). PET responders (≥ 35% decrease in SUV) continued on the same chemotherapy during chemoradiation. Patients underwent surgery at 6 weeks postchemoradiation. Primary end point was pathologic complete response (pCR) rate in nonresponders after switching chemotherapy.

RESULTS

Two hundred forty-one eligible patients received Protocol treatment, of whom 225 had an evaluable repeat PET. The pCR rates for PET nonresponders after induction FOLFOX who crossed over to CP (n = 39) or after induction CP who changed to FOLFOX (n = 50) was 18.0% (95% CI, 7.5 to 33.5) and 20% (95% CI, 10 to 33.7), respectively. The pCR rate in responders who received induction FOLFOX was 40.3% (95% CI, 28.9 to 52.5) and 14.1% (95% CI, 6.6 to 25.0) in responders to CP. With a median follow-up of 5.2 years, median overall survival was 48.8 months (95% CI, 33.2 months to not estimable) for PET responders and 27.4 months (95% CI, 19.4 months to not estimable) for nonresponders. For induction FOLFOX patients who were PET responders, median survival was not reached.

CONCLUSION

Early response assessment using PET imaging as a biomarker to individualize therapy for patients with esophageal and esophagogastric junction adenocarcinoma was effective, improving pCR rates in PET nonresponders. PET responders to induction FOLFOX who continued on FOLFOX during chemoradiation achieved a promising 5-year overall survival of 53%.
Resolving driver events in MLL-r negative high-risk infant ALL.
Authors: Seelisch Jennifer , Zatzman Matthew , Comitani Federico , Fuligni Fabio , Brunga Ledia , Brown Patrick A. , Shlien Adam , Gupta Sumit
Published: June 2021

10030

Background: Infant acute lymphoblastic leukemia (ALL) is the only subtype of childhood ALL whose outcome has not improved over the past two decades. The most important prognosticator is the presence of rearrangements in the Mixed Lineage Leukemia gene (MLL-r), however, many patients present with high-risk clinical features but without MLL-r. We recently identified two cases of infant ALL with high-risk clinical features resembling MLL-r, but were negative for MLL-r by conventional diagnostics. RNA sequencing revealed a partial tandem duplication in MLL (MLL-PTD). We thus aimed to determine if MLL-PTD, other MLL abnormalities, or other genetic or transcriptomic features were driving this subset of high-risk infant ALL without MLL-r. Methods: We obtained 19 banked patient samples from the Children’s Oncology Group (COG) infant ALL trial (AALL0631) from MLL wildtype patients as determined by FISH and cytogenetics. Utilizing deep RNA-sequencing, we manually inspected the MLL gene for MLL-PTD, while also performing automated fusion detection and gene expression profiling in search of defining features of these tumors. Results: 3 additional MLL-PTDs were identified, all in patients with infant T-cell ALL, whereas both index cases were in patients with infant B-cell ALL. Gene expression profiling analysis revealed that all five MLL-PTD infants clustered together. Eight infants (7 with B-cell ALL) were found to have Ph-like expression. Five of these 8 infants were also found to have an IKZF1/JAK2 expression profile; one of these five had a PAX5-JAK2 fusion detected. Two infants (including the one noted above) had novel PAX5 fusions, known drivers of B-cell leukemia. Additional detected fusions included TCF3-PBX1 and TCF4-ZNF384. Conclusions: MLL-PTDs were found in both B- and T-cell infant ALL. Though Ph-like ALL has been described in adolescents and young adults, we found a substantial frequency of Ph-like expression among MLL-WT infants. Further characterization of these infants is ongoing. If replicated in other infant cohorts, these two findings may help explain the poor prognosis of MLL-WT ALL when compared to children with standard risk ALL, and offer the possibility of targeted therapy for select infants.
Novel methods to assess cell-free circulating tumor DNA in acute lymphoblastic leukemia.
Authors: Haney Meghan G , Sampathi Shilpa , Chernyavskaya Yelena , Moore Henry , Badgett Tom C. , Blackburn Jessica S
Published: June 2021

10034

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with a relatively high relapse rate, which is associated with poor prognosis. Currently, minimal residual disease (MRD) at the end of induction and consolidation therapy is the best predictor of patient relapse, however obtaining bone marrow aspirate is invasive and not always accurate. Another major concern in ALL is the presence of central nervous system (CNS) disease, which is often present long before clinical diagnosis can be made by flow cytometry. To circumvent these clinical challenges, we developed a new assay quantifying cell-free, circulating tumor (cfDNA) as a biomarker of disease progression, which can be correlated with MRD status as a predictor of relapse. cfDNA is frequently used to monitor progression of solid tumors, but pediatric leukemias lack common mutations that can be used to distinguish leukemic cfDNA from normal cfDNA. Methods: We examined two possible methods for using ctDNA as a biomarker: leukemia cell clonality and DNA methylation profiling. We developed a novel workflow for identifying VDJ rearrangements in leukemia cells and tracking their presence in cfDNA. We collected bone marrow, blood, and CSF samples from newly diagnosed patients, and cfDNA was isolated from blood and CSF samples throughout treatment. Invivoscribe Lymphotrack PCR assays combined with MinION (Oxford Nanopore Technologies) sequencing were used to identify the VDJ sequence of the immunoglobulin (B-ALL) or T-cell receptor (T-ALL) rearrangements of leukemic clones in genomic DNA. The MinION assay relies on patient-specific sequencing. We are also in the process of developing a universal assay that utilizes recurrent methylation changes in ALL to identify leukemic cfDNA in patient samples. Results: The MinION workflow was used to follow leukemic cfDNA throughout the course of treatment, and accurately identified MRD and CNS disease in patients. This workflow performed equivalent or better at detecting leukemic clones compared to MiSeq and droplet digital polymerase chain reaction (ddPCR), and is faster and less expensive than traditional Illumina sequencing. Methylation analysis of 865 ALL and 79 healthy samples yielded 55 regions and 19 specific methylation sites that were uniquely present in ALL samples. We are validating these sites by ddPCR to establish a panel of biomarkers to track ALL over time via cfDNA. Conclusions: The end goal of our study is provide a more sensitive and less invasive method for tracking MRD and CNS disease than current approaches. Results will ultimately be correlated with patient response to therapy, the presence of relapse or CNS disease, and overall outcomes determined by standard clinical diagnostic procedures.