bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating long chain acylcarnitines and outcomes in diabetic heart failure: an HF-ACTION clinical trial substudy
Authors: Truby Lauren K. , Regan Jessica A. , Giamberardino Stephanie N. , Ilkayeva Olga , Bain James , Newgard Christopher B. , O’Connor Christopher M. , Felker G. Michael , Kraus William E. , McGarrah Robert W. , Shah Svati H.
Published: August 2021

Background

Whether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown. The objective of the current study was to use metabolomic profiling to identify biomarkers that report on exercise capacity, clinical outcomes, and differential response to exercise in HF patients with and without DM.

Methods

Targeted mass spectrometry was used to quantify metabolites in plasma from participants in the heart failure: a controlled trial investigating outcomes of exercise training (HF-ACTION) trial. Principal components analysis was used to identify 12 uncorrelated factors. The association between metabolite factors, diabetes status, exercise capacity, and time to the primary clinical outcome of all-cause mortality or all-cause hospitalization was assessed.

Results

A total of 664 participants were included: 359 (54%) with DM. LCAC factor levels were associated with baseline exercise capacity as measured by peak oxygen consumption (beta 0.86, p  =  2 × 10−7, and were differentially associated in participants with and without DM (beta 1.58, p  =  8  ×  10−8 vs. 0.67, p  =  9  ×  10−4, respectively; p value for interaction  =  0.012). LCAC levels changed to a lesser extent in participants with DM after exercise (mean ∆ 0.09, p  =  0.24) than in those without DM (mean ∆ 0.16, p  =  0.08). In univariate and multivariate modeling, LCAC factor levels were associated with time to the primary outcome (multivariate HR 0.80, p  =  2.74  ×  10−8), and were more strongly linked to outcomes in diabetic participants (HR 0.64, p  =  3.21  ×  10−9 v. HR 0.90, p  =  0.104, p value for interaction  =  0.001). When analysis was performed at the level of individual metabolites, C16, C16:1, C18, and C18:1 had the greatest associations with both exercise capacity and outcomes, with higher levels associated with worse outcomes. Similar associations with time to the primary clinical outcome were not found in a control group of patients without HF from the CATHeterization GENetics (CATHGEN) study.

Conclusions

LCAC biomarkers are associated with exercise status and clinical outcomes differentially in HF patients with and without DM. Impaired fatty acid substrate utilization and mitochondrial dysfunction both at the level of the skeletal muscle and the myocardium may explain the decreased exercise capacity, attenuated response to exercise training, and poor clinical outcomes seen in patients with HF and DM.

Trial Registration clinicaltrials.gov Identifier: NCT00047437.
Ultrastructural analysis of breast cancer patient-derived organoids
Authors: Signati Lorena , Allevi Raffaele , Piccotti Francesca , Albasini Sara , Villani Laura , Sevieri Marta , Bonizzi Arianna , Corsi Fabio , Mazzucchelli Serena
Published: August 2021

Background

Breast cancer Patient Derived Organoids (PDO) have been demonstrated to be a reliable model to study cancer that promised to replace and reduce the use of animals in pre-clinical research. They displayed concordance with the tissue of origin, resuming its heterogenicity and representing a good platform to develop approaches of personalized medicines. Although obtain PDOs from mammary tumour, was a very challenging process, several ongoing studies evaluated them as a platform to study efficacy, sensitivity and specificity of new drugs and exploited them in personalized medicine. Despite tissue organization represented a crucial point to evaluate in a 3-dimensional model, since it could influence drug penetration, morphology of breast cancer PDOs has not been analysed yet. Here, we proposed a complete ultrastructural analysis of breast PDOs obtained from tumour and healthy tissues to evaluate how typical structures observed in mammary gland were resumed in this model.

Methods

81 samples of mammary tissue (healthy or tumour) resulting from surgical resections have been processed to obtain PDO. The resulting PDOs embedded in matrigel drop have been processed for transmission electron microscopy and analysed. A comparison between ones from healthy and ones from cancerous tissue has been performed and PDOs derived from tumour tissue have been stratified according to their histological and molecular subtype.

Result

The morphological analysis performed on 81 PDO revealed an organized structure rich in Golgi, secretion granules and mitochondria, which was typical of cells with a strong secretory activity and active metabolism. The presence of desmosomes, inter and intracellular lumens and of microvilli and interdigitations signified a precise tissue-organization. Each PDO has been classified based on whether or not it possessed (i) peripheral ridges in mitochondria, (ii) intracellular lumens, (iii) intercellular lumens, (iv) micro-vesicles, (v) open desmosomes, (vi) cell debris, (vii) polylobed nuclei, (viii) lysosomes and (ix) secretion granules, in order to identify features coupled with the cancerous state or with a specific histological or molecular subtype.

Conclusion

Here we have demonstrated the suitability of breast cancer PDO as 3-dimensional model of mammary tissue. Besides, some structural features characterizing cancerous PDO have been observed, identifying the presence of distinctive traits.
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal malignancy: initial experience of the first program in the Baltic countries
Authors: Račkauskas Rokas , Baušys Augustinas , Lukšta Martynas , Jurgaitis Jonas , Paškonis Marius , Strupas Kęstutis
Published: August 2021

Background

Peritoneal malignancies include primary and metastatic cancer of the peritoneal cavity. The most common origin for peritoneal metastasis is ovarian, gastric, and colorectal cancers. Irrespective of the origin, peritoneal metastases represent the advanced disease and are associated with poor long-term outcomes. The minimally invasive approach of pressurized intraperitoneal aerosol chemotherapy (PIPAC) allows repeated applications and objective assessment of tumor response by comparing histological samples. This study aimed to investigate the initial experience with PIPAC in the Baltic region.

Methods

All patients who underwent PIPAC at Vilnius University Hospital Santaros Klinikos between 2015 and 2020 were included in this retrospective study. The primary outcome of the study was overall survival (OS) in patients with peritoneal carcinomatosis treated by PIPAC. The secondary outcomes included postoperative morbidity; peritoneal carcinomatosis index (PCI) and ascites reduction after treatment by PIPAC.

Results

In total, 15 patients underwent 34 PIPAC procedures. PIPAC-related intraoperative and postoperative morbidity occurred in 3 (8.8%) of 34 procedures. Following PIPAC, the median PCI decreased from 8 (4; 15) to 5 (1; 16) in GC patients, although, the difference failed for significance, p = 0.581. In OC patients, PCI after PIPAC remained stable. Median overall survival after PIPAC procedure was 25 (95% CI 5–44) months. Ovarian cancer patients (22; 95% CI 12–44 months) had significantly higher OS, compared to gastric cancer patients (8; 95% CI 4–16 months), p = 0.018.

Conclusions

PIPAC is safe and feasible for patients with gastric and ovarian cancers peritoneal metastases.
Changes in total body fat and body mass index among children with juvenile dermatomyositis treated with high-dose glucocorticoids
Authors: Khojah Amer , Liu Victoria , Morgan Gabrielle , Shore Richard M. , Pachman Lauren M.
Published: August 2021

Objective

High-dose glucocorticoids (GC) remain the primary therapy to induce remission in Juvenile Dermatomyositis (JDM). Studies of the natural history of GC associated weight gain in children are very limited, especially in the JDM population. This study aims to measure BMI changes in a cohort of JDM subjects over 60 months and to examine the changes in body composition by DXA.

Methods

We included all subjects with JDM who had 5 years of follow-up data and multiple DXA studies. BMI and total body fat (TBF) percentiles were calculated based on the CDC published percentile charts. To study the natural history of weight gain and TBF, we assessed the data at four-time points (T0 = baseline, T1 > 1.5 years, T2 = 1.51–3.49 years, T3 = 3.5–5 years).

Results

68 subjects (78% female, 70% white) were included in this retrospective study. Paired T-test showed a significant increase in the mean BMI percentile by 17.5 points (P = 0.004) after the initiation of medical treatment, followed by a gradual decrease over the study period. However, the TBF percentile did not change over the study period. TBF in the last visit (T3) had a strong correlation with the T1 BMI, and T1 TBF percentile (correlation coefficients 0.63, 0.56 P < 0.001, 0.002 respectively). Also, there was a positive correlation (correlation coefficients 0.39, P = 0.002) between the TBF percentile and muscle DAS but not the skin DAS.

Conclusions

Although the BMI percentile decreased throughout the study, the TBF percentile remained high until the end of the study (60 months). This finding raises the concern that some of the reduction in the BMI percentile could reflect a drop in the lean body mass from muscle wasting rather than actual fat loss.
High-fat diet-induced diabetes leads to vascular alterations, pericyte reduction, and perivascular depletion of microglia in a 6-OHDA toxin model of Parkinson disease
Authors: Elabi Osama F. , Cunha João Paulo M. C. M. , Gaceb Abderahim , Fex Malin , Paul Gesine
Published: August 2021

Background

Diabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson’s disease (PD). Although several hypotheses suggest a number of different mechanisms underlying the aggravation of PD caused by diabetes, less attention has been paid to the fact that diabetes and PD share pathological microvascular alterations in the brain. The characteristics of the interaction of diabetes in combination with PD at the vascular interface are currently not known.

Methods

We combined a high-fat diet (HFD) model of diabetes mellitus type 2 (DMT2) with the 6-OHDA lesion model of PD in male mice. We analyzed the association between insulin resistance and the achieved degree of dopaminergic nigrostriatal pathology. We further assessed the impact of the interaction of the two pathologies on motor deficits using a battery of behavioral tests and on microglial activation using immunohistochemistry. Vascular pathology was investigated histologically by analyzing vessel density and branching points, pericyte density, blood–brain barrier leakage, and the interaction between microvessels and microglia in the striatum.

Results

Different degrees of PD lesion were obtained resulting in moderate and severe dopaminergic cell loss. Even though the HFD paradigm did not affect the degree of nigrostriatal lesion in the acute toxin-induced PD model used, we observed a partial aggravation of the motor performance of parkinsonian mice by the diet. Importantly, the combination of a moderate PD pathology and HFD resulted in a significant pericyte depletion, an absence of an angiogenic response, and a significant reduction in microglia/vascular interaction pointing to an aggravation of vascular pathology.

Conclusion

This study provides the first evidence for an interaction of DMT2 and PD at the brain microvasculature involving changes in the interaction of microglia with microvessels. These pathological changes may contribute to the pathological mechanisms underlying the accelerated progression of PD when associated with diabetes.
Cathepsin H deficiency decreases hypoxia-ischemia-induced hippocampal atrophy in neonatal mice through attenuated TLR3/IFN-β signaling
Authors: Ni Junjun , Zhao Juan , Zhang Xinwen , Reinheckel Thomas , Turk Vito , Nakanishi Hiroshi
Published: August 2021

Background

Cathepsin H (CatH) is a lysosomal cysteine protease with a unique aminopeptidase activity. Its expression level is increased in activated immune cells including dendritic cells, macrophages, and microglia. We have previously reported that CatH deficiency impairs toll-like receptor 3 (TLR3)-mediated activation of interferon regulatory factor 3 (IRF3), and the subsequent secretion of interferon (IFN)-β from dendritic cells. Furthermore, there is increasing evidence that IFN-β secreted from microglia/macrophages has neuroprotective effects. These observations prompted further investigation into the effects of CatH deficiency on neuropathological changes.

Methods

In this study, neuropathological changes were examined using histochemical staining (both hematoxylin-eosin (H&E) and Nissl) of the hippocampus of wild-type (WT) and CatH-deficient (CatH−/−) mice after hypoxia-ischemia (HI). The density and the localization of CatH and TLR3 were examined by immunofluorescent staining. CatH processing in microglia was assayed by pulse-chase experiments, while immunoblotting was used to examine TLR3 expression and IRF3 activation in microglia/macrophages in the presence of poly(I:C). Microglial cell death was examined by fluorescence-activated cell sorting (FACS), and primary astrocyte proliferation in the presence of IFN-β was examined using scratch wound assay.

Results

WT mice displayed severe atrophy in association with neuronal death and moderate astrogliosis in the hippocampus following neonatal HI. Somewhat surprisingly, CatH−/− mice showed marked neuronal death without severe atrophy in the hippocampus following HI. Furthermore, there was notable microglia/macrophages cell death and strong astrogliosis in the hippocampus. The TLR3 and phosphorylated IRF3 expression level in the hippocampus or splenocytes (mainly splenic macrophages); from CatH−/− mice was lower than in WT mice. In vitro experiments demonstrated that recombinant IFN-β suppressed HI-induced microglial cell death and astrocyte proliferation.

Conclusion

These observations suggest that CatH plays a critical role in the proteolytic maturation and stabilization of TLR3, which is necessary for IFN-β production. Therefore, impaired TLR3/IFN-β signaling resulting from CatH deficiency may induce microglial cell death after activation and astrogliosis/glial scar formation in the hippocampus following HI injury, leading to suppression of hippocampal atrophy.
A robot goes to rehab: a novel gamified system for long-term stroke rehabilitation using a socially assistive robot—methodology and usability testing
Authors: Feingold-Polak Ronit , Barzel Oren , Levy-Tzedek Shelly
Published: August 2021

Background

Socially assistive robots (SARs) have been proposed as a tool to help individuals who have had a stroke to perform their exercise during their rehabilitation process. Yet, to date, there are no data on the motivating benefit of SARs in a long-term interaction with post-stroke patients.

Methods

Here, we describe a robot-based gamified exercise platform, which we developed for long-term post-stroke rehabilitation. The platform uses the humanoid robot Pepper, and also has a computer-based configuration (with no robot). It includes seven gamified sets of exercises, which are based on functional tasks from the everyday life of the patients. The platform gives the patients instructions, as well as feedback on their performance, and can track their performance over time. We performed a long-term patient-usability study, where 24 post-stroke patients were randomly allocated to exercise with this platform—either with the robot or the computer configuration—over a 5–7 week period, 3 times per week, for a total of 306 sessions.

Results

The participants in both groups reported that this rehabilitation platform addressed their arm rehabilitation needs, and they expressed their desire to continue training with it even after the study ended. We found a trend for higher acceptance of the system by the participants in the robot group on all parameters; however, this difference was not significant. We found that system failures did not affect the long-term trust that users felt towards the system.

Conclusions

We demonstrated the usability of using this platform for a long-term rehabilitation with post-stroke patients in a clinical setting. We found high levels of acceptance of both platform configurations by patients following this interaction, with higher ratings given to the SAR configuration. We show that it is not the mere use of technology that increases the motivation of the person to practice, but rather it is the appreciation of the technology’s effectiveness and its perceived contribution to the rehabilitation process. In addition, we provide a list of guidelines that can be used when designing and implementing other technological tools for rehabilitation.

Trial registration: This trial is registered in the NIH ClinicalTrials.gov database. Registration number NCT03651063, registration date 21.08.2018.https://clinicaltrials.gov/ct2/show/NCT03651063.
Remote estimation of leaf area index (LAI) with unmanned aerial vehicle (UAV) imaging for different rice cultivars throughout the entire growing season
Authors: Gong Yan , Yang Kaili , Lin Zhiheng , Fang Shenghui , Wu Xianting , Zhu Renshan , Peng Yi
Published: August 2021

Background

Rice is one of the most important grain crops worldwide. The accurate and dynamic monitoring of Leaf Area Index (LAI) provides important information to evaluate rice growth and production.

Methods

This study explores a simple method to remotely estimate LAI with Unmanned Aerial Vehicle (UAV) imaging for a variety of rice cultivars throughout the entire growing season. Forty eight different rice cultivars were planted in the study site and field campaigns were conducted once a week. For each campaign, several widely used vegetation indices (VI) were calculated from canopy reflectance obtained by 12-band UAV images, canopy height was derived from UAV RGB images and LAI was destructively measured by plant sampling.

Results

The results showed the correlation of VI and LAI in rice throughout the entire growing season was weak, and for all tested indices there existed significant hysteresis of VI vs. LAI relationship between rice pre-heading and post-heading stages. The model based on the product of VI and canopy height could reduce such hysteresis and estimate rice LAI of the whole season with estimation errors under 24%, not requiring algorithm re-parameterization for different phenology stages.

Conclusions

The progressing phenology can affect VI vs. LAI relationship in crops, especially for rice having quite different canopy spectra and structure after its panicle exsertion. Thus the models solely using VI to estimate rice LAI are phenology-specific and have high uncertainties for post-heading stages. The model developed in this study combines both remotely sensed canopy height and VI information, considerably improving rice LAI estimation at both pre- and post-heading stages. This method can be easily and efficiently implemented in UAV platforms for various rice cultivars during the entire growing season with no rice phenology and cultivar pre-knowledge, which has great potential for assisting rice breeding and field management studies at a large scale.
Decoding distinctive features of plasma extracellular vesicles in amyotrophic lateral sclerosis
Authors: Pasetto Laura , Callegaro Stefano , Corbelli Alessandro , Fiordaliso Fabio , Ferrara Deborah , Brunelli Laura , Sestito Giovanna , Pastorelli Roberta , Bianchi Elisa , Cretich Marina , Chiari Marcella , Potrich Cristina , Moglia Cristina , Corbo Massimo , Sorarù Gianni , Lunetta Christian , Calvo Andrea , Chiò Adriano , Mora Gabriele , Pennuto Maria , Quattrone Alessandro , Rinaldi Francesco , D’Agostino Vito Giuseppe , Basso Manuela , Bonetto Valentina
Published: August 2021

Background

Amyotrophic lateral sclerosis (ALS) is a multifactorial, multisystem motor neuron disease for which currently there is no effective treatment. There is an urgent need to identify biomarkers to tackle the disease’s complexity and help in early diagnosis, prognosis, and therapy. Extracellular vesicles (EVs) are nanostructures released by any cell type into body fluids. Their biophysical and biochemical characteristics vary with the parent cell’s physiological and pathological state and make them an attractive source of multidimensional data for patient classification and stratification.

Methods

We analyzed plasma-derived EVs of ALS patients (n = 106) and controls (n = 96), and SOD1G93Aand TDP-43Q331Kmouse models of ALS. We purified plasma EVs by nickel-based isolation, characterized their EV size distribution and morphology respectively by nanotracking analysis and transmission electron microscopy, and analyzed EV markers and protein cargos by Western blot and proteomics. We used machine learning techniques to predict diagnosis and prognosis.

Results

Our procedure resulted in high-yield isolation of intact and polydisperse plasma EVs, with minimal lipoprotein contamination. EVs in the plasma of ALS patients and the two mouse models of ALS had a distinctive size distribution and lower HSP90 levels compared to the controls. In terms of disease progression, the levels of cyclophilin A with the EV size distribution distinguished fast and slow disease progressors, a possibly new means for patient stratification. Immuno-electron microscopy also suggested that phosphorylated TDP-43 is not an intravesicular cargo of plasma-derived EVs.

Conclusions

Our analysis unmasked features in plasma EVs of ALS patients with potential straightforward clinical application. We conceived an innovative mathematical model based on machine learning which, by integrating EV size distribution data with protein cargoes, gave very high prediction rates for disease diagnosis and prognosis.
SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis
Authors: Castelli Lydia M. , Cutillo Luisa , Souza Cleide Dos Santos , Sanchez-Martinez Alvaro , Granata Ilaria , Lin Ya-Hui , Myszczynska Monika A. , Heath Paul R. , Livesey Matthew R. , Ning Ke , Azzouz Mimoun , Shaw Pamela J. , Guarracino Mario R. , Whitworth Alexander J. , Ferraiuolo Laura , Milo Marta , Hautbergue Guillaume M.
Published: August 2021

Background

Loss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to progressive paralysis and death. Dysregulation of thousands of RNA molecules with roles in multiple cellular pathways hinders the identification of ALS-causing alterations over downstream changes secondary to the neurodegenerative process. How many and which of these pathological gene expression changes require therapeutic normalisation remains a fundamental question.

Methods

Here, we investigated genome-wide RNA changes in C9ORF72-ALS patient-derived neurons and Drosophila, as well as upon neuroprotection taking advantage of our gene therapy approach which specifically inhibits the SRSF1-dependent nuclear export of pathological C9ORF72-repeat transcripts. This is a critical study to evaluate (i) the overall safety and efficacy of the partial depletion of SRSF1, a member of a protein family involved itself in gene expression, and (ii) a unique opportunity to identify neuroprotective RNA changes.

Results

Our study shows that manipulation of 362 transcripts out of 2257 pathological changes, in addition to inhibiting the nuclear export of repeat transcripts, is sufficient to confer neuroprotection in C9ORF72-ALS patient-derived neurons. In particular, expression of 90 disease-altered transcripts is fully reverted upon neuroprotection leading to the characterisation of a human C9ORF72-ALS disease-modifying gene expression signature. These findings were further investigated in vivo in diseased and neuroprotected Drosophila transcriptomes, highlighting a list of 21 neuroprotective changes conserved with 16 human orthologues in patient-derived neurons. We also functionally validated the high neuroprotective potential of one of these disease-modifying transcripts, demonstrating that inhibition of ALS-upregulated human KCNN1–3 (Drosophila SK) voltage-gated potassium channel orthologs mitigates degeneration of human motor neurons and Drosophila motor deficits.

Conclusions

Strikingly, the partial depletion of SRSF1 leads to expression changes in only a small proportion of disease-altered transcripts, indicating that not all RNA alterations need normalization and that the gene therapeutic approach is safe in the above preclinical models as it does not disrupt globally gene expression. The efficacy of this intervention is also validated at genome-wide level with transcripts modulated in the vast majority of biological processes affected in C9ORF72-ALS. Finally, the identification of a characteristic signature with key RNA changes modified in both the disease state and upon neuroprotection also provides potential new therapeutic targets and biomarkers.
Impact of baseline beta-blocker use on inotrope response and clinical outcomes in cardiogenic shock: a subgroup analysis of the DOREMI trial
Authors: Di Santo Pietro , Mathew Rebecca , Jung Richard G. , Simard Trevor , Skanes Stephanie , Mao Brennan , Ramirez F. Daniel , Marbach Jeffrey A. , Abdel-Razek Omar , Motazedian Pouya , Parlow Simon , Boczar Kevin E. , D’Egidio Gianni , Hawken Steven , Bernick Jordan , Wells George A. , Dick Alexander , So Derek Y. , Glover Christopher , Russo Juan J. , McGuinty Caroline , Hibbert Benjamin ,   the CAPITAL DOREMI investigators
Published: August 2021

Background

Cardiogenic shock (CS) is associated with significant morbidity and mortality. The impact of beta-blocker (BB) use on patients who develop CS remains unknown. We sought to evaluate the clinical outcomes and hemodynamic response profiles in patients treated with BB in the 24 h prior to the development of CS.

Methods

Patients with CS enrolled in the DObutamine compaREd to MIlrinone trial were analyzed. The primary outcome was a composite of all-cause mortality, resuscitated cardiac arrest, need for cardiac transplant or mechanical circulatory support, non-fatal myocardial infarction, transient ischemic attack or stroke, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary composite and hemodynamic response profiles derived from pulmonary artery catheters.

Results

Among 192 participants, 93 patients (48%) had received BB therapy. The primary outcome occurred in 47 patients (51%) in the BB group and in 52 (53%) in the no BB group (RR 0.96; 95% CI 0.73–1.27;P = 0.78) throughout the in-hospital period. There were fewer early deaths in the BB group (RR 0.41; 95% CI 0.18–0.95;P = 0.03). There were no differences in other individual components of the primary outcome or in hemodynamic response between the two groups throughout the remainder of the hospitalization.

Conclusions

BB therapy in the 24 h preceding the development of CS did not negatively influence clinical outcomes or hemodynamic parameters. On the contrary, BB use was associated with fewer deaths in the early resuscitation period, suggesting a paradoxically protective effect in patients with CS.

Trial registrationClinicalTrials.gov Identifier: NCT03207165
MAAPER: model-based analysis of alternative polyadenylation using 3′ end-linked reads
Authors: Li Wei Vivian , Zheng Dinghai , Wang Ruijia , Tian Bin
Published: August 2021

Most eukaryotic genes express alternative polyadenylation (APA) isoforms. A growing number of RNA sequencing methods, especially those used for single-cell transcriptome analysis, generate reads close to the polyadenylation site (PAS), termednearSitereads, hence inherently containing information about APA isoform abundance. Here, we present a probabilistic model-based method named MAAPER to utilize nearSite reads for APA analysis. MAAPER predicts PASs with high accuracy and sensitivity and examines different types of APA events with robust statistics. We show MAAPER’s performance with both bulk and single-cell data and its applicability in unpaired or paired experimental designs.
Intervention with inulin prior to and during sanative therapy to further support periodontal health: study protocol for a randomized controlled trial
Authors: Zanatta Carly A. R. , Fritz Peter C. , Comelli Elena M. , Ward Wendy E.
Published: August 2021

Background

Periodontal disease is a chronic state of inflammation that can destroy the supporting tissues around the teeth, leading to the resorption of alveolar bone. The initial strategy for treating periodontal disease is non-surgical sanative therapy (ST). Periodontal disease can also induce dysbiosis in the gut microbiota and contribute to low-grade systemic inflammation. Prebiotic fibers such as inulin can selectively alter the intestinal microbiota and support homeostasis by improving gut barrier functions and preventing inflammation. Providing an inulin supplement prior to and post-ST may influence periodontal health while providing insight into the complex relationship between periodontal disease and the gut microbiota. The primary objective is to determine if inulin is more effective than the placebo at improving clinical periodontal outcomes including probing depth (PD) and bleeding on probing (BOP). Secondary objectives include determining the effects of inulin supplementation pre- and post-ST on salivary markers of inflammation and periodontal-associated pathogens, as these outcomes reflect more rapid changes that can occur.

Methods

We will employ a single-center, randomized, double-blind, placebo-controlled study design and recruit and randomize 170 participants who are receiving ST to manage the periodontal disease to the intervention (inulin) or placebo (maltodextrin) group. A pilot study will be embedded within the randomized controlled trial using the first 48 participants to test the feasibility for the larger, powered trial. The intervention period will begin 4 weeks before ST through to their follow-up appointment at 10 weeks post-ST. Clinical outcomes of periodontal disease including the number of sites with PD ≥ 4 mm and the presence of BOP will be measured at baseline and post-ST. Salivary markers of inflammation, periodontal-associated pathogens, body mass index, and diet will be measured at baseline, pre-ST (after 4 weeks of intervention), and post-ST (after 14 weeks of intervention).

Discussion

We expect that inulin will enhance the positive effect of ST on the management of periodontal disease. The results of the study will provide guidance regarding the use of prebiotics prior to and as a supportive adjunct to ST for periodontal health.

Trial registration

ClinicalTrials.gov NCT04670133. Registered on 17 December 2020.
Recurrent Hurthle cell thyroid carcinoma does not preclude long-term survival: a case report and review of the literature
Authors: Blossey Richard David , Kleine-Döpke Dennis , Ringe Kristina Imeen , Pöhnert Daniel , Ringe Bastian , Klempnauer Jürgen , Beetz Oliver
Published: August 2021

Background

Follicular thyroid carcinoma is the second most common malignancy of the thyroid gland. In 2016, the so-called Hurthle cell thyroid carcinoma, formerly known as the oxyphilic variant of the follicular thyroid carcinoma, was reclassified by the World Health Organization as a separate pathological entity, which accounts for approximately 3% of all thyroid cancers. Although Hurthle cell thyroid carcinomas are known for their more aggressive tumor biology, metastases are observed in a minority of cases, and long-term survival can be expected. However, disseminated disease is often associated with poor outcome.

Case presentation

In the presented case, a 63-year-old Caucasian female was incidentally diagnosed with Hurthle cell thyroid carcinoma after undergoing hemithyroidectomy for a nodular goiter. Following completion thyroidectomy, two courses of radioactive iodine therapy were administered. After 4 years of uneventful follow-up, the patient gradually developed metastases in five different organs, with the majority representing unusual sites, such as heart, kidney, and pancreas over a course of 14 years. The lesions were either treated with radioactive iodine therapy or removed surgically, depending on iodine avidity.

Conclusion

Follicular and Hurthle cell thyroid carcinoma are known to potentially spread hematogenously to typical sites, such as lung or bones, however; unusual metastatic sites as presented in our case can also be observed. A search of the literature revealed only scattered reports on patients with multiple metastases in unusual locations. Furthermore, the observed long-term survival of our patient is contradictory to the existing data. As demonstrated, recurrent disease may appear years after the initial diagnosis, emphasizing the importance of consistent aftercare. Radioactive iodine therapy, extracorporeal radiation therapy, and surgical metastasectomy are central therapeutic components. In summary, our case exemplifies that thorough aftercare and aggressive treatment enables long-term survival even in recurrent Hurthle cell thyroid carcinoma displaying unusual multisite metastases.
A qualitative study on generalized Caputo fractional integro-differential equations
Authors: Kassim Mohammed D. , Abdeljawad Thabet , Shatanawi Wasfi , Ali Saeed M. , Abdo Mohammed S.
Published: August 2021

The aim of this article is to discuss the uniqueness and Ulam–Hyers stability of solutions for a nonlinear fractional integro-differential equation involving a generalized Caputo fractional operator. The used fractional operator is generated by iterating a local integral of the form$(I_{a}^{\rho }f)(t)=\int _{a}^{t}f(s)s^{\rho -1}\,ds$(Iaρf)(t)=∫atf(s)sρ−1ds. Our reported results are obtained in the Banach space of absolutely continuous functions that rely on Babenko’s technique and Banach’s fixed point theorem. Besides, our main findings are illustrated by some examples.
Are Latin American ecologists recognized at the world level? A global comparison
Authors: Rau Jaime R. , Jaksic Fabian M.
Published: August 2021

Background

Ioannidis et al. (2020) reported a standardized estimate of scientific productivity obtained from a worldwide database of 6,880,389 scientists who published at least 5 papers picked up by the Scopus database, and elaborated a ranking of ca. 120,000 scientists by both whole trajectory (career-long) impact and their current impact at year 2019. The goal of our paper is to contextualize Latin American ecologists’ contribution at the world level based on the four most scientifically productive countries in the region.

Methods and findings

Ioannidis et al. (2020) proposed a composite index that is the sum of six scientometric indicators: (1) The number of allocites, (2) the h index, (3) a per capita corrected version of h, (4) the allocites received as single author, (5) those received as single + first author, and (6) those as single + first + last author. We selected data for ecologists from Argentina, Brazil, Chile, and Mexico and comparatively analyzed their productivity according to the proposed index. We also compared these data with those obtained from a global sample of the top ecologists worldwide.

Conclusions

Based on Ioannidis et al.’s proposition to evaluate scientific productivity we extract three lessons: (1) It does not pay to publish many papers; what counts is the number of allocites (i.e., self-citations do not add up). (2) Either be single, first, or last author; it does not pay to be in the middle of an authorship line. (3) Even worse it is to be among many co-authors because the proposed index allocates credits on a per capita basis.
Implementation strategy fidelity evaluation for a multidisciplinary Chest Injury Protocol (ChIP)
Authors: Kourouche Sarah , Curtis Kate , Munroe Belinda , Watts Michael , Balzer Sharyn , Buckley Thomas
Published: August 2021

Background

Blunt chest wall injuries can lead to complications, especially without early intervention. A blunt Chest Injury Protocol (ChIP) was developed to help improve the consistency of evidence-based care following admission to the emergency department. Implementation strategy fidelity is the extent to which the strategies of implementation are delivered in line with the intended plan. The aim of this study was to assess fidelity to the strategies of the implementation plan developed for ChIP.

Methods

A retrospective evaluation of strategies used for implementation was performed, specifically the behaviour change techniques (BCTs). BCTs were used as part of an implementation plan derived based on the Behaviour Change Wheel from results from a staff survey at two hospitals.

Levels of implementation or adaptation for BCTs were scored by implementers as follows: ‘Were the behaviour change interventions implemented?’ (0 = ‘not implemented’, 1 = partially implemented, and 2 = fully implemented); ‘Were adaptations made to the implementation plan?’, scored 1 (many changes from plan) to 4 (just as planned). Free text explanation to their responses was also collected with supporting evidence and documentation (such as emails, implementation checklists, audit reports, and incident reports).

Results

There was high overall fidelity of 97.6% for BCTs partially or fully implemented. More than three quarters (32/42, 76.2%) of the BCTs were fully implemented with an additional 9/42 (21.4%) partially implemented. BCTs that were not fully implemented were social support, feedback on behaviour, feedback on outcomes of behaviour, adding objects to the environment, and restructuring the environment. The modes of delivery with poorer implementation or increased adaptations were clinical champions and audit/feedback.

Conclusions

This study describes the evaluation of implementation strategy fidelity in the acute care context. The systematic use and application of the behaviour change wheel was used to develop an implementation plan and was associated with high implementation strategy fidelity. A fidelity checklist developed during the implementation process may help implementers assess fidelity.

Trial registration

Trial registered on ANZCTR. Registration number ACTRN12618001548224, date approved 17/09/2018
The molecular mechanism of acute liver injury and inflammatory response induced by Concanavalin A
Authors: Liu Xiaoxiao , Yu Ting , Hu Yuzhu , Zhang Longzhen , Zheng Junnian , Wei Xiawei
Published: August 2021

Acute liver injury is a common but urgent clinical condition, and its underlying mechanism remains to be further elucidated. Concanavalin A (ConA)-induced liver injury was investigated in the study. Different from the caspase-dependent cell apoptosis in lipopolysaccharide/D-aminogalactose (LPS/D-GalN) induced liver injury, ConA-induced hepatocyte death was independent on caspase. Increased hepatocytic expressions of mixed lineage kinase domain like (MLKL) and receptor-interacting protein kinase 1 (RIPK1), and higher serum concentration of tumor necrosis factor-α (TNF-α) were noticed in mice with ConA-induced liver injury. Inhibition of RIPK1 protein or deletion of MLKL gene could significantly attenuate the acute liver injury and improve mice survival. Besides, the ConA treatment induced severe hepatic inflammation in wide type (WT) mice in comparison with Mlkl−/− mice, suggesting the RIPK1-MLKL-mediated hepatocellular necroptosis might participate in the process of liver injury. Moreover, mitochondrial damage associated molecular patterns (DAMPs) were subsequently released after the hepatocyte death, and further activated the p38 mitogen-activated protein kinase (MAPK) pathway, which could be reduced by deletion or inhibition of Toll-like receptor 9 (TLR9). Taken together, our research revealed that ConA-induced acute liver injury was closely related to TNF-α-mediated cell necroptosis, and inhibiting RIPK1 or deleting MLKL gene could alleviate liver injury in mice. The mitochondrial DNA released by dead hepatocytes further activated neutrophils through TLR9, thus resulting in the exacerbation of liver injury.
Near-Infrared Hyperspectral Imaging as a Monitoring Tool for On-Demand Manufacturing of Inkjet-Printed Formulations
Authors: Stranzinger Sandra , Wolfgang Matthias , Klotz Emma , Scheibelhofer Otto , Ghiotti Patrizia , Khinast Johannes G. , Hsiao Wen-Kai , Paudel Amrit
Published: August 2021

This study evaluates the potential use of near-infrared hyperspectral imaging (NIR-HSI) for quantitative determination of the drug amount in inkjet-printed dosage forms. We chose metformin hydrochloride as a model active pharmaceutical ingredient (API) and printed it onto gelatin films using a piezoelectric inkjet printing system. An industry-ready NIR-HSI sensor combined with a motorized movable linear stage was applied for spectral acquisition. Initial API-substrate screening revealed best printing results for gelatin films with TiO2 filling. For calibration of the NIR-HSI system, escalating drug doses were printed on the substrate. After spectral pre-treatments, including standard normal variate (SNV) and Savitzky-Golay filtering for noise reduction and enhancement of spectral features, principal component analysis (PCA) and partial least squares (PLS) regression were applied to create predictive models for the quantification of independent printed metformin hydrochloride samples. It could be shown that the concentration distribution maps provided by the developed HSI models were capable of clustering and predicting the drug dose in the formulations. HSI model prediction showed significant better correlation to the reference (HPLC) compared to on-board monitoring of dispensed volume of the printer. Overall, the results emphasize the capability of NIR-HSI as a fast and non-destructive method for the quantification and quality control of the deposited API in drug-printing applications.

Graphical abstract
Mapping of pseudouridine residues on cellular and viral transcripts using a novel antibody-based technique
Authors: Martinez Campos Cecilia , Tsai Kevin , Courtney David G. , Bogerd Hal P. , Holley Christopher L. , Cullen Bryan R.
Published: August 2021

Pseudouridine (Ψ) is the most common noncanonical ribonucleoside present on mammalian noncoding RNAs (ncRNAs), including rRNAs, tRNAs, and snRNAs, where it contributes ∼7% of the total uridine level. However, Ψ constitutes only ∼0.1% of the uridines present on mRNAs and its effect on mRNA function remains unclear. Ψ residues have been shown to inhibit the detection of exogenous RNA transcripts by host innate immune factors, thus raising the possibility that viruses might have subverted the addition of Ψ residues to mRNAs by host pseudouridine synthase (PUS) enzymes as a way to inhibit antiviral responses in infected cells. Here, we describe and validate a novel antibody-based Ψ mapping technique called photo-crosslinking-assisted Ψ sequencing (PA-Ψ-seq) and use it to map Ψ residues on not only multiple cellular RNAs but also on the mRNAs and genomic RNA encoded by HIV-1. We describe 293T-derived cell lines in which human PUS enzymes previously reported to add Ψ residues to human mRNAs, specifically PUS1, PUS7, and TRUB1/PUS4, were inactivated by gene editing. Surprisingly, while this allowed us to assign several sites of Ψ addition on cellular mRNAs to each of these three PUS enzymes, Ψ sites present on HIV-1 transcripts remained unaffected. Moreover, loss of PUS1, PUS7, or TRUB1 function did not significantly reduce the level of Ψ residues detected on total human mRNA below the ∼0.1% level seen in wild-type cells, thus implying that the PUS enzyme(s) that adds the bulk of Ψ residues to human mRNAs remains to be defined.
Primary hepatic sarcoidosis presenting with cholestatic liver disease and mimicking primary biliary cholangitis: a case report
Authors: Park Young Joo , Woo Hyun Young , Kim Moon Bum , Ahn Jihyun , Heo Jeong
Published: August 2021

Sarcoidosis often involves the liver. However, primary hepatic sarcoidosis confined to the liver without evidence of systemic involvement is rare. We report the case of a 37-year-old man with hepatic sarcoidosis who initially presented with elevated liver enzymes and suspicious cirrhotic nodules on computed tomography. The patient had cirrhosis but did not have portal hypertension. Based on the initial histopathologic finding of chronic granulomatous inflammation and the common clinical characteristics of sarcoidosis, he was initially diagnosed with primary biliary cholangitis, and his daily dosage of ursodeoxycholic acid was increased to 900 mg. After 14 months of treatment, his total serum bilirubin concentration was 10.9 mg/dL (upper normal limit, 1.2 mg/dL). Additionally, a transjugular liver biopsy revealed multiple noncaseating granulomas. He was diagnosed with primary hepatic sarcoidosis involving the lungs, heart, spleen, kidneys, and skin. Treatment with methylprednisolone was initiated. Two weeks later, he was started on azathioprine, and the dose of steroid was simultaneously reduced. These findings indicate the importance of including hepatic sarcoidosis as a possible diagnosis in patients with elevated liver enzymes or cryptogenic cirrhosis.
Effects of a randomized controlled study on the behaviors of overweight schoolchildren
Authors: Souza Filho Anastácio Neco de , Bezerra Thaynã Alves , Bandeira Paulo Felipe Ribeiro , Cabral Luciana Gatto Azevedo , Moraes José Fernando Vila Nova de , Martins Clarice Maria de Lucena , Carvalho Ferdinando Oliveira
Published: August 2021

This study aimed to determine the effects of a school-based multi-component intervention on accelerometer- measured physical activity (PA) and sedentary behavior (SB) in schoolchildren overweight. This is a randomized controlled study with overweight schoolchildren, allocated to experimental group (EG; n = 13; 7.6 ± 0.8 years; 42.9% boys) and control group (CG; n = 17; 8.2 ± 0.9 years; 26.7% boys). The EG was submitted to a 10-week school-based intervention, comprised of PA and psychological sessions (behavioral therapy), and nutritional guidance. The CG followed the daily routine of life. The time of PA and SB were measured using accelerometers used for seven days. To compare mean SB, moderate to vigorous physical activity (MVPA) and total physical activity (TPA), generalized estimation equations (GEE) were used. It was observed that the average time in MVPA and TPA increased significantly in EG at the weekend (+ 40.9 min / day, p < 0.001; and + 51.6 min/day, p = 0.035, respectively) and at full week (+ 62.9 min/day, p < 0.001; and + 225.0 9 min/day, p = 0.038, respectively). There was no significant difference in time spent in SB after the intervention in both groups. Thus, it was concluded that the proposed school-based multicomponent intervention was effective in increasing levels of MVPA and TPA in overweight schoolchildren. This finding can optimize future interventions to promote a healthy lifestyle for schoolchildren in the school environment.