bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomised controlled multicentre investigator-blinded clinical trial comparing efficacy and safety of surgery versus complex physical decongestive therapy for lipedema (LIPLEG)
Authors: Podda Maurizio , Kovacs Maximilian , Hellmich Martin , Roth Rebecca , Zarrouk Marouan , Kraus Daria , Prinz-Langenohl Reinhild , Cornely Oliver A.
Published: October 2021

Background

Lipedema is a chronic disorder of the adipose tissue that affects mainly women, characterised by symmetrical, excessive fatty tissue on the legs and pain. Standard conservative treatment is long-term comprehensive decongestive therapy (CDT) to alleviate lipedema-related pain and to improve psychosocial well-being, mobility and physical activity. Patients may benefit from surgical removal of abnormally propagated adipose tissue by liposuction. The LIPLEG trial evaluates the efficacy and safety of liposuction compared to standard CDT.

Methods/design

LIPLEG is a randomised controlled multicentre investigator-blinded trial. Women with lipedema (n=405) without previous liposuction will be allocated 2:1 to liposuction or CDT. The primary outcome of the trial is leg pain reduction by ≥2 points on a visual analogue scale ranging 0–10 at 12 months on CDT or post-completion of liposuction. Secondary outcomes include changes in leg pain severity, health-related quality of life, depression tendency, haematoma tendency, prevalence of oedema, modification physical therapy scope, body fat percentage, leg circumference and movement restriction.

The primary analysis bases on intention-to-treat. Success proportions are compared using the Mantel-Haenszel test stratified by lipedema stage at a 5% two-sided significance level. If this test is statistically significant, the equality of the response proportions in the separate strata is evaluated by Fisher’s exact test in a hierarchical test strategy.

Discussion

LIPLEG assesses whether surgical treatment of lipedema is safe and effective to reduce pain and other lipedema-related health issues. The findings of this trial have the potential to change the standard of care in lipedema.

Trial registration

ClinicalTrials.gov NCT04272827. Registered on February 14, 2020.

Trial status

Protocol version is 02_0, December 17, 2019
Comparison of binocular game and patching in treating mild to moderate anisometropic amblyopia: a study protocol for a randomized controlled trial
Authors: Razavi Mohammad Etezad , Najjaran Marzieh , Mohseni Jaber , Aalaei Shokoufeh
Published: October 2021

Background

Amblyopia, as a neurodevelopmental preventable visual disorder, affects approximately 1.1 % in Asia. A binocular approach to treating amblyopia has been recently proposed. Whether the binocular playing game treatment is comparable to patching treatment needs further randomized clinical trials. To address this, the present research, designs, develops, and evaluates a new binocular game to treat amblyopia.

Methods

This study has been designed as a non-inferiority, randomized, two parallel-group, controlled trial. Forty-four patients between 4 and 12 years diagnosed with amblyopia will be randomly assigned to the control and intervention groups. In the intervention group, amblyopia treatment is provided with red-green anaglyphic glasses and a red filter placed in front of the amblyopic eye, along with a game to be played for 30 min twice a day. Those in the control group will receive patch therapy according to amblyopia treatment study protocol. The primary outcome is to change visual acuity in the amblyopic eye from the baseline to 3 months after randomization.

Ethics and dissemination

The Ethics Committee of Mashhad University of Medical sciences’ approval date was February 28, 2018, with a reference code of IR.MUMS.fm.REC.1396.783. Thus far, the recruitment of participants has not been completed and is scheduled to end in September 2021. The results will be disseminated in a peer-reviewed journal.

Trial registration

Iranian Registry of Clinical Trials IRCT20180217038768N1. Registered on 22 April 2019.
Exercise prevents HFD-induced insulin resistance risk: involvement of TNF-α level regulated by vagus nerve-related anti-inflammatory pathway in the spleen
Authors: Huang Zhengxi , Tang Jialing , Ji Kai
Published: October 2021

Objectives

Regular physical exercise can improve insulin resistance in insulin target tissues. However, the mechanisms about the beneficial effect of exercise on insulin resistance are not yet fully resolved. This study was carried out to address whether insulin resistance improvement by exercise is involved in an anti-inflammatory pathway in the spleen in high-fat diet (HFD) feeding mice.

Methods

Male C57Bl/6J mice with or without subdiaphragmatic vagotomy (sVNS) were subjected to medium-intensity treadmill exercise during HFD feeding. Glucose tolerance test and insulin tolerance test were detected, and spleen acetylcholine level, choline acetyltransferase activity (ChAT), protein kinase C (PKC) and tumor necrosis factor-alpha (TNF-α) were assayed.

Results

We found that exercise significantly improves HFD-induced glucose intolerance and insulin resistance, along with an increase in acetylcholine level, ChAT activity, and PKC activity, and decrease in TNF-α level in the system and the spleen from HFD-fed mice. However, sVNS abolished the beneficial effect of exercise on glucose intolerance and insulin resistance, decreased acetylcholine level, ChAT activity, and PKC activity, and increase TNF-α level of the spleen in HFD-mice exercise intervention.

Conclusions

These data reveal that the prevention of HFD-associated insulin resistance by exercise intervention involves reducing splenic TNF-α level, which is mediated by cholinergic anti-inflammatory activity via influencing PKC activity, ChAT activity, and acetylcholine concentration in mice spleen.
Impact of diabetes mellitus developing after kidney transplantation on patient mortality and graft survival: a meta-analysis of adjusted data
Authors: Lin Hailing , Yan Jiqiang , Yuan Lei , Qi Beibei , Zhang Zhujing , Zhang Wanlu , Ma Aihua , Ding Fuwan
Published: October 2021

Background

Post-transplant diabetes mellitus (PTDM) occurs in 10–30% of kidney transplant recipients. However, its impact on mortality and graft survival is still ambiguous. Therefore, the current study aimed to analyze if PTDM increases mortality and graft failure by pooling multivariable-adjusted data from individual studies.

Methods

PubMed, Embase, and CENTRAL, and Google Scholar were searched for studies comparing mortality and graft failure between PTDM and non-diabetic patients. Multivariable-adjusted hazard ratios (HR) were pooled in a random-effects model.

Results

Fourteen retrospective studies comparing 9872 PTDM patients with 65,327 non-diabetics were included. On pooled analysis, we noted a statistically significant increase in the risk of all-cause mortality in patients with PTDM as compared to non-diabetics (HR: 1.67 95% CI 1.43, 1.94 I2 = 57% p < 0.00001). The meta-analysis also indicated a statistically significant increase in the risk of graft failure in patients with PTDM as compared to non-diabetics (HR: 1.35 95% CI 1.15, 1.58 I2 = 78% p = 0.0002). Results were stable on sensitivity analysis. There was no evidence of publication bias on funnel plots.

Conclusion

Kidney transplant patients developing PTDM have a 67% increased risk of all-cause mortality and a 35% increased risk of graft failure. Further studies are needed to determine the exact cause of increased mortality and the mechanism involved in graft failure.
Hepatitis D: challenges in the estimation of true prevalence and laboratory diagnosis
Authors: Chen Lin-Yuan , Pang Xiao-Yu , Goyal Hemant , Yang Rui-Xia , Xu Hua-Guo
Published: October 2021

Hepatitis delta virus (HDV) is a defective single negative chain RNA virus, as its envelope protein synthesis is dependent on hepatitis B virus (HBV). Studies have consistently shown that coinfection of HBV and HDV is the most serious form of viral hepatitis, with accelerated progression to liver cirrhosis and hepatocellular carcinoma. About 74 million of HBV surface antigen (HBsAg) positive patients worldwide are also co-infected with HDV. Besides, patients with intravenous drug use and high-risk sexual behavior are at higher risk of HDV infection. Therapeutic schedules for HDV are limited, and relapse of HDV has been observed after treatment with pegylated interferon alpha. To reduce the transmission of HDV, all people infected with HBV should be screened for HDV. At present, several serological and molecular detection methods are widely used in the diagnosis of HDV. However, due to the lack of international standards diagnostic results from different laboratories are often not comparable. Therefore, the true prevalence of HDV is still unclear. In this manuscript, we have analyzed various factors influencing the estimation of HDV prevalence. We have also discussed about the advantages and disadvantages of currently available HDV laboratory diagnostic methods, in order to provide some ideas for improving the detection of HDV.
Effect of early cardiac rehabilitation on prognosis in patients with heart failure following acute myocardial infarction
Authors: Cai He , Cao Pengyu , Zhou Wenqian , Sun Wanqing , Zhang Xinying , Li Rongyu , Shao Wangshu , Wang Lin , Zou Lin , Zheng Yang
Published: October 2021

Objective

The purpose of this retrospective study is to evaluate the effectiveness of early cardiac rehabilitation on patients with heart failure following acute myocardial infarction.

Methods

Two hundred and thirty-two patients who developed heart failure following acute myocardial infarction were enrolled in this study. Patients were divided into heart failure with reduced ejection fraction group (n = 54) and heart failure with mid-range ejection fraction group (n = 178). Seventy-eight patients who accepted a two-week cardiac rehabilitation were further divided into two subgroups based on major adverse cardiovascular events. Key cardio-pulmonary exercise testing indicators that may affect the prognosis were identified among the cardiac rehabilitation patients.

Results

Early cardiac rehabilitation significantly reduced cardiac death and re-hospitalization in patients. There was more incidence of diabetes, hyperkalemia and low PETCO2 in the cardiac rehabilitation group who developed re-hospitalization. Low PETCO2 at anaerobic threshold (≤ 33.5 mmHg) was an independent risk factor for re-hospitalization.

Conclusions

Early cardiac rehabilitation reduced major cardiac events in patients with heart failure following acute myocardial infarction. The lower PETCO2 at anaerobic threshold is an independent risk factor for re-hospitalization, and could be used as a evaluating hallmark for early cardiac rehabilitation.
Risk factors for development of nephropathy in patients with a diabetic Charcot foot
Authors: Jansen Rasmus Bo , Holstein Per E. , Jørgensen Bo , Møller Klaus Kirketerp , Svendsen Ole Lander
Published: October 2021

Objective

Charcot foot is a rare complication to neuropathy and can cause severe foot deformities and ulcerations, which often require prolonged antibiotical treatment. The objective of this retrospective study was to investigate whether this treatment is associated to impaired renal function.

Results

In total, 163 patients were included, of whom 105 (64%) had received β-lactam antibiotics for a mean total duration of 13.0 months. There was a significant increase in the urine albumin/creatinine ratio in the group that received antibiotics (p = 0.017), and the use of antibiotics was associated to a subsequent diagnosis of nephropathy (p = 0.01). Patients treated with antibiotics had a 21.9% risk of developing subsequent nephropathy versus 5.2% for patients not treated with antibiotics. We suggest increased awareness on signs of nephropathy in patients with severe Charcot foot.
Gender representation in food and beverage print advertisements found in corner stores around schools in Peru and Guatemala
Authors: Mus Sophia , Rozas Lucila , Barnoya Joaquin , Busse Peter
Published: October 2021

Objective

The objective of this study is to assess gender representation in food and beverage print advertisements.

Results

The study follows a quantitative descriptive approach. Using a content analysis technique, we assessed the gender representation in 200 food and beverage print advertisements found in corner stores located in four areas around schools in Lima, Peru, and Guatemala City, Guatemala (100 advertisements per country). A total of 36% of the print advertisements exhibited a male main character for the case of Guatemala, while in Peru 14% of the print advertisements presented a male main character. Furthermore, in Guatemala, 22% of the main characters were male animated characters. Moreover, 27% of the print advertisements in Guatemala and 17%, in Peru were visually male-oriented. Overall, male characters appeared alongside sports references and in varied settings, whereas female characters were usually holding or consuming the product. In conclusion, although the majority of variables used to assess the representation of gender in food and beverage print advertisements were gender-neutral, those showing gender representation were mostly male-oriented. Despite its limited findings, the study provides evidence for the formulation of public policies and educational content aimed to protect children’s and adolescents’ health from the effects of food marketing.
Imaging of congenital lung diseases presenting in the adulthood: a pictorial review
Authors: Durhan Gamze , Ardali Duzgun Selin , Akpınar Meltem Gülsün , Demirkazık Figen , Arıyürek Orhan Macit
Published: October 2021

Congenital lung diseases in adults are rare diseases that can present with symptoms or be detected incidentally. Familiarity with the imaging features of different types of congenital lung diseases helps both in correct diagnosis and management of these diseases. Congenital lung diseases in adults are classified into three main categories as bronchopulmonary anomalies, vascular anomalies, and combined bronchopulmonary and vascular anomalies. Contrast-enhanced computed tomography, especially 3D reconstructions, CT, or MR angiography, can show vascular anomalies in detail. The tracheobronchial tree, parenchymal changes, and possible complications can also be defined on chest CT, and new applications such as quantitative 3D reconstruction CT images, dual-energy CT (DECT) can be helpful in imaging parenchymal changes. In addition to the morphological assessment of the lungs, novel MRI techniques such as ultra-short echo time (UTE), arterial spin labeling (ASL), and phase-resolved functional lung (PREFUL) can provide functional information. This pictorial review aims to comprehensively define the radiological characteristics of each congenital lung disease in adults and to highlight differential diagnoses and possible complications of these diseases.
Decoding intra-tumoral spatial heterogeneity on radiological images using the Hilbert curve
Authors: Wang Lu , Xu Nan , Song Jiangdian
Published: October 2021

Background

Current intra-tumoral heterogeneous feature extraction in radiology is limited to the use of a single slice or the region of interest within a few context-associated slices, and the decoding of intra-tumoral spatial heterogeneity using whole tumor samples is rare. We aim to propose a mathematical model of space-filling curve-based spatial correspondence mapping to interpret intra-tumoral spatial locality and heterogeneity.

Methods

A Hilbert curve-based approach was employed to decode and visualize intra-tumoral spatial heterogeneity by expanding the tumor volume to a two-dimensional (2D) matrix in voxels while preserving the spatial locality of the neighboring voxels. The proposed method was validated using three-dimensional (3D) volumes constructed from lung nodules from the LIDC-IDRI dataset, regular axial plane images, and 3D blocks.

Results

Dimensionality reduction of the Hilbert volume with a single regular axial plane image showed a sparse and scattered pixel distribution on the corresponding 2D matrix. However, for 3D blocks and lung tumor inside the volume, the dimensionality reduction to the 2D matrix indicated regular and concentrated squares and rectangles. For classification into benign and malignant masses using lung nodules from the LIDC-IDRI dataset, the Inception-V4 indicated that the Hilbert matrix images improved accuracy (85.54% vs. 73.22%,p < 0.001) compared to the original CT images of the test dataset.

Conclusions

Our study indicates that Hilbert curve-based spatial correspondence mapping is promising for decoding intra-tumoral spatial heterogeneity of partial or whole tumor samples on radiological images. This spatial-locality-preserving approach for voxel expansion enables existing radiomics and convolution neural networks to filter structured and spatially correlated high-dimensional intra-tumoral heterogeneity.
Ex vivo expansion and characterization of human corneal endothelium for transplantation: a review
Authors: Smeringaiova Ingrida , Utheim Tor Paaske , Jirsova Katerina
Published: October 2021

The corneal endothelium plays a key role in maintaining corneal transparency. Its dysfunction is currently treated with penetrating or lamellar keratoplasty. Advanced cell therapy methods seek to address the persistent global deficiency of donor corneas by enabling the renewal of the endothelial monolayer with tissue-engineered grafts. This review provides an overview of recently published literature on the preparation of endothelial grafts for transplantation derived from cadaveric corneas that have developed over the last decade (2010–2021). Factors such as the most suitable donor parameters, culture substrates and media, endothelial graft storage conditions, and transplantation methods are discussed. Despite efforts to utilize alternative cellular sources, such as induced pluripotent cells, cadaveric corneas appear to be the best source of cells for graft preparation to date. However, native endothelial cells have a limited natural proliferative capacity, and they often undergo rapid phenotype changes in ex vivo culture. This is the main reason why no culture protocol for a clinical-grade endothelial graft prepared from cadaveric corneas has been standardized so far. Currently, the most established ex vivo culture protocol involves the peel-and-digest method of cell isolation and cell culture by the dual media method, including the repeated alternation of high and low mitogenic conditions. Culture media are enriched by additional substances, such as signaling pathway (Rho-associated protein kinase, TGF-β, etc.) inhibitors, to stimulate proliferation and inhibit unwanted morphological changes, particularly the endothelial-to-mesenchymal transition. To date, this promising approach has led to the development of endothelial grafts for the first in-human clinical trial in Japan. In addition to the lack of a standard culture protocol, endothelial-specific markers are still missing to confirm the endothelial phenotype in a graft ready for clinical use. Because the corneal endothelium appears to comprise phenotypically heterogeneous populations of cells, the genomic and proteomic expression of recently proposed endothelial-specific markers, such as Cadherin-2, CD166, or SLC4A11, must be confirmed by additional studies. The preparation of endothelial grafts is still challenging today, but advances in tissue engineering and surgery over the past decade hold promise for the successful treatment of endothelial dysfunctions in more patients worldwide.
Synergistic stimulation of osteoblast differentiation of rat mesenchymal stem cells by leptin and 25(OH)D3 is mediated by inhibition of chaperone-mediated autophagy
Authors: He Qiting , Qin Ruixi , Glowacki Julie , Zhou Shuanhu , Shi Jie , Wang Shaoyi , Gao Yuan , Cheng Lei
Published: October 2021

Background

Vitamin D is important for the mineralization of bones by stimulating osteoblast differentiation of bone marrow mesenchymal stem cells (BMMSCs). BMMSCs are a target of vitamin D action, and the metabolism of 25(OH)D3 to biologically active 1α,25(OH)2D3 in BMMSCs promotes osteoblastogenesis in an autocrine/paracrine manner. Our previous study with human BMMSCs showed that megalin is required for the 25(OH)D3-DBP complex to enter cells and for 25(OH)D3 to stimulate osteoblast differentiation in BMMSCs. Furthermore, we reported that leptin up-regulates megalin in those cells. Leptin is a known inhibitor of PI3K/AKT-dependent chaperone-mediated autophagy (CMA). In this study, we tested the hypothesis that leptin acts synergistically with 25(OH)D3 to promote osteoblastogenesis in rat BMMSCs by a mechanism that entails inhibition of PI3K/AKT-dependent CMA.

Methods

BMMSCs were isolated from rat bone marrow (4-week-old male SD rats); qRT-PCR and western immunoblots or immunofluorescence were used to evaluate the expression of megalin, ALP, COL1A1, RUNX2, OSX, OSP, and CMA in rBMMSCs. The osteoblast differentiation was evaluated by ALP activity, ALP staining, and calcium deposition. The viability of rBMMSCs was assessed with the CCK-8 kit. Biosynthesis of 1α,25(OH)2D3 was measured by a Rat 1α,25(OH)2D3 ELISA Kit.

Results

The combination of leptin and 25(OH)D3 treatment significantly enhanced osteoblast differentiation as shown by ALP activity, ALP staining, and calcium deposition, the expression of osteogenic genes ALP, COL1A1, RUNX2, OSX, and OSP by qRT-PCR and western immunoblots in rBMMSCs. Leptin enhanced the expression of megalin and synthesis of 1α,25(OH)2D3 in rBMMSCs. Our data showed that leptin inhibited CMA activity of rBMMSCs by activating PI3K/AKT signal pathway; the ability of leptin to enhance 25(OH)D3 promoted osteoblast differentiation of rBMMSCs was weakened by the PI3K/AKT signal pathway inhibitor.

Conclusions

Our data reveal the mechanism by which leptin and 25(OH)D3 promote osteoblast differentiation in rBMMSCs. Leptin promoted the expression of megalin by inhibiting CMA, increased the utilization of 25(OH)D3 by rBMMSCs, and enhanced the ability of 25(OH)D3 to induce osteoblast differentiation of rBMMSCs. PI3K/AKT is at least partially involved in the regulation of CMA. These data indicate the importance of megalin in BMMSCs for vitamin D’s role in skeletal health.
Wharton’s jelly mesenchymal stem cells embedded in PF-127 hydrogel plus sodium ascorbyl phosphate combination promote diabetic wound healing in type 2 diabetic rat
Authors: Jiao Yiren , Chen Xiaolin , Niu Yongxia , Huang Sunxing , Wang Jingwen , Luo Mingxun , Shi Guang , Huang Junjiu
Published: October 2021

Background

Diabetic cutaneous ulcers (DCU) are a complication of diabetes with diabetic foot ulcers being the most common, and the wounds are difficult to heal, increasing the risk of bacterial infection. Cell-based therapy utilizing mesenchymal stem cells (MSCs) is currently being investigated as a therapeutic avenue for both chronic diabetic ulcers and severe burns. Wharton’s jelly mesenchymal stem cell (WJMSC) with PF-127 hydrogel and sodium ascorbyl phosphate (SAP) improved skin wound healing in mice. Whether this combination strategy is helpful to diabetic ulcers wound healing remains to be explored.

Methods

Firstly, the WJMSCs embedded in PF-127 and SAP combination were transplanted onto excisional cutaneous wound bed in type 2 diabetic Sprague Dawley (SD) rats. Two weeks after transplantation, the skin tissue was collected for histological and immunohistochemical analysis. Further, overexpressing-EGFP WJMSCs were performed to investigate cell engraftment in the diabetic cutaneous ulcer. The apoptosis of WJMSCs which encapsulated with combination of PF-127 and SAP was detected by TUNEL fluorescence assay and RT-PCR in vitro. And the mitochondrial damage induced by oxidative stress assessed by MitoTracker and CMH2DCFDA fluorescence assay.

Results

In diabetic cutaneous wound rat model, PF-127 plus SAP-encapsulated WJMSCs transplantation promoted diabetic wound healing, indicating improving dermis regeneration and collagen deposition. In diabetic wound healing, less pro-inflammatory M1 macrophages, more anti-inflammatory M2 tissue-healing macrophages, and neovascularization were observed in PF-127 + SAP + WJMSCs group compared with other groups. SAP supplementation alleviated the apoptosis ratio of WJMSCs embedded in the PF-127 in vitro and promoted cell survival in vivo.

Conclusion

PF-127 plus SAP combination facilitates WJMSCs-mediated diabetic wound healing in rat through promoting cell survival, the macrophage transformation, and angiogenesis. Our findings may potentially provide a helpful therapeutic strategy for patients with diabetic cutaneous ulcer.
Activation of adult mammalian retinal stem cells in vivo via antagonism of BMP and sFRP2
Authors: Grisé Kenneth N. , Coles Brenda L. K. , Bautista Nelson X. , van der Kooy Derek
Published: October 2021

Background

The adult mammalian retina does not have the capacity to regenerate cells lost due to damage or disease. Therefore, retinal injuries and blinding diseases result in irreversible vision loss. However, retinal stem cells (RSCs), which participate in retinogenesis during development, persist in a quiescent state in the ciliary epithelium (CE) of the adult mammalian eye. Moreover, RSCs retain the ability to generate all retinal cell types when cultured in vitro, including photoreceptors. Therefore, it may be possible to activate endogenous RSCs to induce retinal neurogenesis in vivo and restore vision in the adult mammalian eye.

Methods

To investigate if endogenous RSCs can be activated, we performed combinatorial intravitreal injections of antagonists to BMP and sFRP2 proteins (two proposed mediators of RSC quiescence in vivo), with or without growth factors FGF and Insulin. We also investigated the effects of chemically-induced N-methyl-N-Nitrosourea (MNU) retinal degeneration on RSC activation, both alone and in combination withthe injected factors. Further, we employed inducible Msx1-CreERT2 genetic lineage labeling of the CE followed by stimulation paradigms to determine if activated endogenous RSCs could migrate into the retina and differentiate into retinal neurons.

Results

We found that in vivo antagonism of BMP and sFRP2 proteins induced CE cells in the RSC niche to proliferate and expanded the RSC population. BMP and sFRP2 antagonism also enhanced CE cell proliferation in response to exogenous growth factor stimulation and MNU-induced retinal degeneration. Furthermore, Msx1-CreERT2 genetic lineage tracing revealed that CE cells migrated into the retina following stimulation and/or injury, where they expressed markers of mature photoreceptors and retinal ganglion cells.

Conclusions

Together, these results indicate that endogenous adult mammalian RSCs may have latent regenerative potential that can be activated by modulating the RSC niche and hold promise as a means for endogenous retinal cell therapy to repair the retina and improve vision.
Treatment of knee osteoarthritis with intra-articular injection of allogeneic adipose-derived stem cells (ADSCs) ELIXCYTE®: a phase I/II, randomized, active-control, single-blind, multiple-center clinical trial
Authors: Chen Cheng-Fong , Hu Chih-Chien , Wu Chen-Te , Wu Hung-Ta H. , Chang Chun-Shin , Hung Yi-Pei , Tsai Chia-Chu , Chang Yuhan
Published: October 2021

Objective

To evaluate the safety and efficacy of intra-articular (IA) injection of allogeneic adipose-derived stem cells (ADSCs) ELIXCYTE® for knee osteoarthritis.

Methods

This was a patient-blind, randomized, active-control trial consisted of 4 arms including hyaluronic acid (HA) control and 3 ELIXCYTE® doses. A total of 64 subjects were screened, and 57 subjects were randomized. The primary endpoints included the changes from baseline to post-treatment visit of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at Week 24 and the incidence of adverse events (AEs) and serious adverse events (SAEs).

Results

No ELIXCYTE®-related serious adverse events were reported during 96 weeks of follow-up and no suspected unexpected serious adverse reaction (SUSAR) or death was reported. The changes of the primary endpoint, WOMAC pain score at Week 24, showed significant differences in all ELIXCYTE® groups, as well as in HA groups between post-treatment visit and baseline. The ELIXCYTE® groups revealed significant decreases at Week 4 compared to HA group in WOMAC total scores, stiffness scores, functional limitation scores suggested the potential of ELIXCYTE® in earlier onset compared to those from HA. The significant differences of visual analog scale (VAS) pain score and Knee Society Clinical Rating System (KSCRS) functional activities score at Week 48 after ELIXCYTE® administration suggested the potential of ELIXCYTE® in the longer duration of the effectiveness compared to HA group.

Conclusions

ELIXCYTE® for knee osteoarthritis treatment was effective, safe, and well-tolerated. The efficacy results were showed that ELIXCYTE® conferred the earlier onset of reductions in pain scores and improvements in functional scores than HA group.

Trial registration: ClinicalTrials.gov Identifier: NCT02784964. Registered 16 May, 2016—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02784964
[68Ga]Ga-4HMSA a promising new PET tracer for imaging inflammation
Authors: Kahn Ali Shigufa , Ait-Mohand Samia , Dumulon-Perreault Véronique , Guérin Brigitte
Published: October 2021

Background

Imaging diagnosis of inflammation has been challenging for many years. Inflammation imaging agents commonly used in nuclear medicine, such as [67Ga]Ga-citrate and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) showed some limitations. The identification of a radiotracer with high specificity and low radiation dose is clinically important. With the commercialization of68Ge/68Ga generators and the high68Ga cyclotron production capacity, the study of68Ga-based tracer for inflammation has increased and shown good potential. In the present work, we report the synthesis of 4HMSA, a new acyclic chelator, and its first investigation for68Ga complexation and as a new positron emission tomography (PET) imaging agent of inflammation in comparison to [68Ga]Ga-citrate.

Results

The present experimental studies have shown that the novel [68Ga]Ga-4HMSA is stable allowing imaging of inflammation in a preclinical model of adjuvant- and pathogen-based inflammation involving intraplantar injection of complete Freund’s adjuvant (CFA). We also found that [68Ga]Ga-4HMSA displayed similar uptakes in the inflamed paw than [68Ga]Ga-citrate, which are superior compared to those of contralateral (non-injected) paws at days 1–3 from PET imaging. [68Ga]Ga-citrate accumulated in the upper body of the animal such as the liver, lungs and the heart, whereas the [68Ga]Ga-4HMSA revealed low uptakes in the majority of the organs and was cleared relatively rapidly from blood circulation through the kidneys and bladder.

Conclusion

The results highlight the potential of [68Ga]Ga-4HMSA as an interesting alternative to [68Ga]Ga-citrate for inflammation imaging by PET. The new PET tracer also offers additional advantages than [68Ga]Ga-citrate in term of dosimetry and lower overall background activity.
Mitochondrial dysfunction, UPRmt signaling, and targeted therapy in metastasis tumor
Authors: Keerthiga Rajendiran , Pei De-Sheng , Fu Ailing
Published: October 2021

In modern research, mitochondria are considered a more crucial energy plant in cells. Mitochondrial dysfunction, including mitochondrial DNA (mtDNA) mutation and denatured protein accumulation, is a common feature of tumors. The dysfunctional mitochondria reprogram molecular metabolism and allow tumor cells to proliferate in the hostile microenvironment. One of the crucial signaling pathways of the mitochondrial dysfunction activation in the tumor cells is the retrograde signaling of mitochondria-nucleus interaction, mitochondrial unfolded protein response (UPRmt), which is initiated by accumulation of denatured protein and excess ROS production. In the process of UPRmt, various components are activitated to enhance the mitochondria-nucleus retrograde signaling to promote carcinoma progression, including hypoxia-inducible factor (HIF), activating transcription factor ATF-4, ATF-5, CHOP, AKT, AMPK. The retrograde signaling molecules of overexpression ATF-5, SIRT3, CREB, SOD1, SOD2, early growth response protein 1 (EGR1), ATF2, CCAAT/enhancer-binding protein-d, and CHOP also involved in the process. Targeted blockage of the UPRmtpathway could obviously inhibit tumor proliferation and metastasis. This review indicates the UPRmtpathways and its crucial role in targeted therapy of metastasis tumors.
Characteristics of Sepsis-2 septic shock patients failing to satisfy the Sepsis-3 septic shock definition: an analysis of real-time collected data
Authors: Vermassen Joris , Decruyenaere Johan , De Bus Liesbet , Depuydt Pieter , Colpaert Kirsten
Published: October 2021

Background

Baseline characteristics and disease severity of patients with septic shock according to the new Sepsis-3 definition may differ from patients that only comply with the Sepsis-2 definition. We conducted a retrospective cohort study on the ICU of a Belgian tertiary care facility to seek out differences between these two patient groups and to identify variables associated with no longer satisfying the latest definition of septic shock.

Results

Of 1198 patients with septic shock according to the Sepsis-2 consensus definition, 233 (19.4%) did not have septic shock according to the Sepsis-3 shock definition. These patients more often had medical admission reasons and a respiratory infection as cause for the septic shock. They less often had surgery on admission and were less likely to have chronic liver disease (5.6% vs 16.2%, absolute difference 10.6% (95% CI 6.4–14.1%). Patients with septic shock only according to the old definition had significant lower APACHE II and SOFA scores and lower hospital mortality (31.6% vs 55.3%, p < 0.001). In a multivariate analysis, following variables were associated with Sepsis-2 shock patients no longer being defined as such by the Sepsis-3 definition: respiratory infection (OR 1.485 (95% CI 1.56–2.089), p = 0.023), a medical admission reason (OR 1.977 (95% CI 1.396–2.800) and chronic liver disease (OR 0.345 (95% CI 0.181–0.660), p < 0.001).

Conclusions

One in five patients with septic shock according to the Sepsis-2 consensus definition is no longer considered as such when the Sepsis-3 shock criteria are applied. A medical admission reason, a respiratory infection and absence of chronic liver disease are independently associated with no longer being identified as having septic shock by the Sepsis-3 criteria.
Comparative evaluation of interpolation methods for the directivity of musical instruments
Authors: Ackermann David , Brinkmann Fabian , Zotter Franz , Kob Malte , Weinzierl Stefan
Published: October 2021

Measurements of the directivity of acoustic sound sources must be interpolated in almost all cases, either for spatial upsampling to higher resolution representations of the data, for spatial resampling to another sampling grid, or for use in simulations of sound propagation. The performance of different interpolation techniques applied to sparsely sampled directivity measurements depends on the sampling grid used but also on the radiation pattern of the sources themselves. Therefore, we evaluated three established approaches for interpolation from a low-resolution sampling grid using high-resolution measurements of a representative sample of musical instruments as a reference. The smallest global error on average occurs for thin plate pseudo-spline interpolation. For interpolation based on spherical harmonics (SH) decomposition, the SH order and the spatial sampling scheme applied have a strong and difficult to predict influence on the quality of the interpolation. The piece-wise linear, spherical triangular interpolation provides almost as good results as the first-order spline approach, albeit with on average 20 times higher computational effort. Therefore, for spatial interpolation of sparsely sampled directivity measurements of musical instruments, the thin plate pseudo-spline method applied to absolute-valued data is recommended and, if necessary, a subsequent modeling of the phase.
Discrete epidemic models with two time scales
Authors: Bravo de la Parra Rafael , Sanz-Lorenzo Luis
Published: October 2021

The main aim of the work is to present a general class of two time scales discrete-time epidemic models. In the proposed framework the disease dynamics is considered to act on a slower time scale than a second different process that could represent movements between spatial locations, changes of individual activities or behaviors, or others.

To include a sufficiently general disease model, we first build up from first principles a discrete-time susceptible–exposed–infectious–recovered–susceptible (SEIRS) model and characterize the eradication or endemicity of the disease with the help of its basic reproduction number $\mathcal{R}_{0}$

R
0

.

Then, we propose a general full model that includes sequentially the two processes at different time scales and proceed to its analysis through a reduced model. The basic reproduction number $\overline{\mathcal{R}}_{0}$

R
‾

0

of the reduced system gives a good approximation of $\mathcal{R}_{0}$

R
0

of the full model since it serves at analyzing its asymptotic behavior.

As an illustration of the proposed general framework, it is shown that there exist conditions under which a locally endemic disease, considering isolated patches in a metapopulation, can be eradicated globally by establishing the appropriate movements between patches.
Low frequency of community-acquired bacterial co-infection in patients hospitalized for COVID-19 based on clinical, radiological and microbiological criteria: a retrospective cohort study
Authors: Coenen Sophie , de la Court Jara R. , Buis David T. P. , Meijboom Lilian J. , Schade Rogier P. , Visser Caroline E. , van Hest Reinier , Kuijvenhoven Marianne , Prins Jan M. , Nijman Suzan F. M. , Sieswerda Elske , Sigaloff Kim C. E.
Published: October 2021

Background

We defined the frequency of respiratory community-acquired bacterial co-infection in patients with COVID-19, i.e. patients with a positive SARS-CoV-2 PCR or a COVID-19 Reporting and Data System (CO-RADS) score ≥ 4, based on a complete clinical assessment, including prior antibiotic use, clinical characteristics, inflammatory markers, chest computed tomography (CT) results and microbiological test results.

Methods

Our retrospective study was conducted within a cohort of prospectively included patients admitted for COVID-19 in our tertiary medical centres between 1-3-2020 and 1-6-2020. A multidisciplinary study team developed a diagnostic protocol to retrospectively categorize patients as unlikely, possible or probable bacterial co-infection based on clinical, radiological and microbiological parameters in the first 72 h of admission. Within the three categories, we summarized patient characteristics and antibiotic consumption.

Results

Among 281 included COVID-19 patients, bacterial co-infection was classified as unlikely in 233 patients (82.9%), possible in 35 patients (12.4%) and probable in 3 patients (1.1%). Ten patients (3.6%) could not be classified due to inconclusive data. Within 72 h of hospital admission, 81% of the total study population and 78% of patients classified as unlikely bacterial co-infection received antibiotics.

Conclusions

COVID-19 patients are unlikely to have a respiratory community-acquired bacterial co-infection. This study underpins recommendations for restrictive use of antibacterial drugs in patients with COVID-19.
Antimicrobial property of recombinant Lactolisterin BU in vitro and its initial application in pork refrigerated storage
Authors: Dong Bin , Zhou Guowen , Lin Yanjun , Yu Cailing , Wang Jun , Sun Chunlong , Wu Tao
Published: October 2021

Lactolisterin BU is a novel bacteriocin identified from Lactococcus lactis in 2017. It exhibits antimicrobial activity against food spoilage and foodborne pathogens. In this study, Lactolisterin BU was expressed in Pichia pastoris (P.pastoris) and isolated from the supernatant of yeast culture for the first time. It was found to exhibit a broad antimicrobial spectrum and rapid bactericidal activity against foodborne bacterial pathogens, both gram-positive and gram-negative ones, with minimum inhibition concentrations ranging within 10–60 μg/mL. The recombinant Lactolisterin BU (rLactolisterin BU) also had an antioxidant effect and was resistant to heating, acid–base, and high-dose-saline treatments and barely had any hemolytic activity or cytotoxicity. Moreover, rLactolisterin BU effectively suppressed the growth of bacterial pathogens; suppressed the increases in pH, total volatile basic nitrogen (TVB-N), and thiobarbituric acid reactive substances (TBARS) of pork samples; and maintained a high quality of fresh pork during storage at 4 ℃. Furthermore, rLactolisterin BU effectively inhibited the growth of three kinds of bacteria in a pork-spoilage model. Taken together, rLactolisterin BU could be a promising preservative for food storage.
The effects and safety of pirfenidone in the treatment of idiopathic pulmonary fibrosis: a meta-analysis and systematic review
Authors: Zang Chenchen , Zheng Yan , Wang Yanqing , Li Lisha
Published: October 2021

Background

It is necessary to systematically evaluate the efficacy and adverse reactions of pirfenidone in the treatment of patients with idiopathic pulmonary fibrosis (IPF).

Methods

Pubmed et al. databases were searched up to March 15, 2021 for randomized controlled trials (RCT) of pirfenidone in the treatment of IPF. Two authors collected and compared the indicators including progression-free survival (PFS), vital capacity (VC), forced vital capacity (FVC), and adverse reactions. RevMan 5.3 software and Stata 15.0 software were used for meta-analysis.

Results

A total of 8 reports with 9 RCTs involving 1824 IPF patients were included. Meta-analysis results showed that compared with the control group, pirfenidone could prolong the PFS phase of IPF patients (HR = 0.65, 95% CI 0.55 ~ 0.76, P < 0.001), slow down the VC of IPF patients (SMD = 0.43, 95% CI 0.21 ~ 0.66, P < 0.001), and decrease FVC (SMD = 0.31, 95% CI 0.14 ~ 0.48, P < 0.001). The main adverse reactions of pirfenidone were gastrointestinal reactions, photosensitivity and skin rashes.

Conclusion

Pirfenidone is beneficial to prolong the PFS of IPF patients, improve lung function, and it is safe for clinical use. However, more high-quality RCTs are still needed to provide reliable evidence for the treatment of IPF.
Acceptability and face validity of two mental health screening tools for use in the routine surgical setting
Authors: McBride Kate E. , Steffens Daniel , Lambert Tim , Glozier Nick , Roberts Rachael , Solomon Michael J.
Published: October 2021

Background

Preoperative assessment of mental health rarely occurs within routine surgery. Any screening tool selected to form part of this process must be deemed practical, acceptable and valid by clinicians and consumers alike. This study aims to assess the acceptability and face validity of two existing mental health screening tools to select one for further development and use in the routine surgical setting.

Methods

A survey of clinicians and consumers was conducted from October 2020 to March 2021 at a tertiary hospital in Sydney, Australia. Using a Likert scale (1–5, lowest to highest rating), the clinicians evaluated four domains for acceptability and two for validity (six overall) and the consumers four domains for acceptability and one for validity (five overall) on the preoperative use of the amended Kessler Psychological Distress Scale (K10) and the Somatic and Psychological Health Report-12 (SPHERE-12). Consensus was achieved through a rating of 4 or 5 being given by 70% or more of participants with domains able to remain unchanged. Free text responses were analysed into themes.

Results

A total of 73 participants (51 clinicians; 22 consumers) were included. The K10 received consensus scores (≥ 70%) in four out of six domains for clinicians (4/4 acceptability; 0/2 validity), and all five domains for consumers (4/4 acceptability; 1/1 validity). The SPHERE-12 received consensus scores (≥ 70%) in three domains for clinicians (3/4 acceptability; 0/2 validity), and three domains for consumers (3/4 acceptability; 0/1 validity). Six qualitative themes were described including (1) amendments to tool structure and language; (2) scale response options; (3) difficulty with somatic questions; (4) practicality and familiarity with K10; (5) challenges for specific patient cohorts and (6) timing considerations for patients.

Conclusion

Adequate acceptability was established for the K10. However further development is required to strengthen its validity for this specific surgical cohort and purpose. Future research to determine the feasibility and acceptability of implementing and using the K10 in the routine surgical setting is now needed.
Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies
Authors: Brockmann Kathrin , Quadalti Corinne , Lerche Stefanie , Rossi Marcello , Wurster Isabel , Baiardi Simone , Roeben Benjamin , Mammana Angela , Zimmermann Milan , Hauser Ann-Kathrin , Deuschle Christian , Schulte Claudia , Waniek Katharina , Lachmann Ingolf , Sjödin Simon , Brinkmalm Ann , Blennow Kaj , Zetterberg Henrik , Gasser Thomas , Parchi Piero
Published: October 2021

The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF.

These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn.