bluuebunny/crossref_metadata_2025 huggingface dataset:
Knee Joint Menisci Are Shock Absorbers: A Biomechanical In-Vitro Study on Porcine Stifle Joints
Authors: Seitz Andreas M. , Schwer Jonas , de Roy Luisa , Warnecke Daniela , Ignatius Anita , Dürselen Lutz
Published: March 2022

The aim of this biomechanical in vitro study was to answer the question whether the meniscus acts as a shock absorber in the knee joint or not. The soft tissue of fourteen porcine knee joints was removed, leaving the capsuloligamentous structures intact. The joints were mounted in 45° neutral knee flexion in a previously validated droptower setup. Six joints were exposed to an impact load of 3.54 J, and the resultant loss factor (η) was calculated. Then, the setup was modified to allow sinusoidal loading under dynamic mechanical analysis (DMA) conditions. The remaining eight knee joints were exposed to 10 frequencies ranging from 0.1 to 5 Hz at a static load of 1210 N and a superimposed sinusoidal load of 910 N (2.12 times body weight). Forces (F) and deformation (l) were continuously recorded, and the loss factor (tan δ) was calculated. For both experiments, four meniscus states (intact, medial posterior root avulsion, medial meniscectomy, and total lateral and medial meniscectomy) were investigated. During the droptower experiments, the intact state indicated a loss factor of η = 0.1. Except for the root avulsion state (−15%, p = 0.12), the loss factor decreased (p < 0.046) up to 68% for the total meniscectomy state (p = 0.028) when compared to the intact state. Sinusoidal DMA testing revealed that knees with an intact meniscus had the highest loss factors, ranging from 0.10 to 0.15. Any surgical manipulation lowered the damping ability: Medial meniscectomy resulted in a reduction of 24%, while the resection of both menisci lowered tan δ by 18% compared to the intact state. This biomechanical in vitro study indicates that the shock-absorbing ability of a knee joint is lower when meniscal tissue is resected. In other words, the meniscus contributes to the shock absorption of the knee joint not only during impact loads, but also during sinusoidal loads. The findings may have an impact on the rehabilitation of young, meniscectomized patients who want to return to sports. Consequently, such patients are exposed to critical loads on the articular cartilage, especially when performing sports with recurring impact loads transmitted through the knee joint surfaces.
Prostaglandin EP4 Selective Agonist AKDS001 Enhances New Bone Formation by Minimodeling in a Rat Heterotopic Xenograft Model of Human Bone
Authors: Ukon Yuichiro , Nishida Masahiro , Yamamori Natsumi , Takeyama Kazuhiro , Sakamoto Kazuhito , Takenaka Shota , Makino Takahiro , Fujimori Takahito , Sakai Yusuke , Kanie Yuya , Kodama Joe , Bal Zeynep , Tateiwa Daisuke , Nakagawa Shinichi , Hirai Hiromasa , Okada Seiji , Kaito Takashi
Published: March 2022

To enhance bone regeneration, the use of bone morphogenetic protein (BMP)-2 is an attractive option. Unfortunately, the dose-dependent side effects prevent its widespread use. Therefore, a novel osteogenic agent using a different mechanism of action than BMP-2 is highly desirable. Previous reports demonstrated that prostaglandin E2 receptor 4 (EP4) agonists have potent osteogenic effects on non-human cells and are one of the potential alternatives for BMP-2. Here, we investigated the effects of an EP4 agonist (AKDS001) on human cells with a rat heterotopic xenograft model of human bone. Bone formation in the xenograft model was significantly enhanced by AKDS001 treatment. Histomorphometric analysis showed that the mode of bone formation by AKDS001 was minimodeling rather than remodeling. In cultured human mesenchymal stem cells, AKDS001 enhanced osteogenic differentiation and mineralization via the cAMP/PKA pathway. In cultured human preosteoclasts, AKDS001 suppressed bone resorption by inhibiting differentiation into mature osteoclasts. Thus, we conclude that AKDS001 can enhance bone formation in grafted autogenous bone by minimodeling while maintaining the volume of grafted bone. The combined use of an EP4 agonist and autogenous bone grafting may be a novel treatment option to enhance bone regeneration. However, we should be careful in interpreting the results because male xenografts were implanted in male rats in the present study. It remains to be seen whether females can benefit from the positive effects of AKDS001 MS by using female xenografts implanted in female rats in clinically relevant animal models.
Encapsulated Fecal Microbiota Transplantation: Development, Efficacy, and Clinical Application
Authors: Halaweish Hossam F. , Boatman Sonja , Staley Christopher
Published: March 2022

Fecal microbiota transplantation (FMT) has been established as a highly restorative therapeutic approach for treating recurrent Clostridioides difficile infection (rCDI). Recently, the use of capsule-based fecal microbiota transplantation (cFMT) has been shown to be a clinically effective approach to restore intestinal microbiota composition. This convenient, oral delivery provides an easy route of administration and a newfound flexibility for clinicians and patients. In this review, we discuss the development of cFMT, paying particular attention to lyophilized cFMT products. We review the available published clinical studies comparing cFMT with lower endoscopic FMT (eFMT) or placebo. We further discuss the pharmacokinetics of FMT, which should be understood in a framework of microbial ecology that considers the complex and dynamic interactions of gut microbiota with host factors and other microorganisms. Promisingly, the results of multiple trials investigating cFMT vs. eFMT in rCDI show cFMT to be as effective as eFMT at preventing rCDI. However, its efficacy in non-rCDI conditions, including obesity and metabolic syndrome, inflammatory bowel disease, HIV, and neurologic conditions, is less clear and more research is needed in these areas. Standardization of formulation, dose, and timing of administration to ensure optimal microbiota engraftment and clinical response is also a challenge to be addressed. Overall, cFMT is a practical method for fecal microbiota transplantation, with similar efficacy to eFMT in the resolution of rCDI, that holds therapeutic potential in a variety of other diseases.
Matrix Metalloproteinase 2 and 9 Enzymatic Activities are Selectively Increased in the Myocardium of Chronic Chagas Disease Cardiomyopathy Patients: Role of TIMPs
Authors: Baron Monique Andrade , Ferreira Ludmila Rodrigues Pinto , Teixeira Priscila Camillo , Moretti Ana Iochabel Soares , Santos Ronaldo Honorato Barros , Frade Amanda Farage , Kuramoto Andréia , Debbas Victor , Benvenuti Luiz Alberto , Gaiotto Fabio Antônio , Bacal Fernando , Pomerantzeff Pablo , Chevillard Christophe , Kalil Jorge , Cunha-Neto Edecio
Published: March 2022

Chronic Chagas disease (CCC) is an inflammatory dilated cardiomyopathy with a worse prognosis compared to other cardiomyopathies. We show the expression and activity of Matrix Metalloproteinases (MMP) and of their inhibitors TIMP (tissue inhibitor of metalloproteinases) in myocardial samples of end stage CCC, idiopathic dilated cardiomyopathy (DCM) patients, and from organ donors. Our results showed significantly increased mRNA expression of several MMPs, several TIMPs and EMMPRIN in CCC and DCM samples. MMP-2 and TIMP-2 protein levels were significantly elevated in both sample groups, while MMP-9 protein level was exclusively increased in CCC. MMPs 2 and 9 activities were also exclusively increased in CCC. Results suggest that the balance between proteins that inhibit the MMP-2 and 9 is shifted toward their activation. Inflammation-induced increases in MMP-2 and 9 activity and expression associated with imbalanced TIMP regulation could be related to a more extensive heart remodeling and poorer prognosis in CCC patients.
Reassembling the Pimped Ride: A Quantitative Look at the Integration of a Borrowed Expression
Authors: De Pascale Stefano , Pijpops Dirk , Van de Velde Freek , Zenner Eline
Published: March 2022

Over the past decades, research on the linguistic impact of globalization has foregrounded the socio-pragmatic meaning potential and mental categorization of anglicisms, looking for signs of agentivity and contextual sensitivity in the way receptor language users incorporate borrowed English resources into their speech, both in form and in function. This brought attention to understudied phenotypes of contact-induced variation and change that go beyond the borrowing of individual lexical items (loanwords) from English. This paper aims to contribute to this endeavor, illustrating the potential of construction grammar to uncover the integration of borrowed chunks. In focus is the emergence of the verbpimpen“to pimp” in Dutch, a rapid innovation from the English proper namePimp My Ride. A sample of 4,561 Dutch tweets containing (strings of)pimpposted between January 2007 and April 2020 was coded manually for formal and semantic properties. This allowed us to calculate an aggregate score of “deconstructionalization” both within and outside of the target construction [pimpPOSS N]. Results indeed reveal a gradual blurring of the sharp contours of the construction, but also indicate that this process mainly affects the instantiations closest to the original. Linked up with the mediatized origin of the construction, our results add to our understanding of the relationship between media, language contact, and what is referred to as glocalization.
Myocardial Extracellular Volume Fraction Measured by Cardiac Magnetic Resonance Imaging Negatively Correlates With Cardiomyocyte Breadth in a Healthy Porcine Model
Authors: Zhang Shi-Jun , Chang Di , Jin Ji-Yang , Wang Ya-Ling , Wang Lin , Wang Yuan-Cheng , Wang Zhen , Ju Shenghong
Published: March 2022

Background

The extracellular volume fraction (ECV) derived from cardiac magnetic resonance imaging (MRI) is extensively used to evaluate myocardial fibrosis. However, due to the limited histological verification in healthy individuals, it remains unclear whether the size of cardiomyocytes may play a potential role in the physiological changes of ECV. The aim of this study was to examine the association between cardiomyocyte size and myocardial ECV by using a healthy porcine model.

Methods

Sixteen domestic healthy pigs were anesthetized and underwent cardiac MRI with mechanical controlled breathing. Intravenous contrast medium was introduced at a dose of 0.2–0.25 mmol/kg. The interventricular septum ECV was calculated using an established MRI procedure, which was based on the pre- and post-contrast T1 values of the heart and individual blood hematocrit. The cardiomyocyte breadth (CmyB) in cross section was measured by hematoxylin and eosin staining to reflect the cardiomyocyte size.

Results

Data were successfully acquired from 14 pigs. The CmyB was obtained from the myocardial tissues corresponding to the region of interest on cardiac MRI. The mean ± SD of the ECV was 0.253 ± 0.043, and the mean ± SD of the CmyB was 10.02 ± 0.84 μm. The ECV exhibited a negative correlation with the CmyB (r = −0.729, p = 0.003).

Conclusion

The myocardial ECV detected by cardiac MRI is negatively correlated with the CmyB in healthy pigs, demonstrating that the size of cardiomyocytes is potentially associated with the ECV under physiological conditions.
Association Between Circulating Retinol-Binding Protein 4 and Adverse Cardiovascular Events in Stable Coronary Artery Disease
Authors: Qian Ke , Yan Xin , Xu Cheng , Fang Yijia , Ma Moshuang
Published: March 2022

Background

The predictive role of retinol-binding protein 4 (RBP4) in the adverse prognosis of patients with stable coronary artery disease (CAD) has not been well-defined. We thus conducted this cohort study to investigate the association between circulating RBP4 level and major adverse cardiovascular events (MACEs) in Chinese patients with stable CAD.

Methods

Patients with stable CAD and serum RBP4 concentration measurement at admission between July 2012 and January 2015 were included. The primary outcome in this study was incident MACEs, which included acute coronary syndrome, heart failure, stroke, peripheral vascular disease, and cardiovascular death. Cox proportional hazards regression was adopted to investigate the association between RBP4 and the incidence of MACEs.

Results

A total of 840 patients with stable CAD were analyzed. The mean age of patients was 61.2 ± 15.9 years, and 56.1% of them were men. After a median follow-up of 2.3 years, 129 MACEs were observed. Compared to participants exposed to the first quartile of serum RBP4 level, those in the second, the third, and the fourth quartiles had associated hazard ratios (HRs) of 2.38 [95% confidence interval (CI): 1.33–4.26], 2.35 (95% CI: 1.31–4.21), and 2.27 (95% CI: 1.28–4.04) after adjusted for confounders, respectively. Every 5 μg/ml increment in serum RBP4 concentration was associated with an adjusted HR of 1.13 (95% CI: 1.05–1.22) for the occurrence of MACEs. Subgroup analyses suggested no significant modifying effects of baseline characteristics for the association between RBP4 and MACEs in patients with stable CAD.

Conclusion

Our finding suggested that the higher circulating RBP4 level was significantly associated with an increased risk of MACEs in patients with stable CAD.
Methodological Quality and Risk of Bias Assessment of Cardiovascular Disease Research: Analysis of Randomized Controlled Trials Published in 2017
Authors: Baasan Odgerel , Freihat Omar , Nagy David U. , Lohner Szimonetta
Published: March 2022

Background

All randomized-controlled trials (RCTs) are required to follow high methodological standards. In this study, we aimed to assess the methodological quality of published cardiovascular clinical research trials in a representative sample of RCTs published in 2017.

Methods

Cochrane Central Register of Controlled Trials was used to identify cardiovascular clinical research trials with adult participants published in 2017. Overall, 250 (10%) RCTs were randomly selected from a total of 2,419 studies. Data on general trial characteristics were extracted and the risk of bias (RoB) was determined.

Results

Overall, 86% of RCTs have reported at least one statistically significant result, with the primary outcome significant in 69%, treatment favored in 55%, and adverse events reported in 68%. Less than one-third (29%) of trials were overall low RoB, while the other two-thirds were rated unclear (40%) or with high RoB (31%). Sequence generation, allocation concealment, and selective reporting were the domains most often rated with high RoB. Drug trials were more likely to have low RoB than non-drug trials. Significant differences were found in RoB for the allocation concealment and blinding of participants and personnel between industry-funded and non-industry-funded trials, with industry-funded trials more often rated at low RoB.

Conclusion

Almost two-thirds of RCTs in the field of cardiovascular disease (CVD) research, were at high or unclear RoB, indicating a need for more rigorous trial planning and conduct. Prospective trial registration is a factor predicting a lower risk of bias.
Clinical Outcomes of Permanent Left Bundle Branch Area Pacing in Patients With Left Bundle Branch Block and Left Ventricular Ejection Fraction >35 vs. ≤35%
Authors: Jiang Zhixin , Wu Tian , Wu Yixian , Chen Zenghong , Yang Wen , Chen Chongchong , Zhou Xiujuan , Shan Qijun
Published: March 2022

Aims

The present study aimed to compare the effects of left bundle branch area pacing (LBBAP) on cardiac function and clinical outcomes in patients with left bundle branch block (LBBB) and left ventricular ejection fraction (LVEF) >35 vs. ≤35%.

Methods and Results

Thirty-six consecutive patients with LBBB and LVEF <50% were enrolled. All patients were followed up for a mean of 6 months. The successful LBBAP was defined as a paced QRS complex presented as right bundle branch block (RBBB) morphology and QRSd < 130 ms. Echocardiography parameters, pacing parameters and clinical outcomes were collected. The successful LBBAP was achieved in 77.8% of all cases (28/36). In LVEF > 35% group (70 ± 8 years, 9 male), the success rate was 81.0% (17/21). QRSd significantly decreased from 174 ± 23 ms to 108 ± 13 ms (P < 0.001). The pacing threshold and R-wave amplitude were 0.6 ± 0.2 V @ 0.5 ms and 12 ± 7 mV, respectively. In LVEF ≤ 35% group (69 ± 5 years, 9 male), the success rate was 73.3% (11/15) with QRSd decreasing from 188 ± 25 ms to 107 ± 11 ms (P < 0.001). The hyperresponders to LBBAP (functional recovery and LVEF ≥ 50%) in LVEF > 35% group was 52.9%, which were almost twice of that in LVEF ≤ 35% group (33.3%). Whether patients had LBBAP or left ventricular septal pacing (LVSP), patients in the LVEF > 35% group showed significantly lower incidence of heart failure hospitalizations or death from any cause (hazard ratio in LVEF > 35% group, 0.22; 95%CI, 0.06 to 0.75, P = 0.011).

Conclusions

LBBAP can significantly shorten the QRSd and improve cardiac function in LBBB patients with either LVEF > 35 or ≤ 35%. LBBAP should be considered as an effective therapy for preventing the deterioration of cardiac function in early-stage heart failure patients with LBBB and LVEF > 35%.
Constraints on Pore Development in Marine Shales of the Upper Yangtze Area, South China: A Comparative Case of Lower Cambrian and Lower Silurian Formations
Authors: Miao Yanan , Zhang Fan , Wang Shuai , Wu Fan , Li Xin
Published: March 2022

Both Lower Cambrian and Lower Silurian shale are typical of oil-prone kerogen and siliceous composition, but differ in thermal maturities with 3.56% Ro and 2.31% Ro, respectively. In this paper, pore characteristics were explored between these two shales. All samples were studied by a combination of organic geochemistry, x-ray diffraction, N2 adsorption, helium porosity, and focused ion beam milling and scanning electron microscopy. In particular, N2 adsorption of isolated OM was conducted to compare physical properties of OM-hosted pores, and fractal dimension was exploited to analyze morphologic characteristics of pores. N2 adsorption indicated that the Lower Silurian shale presented superior pore characteristics than the Lower Cambrian shale, in terms of pore volume (PV), pore surface area (PSA), and pore diameter. FIB-SEM manifested that pinhole OM-hosted pores and open-ended dissolved pores were primarily in the Lower Cambrian shale, while cellular OM-hosted pores were dominant in the Lower Silurian shale. Statistical and fractal analysis demonstrated that OM, rather than minerals, played a dominant role in pore development in marine shales at late diagenetic or metamorphic epoch. Furthermore, OM-hosted pores were not increased monotonously with increasing thermal maturity, but presented a unimodal trend, peaking at 2.8% Ro. PV (PSA) of isolated OM in the Lower Silurian shale was approximately 6.6 (4.3) times higher than that in the Lower Cambrian shale. With similar matrix basics and distinctive pore features, a comparison of these two marine shales markedly emphasizes the impact of thermal maturity on the state of OM-hosted pores.
Effects of Antidiabetic Drugs on Endothelial Function in Patients With Type 2 Diabetes Mellitus: A Bayesian Network Meta-Analysis
Authors: Wang Yuhan , Yao Mingyan , Wang Jincheng , Liu Hongzhou , Zhang Xuelian , Zhao Ling , Hu Xiaodong , Guan Haixia , Lyu Zhaohui
Published: March 2022

Background

The changes of endothelial function in type 2 diabetes mellitus (T2DM) patients are closely associated with the development of cardiovascular disease (CVD). However, it is still unclear whether commonly used antidiabetic drugs can improve endothelial function. Flow-mediated dilation (FMD) is a noninvasive tool for evaluating endothelial function, which typically examines changes in the brachial artery diameter in response to ischemia using ultrasound. We performed a network meta-analysis (NMA) to explore the associations between changes in endothelial function and antidiabetic drugs by evaluating FMD in T2DM patients.

Methods

We systematically searched several electronic databases for randomized controlled trials (RCTs) published from inception until January 25, 2022 with no language restriction. The primary outcome was FMD change in all studies, and we performed subgroup analysis in T2DM patients without CVD. NMA was performed to calculate the mean differences (MDs) with 95% confidence intervals (CIs).

Results

From the 1,987 candidate articles identified in the initial search, 30 RCTs were eventually included in the analysis. In all studies, glucagon-like peptide-1 receptor (GLP-1R) agonists [MD = 3.70 (1.39–5.97)], TZD [MD = 1.96 (0.006–3.89)] produced improvement of FMD change compared to lifestyle intervention. GLP-1R agonists [MD = 3.33 (1.36–5.34) and MD = 3.30 (1.21–5.43)] showed significantly greater improvements in FMD change in pairwise comparisons with sulfonylureas and placebo. SGLT-2i also showed efficacy compared to sulfonylureas (MD = 1.89, 95% CI, 0.10, 3.75). In studies of T2DM patients without CVD, GLP-1R agonists [MD = 3.53 (1.24–5.76)], and TZD [MD = 2.30 (0.27–3.24)] produced improvements in FMD change compared to lifestyle treatment. GLP-1R agonists [MD = 3.25 (1.13–5.40), and MD = 3.85 (1.68–6.13)] showed significantly greater improvements in pairwise comparisons with sulfonylureas, and placebo.

Conclusion

In T2DM patients, both GLP-1R agonists, SGLT-2i and TZD have favorable effects to improve endothelial function in T2DM patients. In T2DM patients without CVD, GLP-1R agonists had a greater effect to improve endothelial function than sulfonylureas. These suggested that GLP-1R agonists are associated with significantly improved endothelial function in T2DM patients.
Case Report: Onset of Type 1 Diabetes Mellitus in a Patient With Ulcerative Colitis and Sjogren’s Syndrome Under Euthyroid Hashimoto’s Thyroiditis
Authors: Takahashi Kaio , Anno Takatoshi , Matsuda Akio , Kimura Yukiko , Kawasaki Fumiko , Kaku Kohei , Tomoda Koichi , Kawamoto Hirofumi , Kaneto Hideaki
Published: March 2022

Type 1 diabetes mellitus (T1DM) is often complicated with some other autoimmune disorders. The complication of various autoimmune disorders is known as autoimmune polyglandular syndrome (APS). Once autoimmune thyroid disease develops, various autoimmune diseases can also occur. Such phenomena are classified as APS types 3A to 3D. In this report, we show the onset of T1DM in a patient with ulcerative colitis (UC) and Sjogren’s syndrome. The most important and interesting point in this case is that, if we did not check her thyroid-associated antibodies, we could not have diagnosed her as APS. From the data of this case, we assumed that the patient suffered from APS type 3A, 3B, and 3D variants. This case pointed out very clearly the importance of testing for thyroid-associated antibodies under various autoimmune disease conditions even if the thyroid hormone levels are euthyroid. Moreover, based on the strong linkage between inflammatory bowel disease and T1DM and the compatibility with both T1DM and APS type 3, we think it is possible that Hashimoto’s disease is present under complicated conditions together with UC and T1DM. It would be important to repeatedly check for thyroid-associated antibodies even in euthyroid patients, especially under various autoimmune disease conditions.
The Nursing Effect of Individualized Management on Patients With Diabetes Mellitus Type 2 and Hypertension
Authors: Li Ran , Xu Weiwei , Yang Ping , Tan Lian , Ling Zhiyu , Gan Xiuni
Published: March 2022

It focused on clinical effects of individualized nursing and health education (INHE) on patients with diabetes mellitus type 2 (T2DM) and hypertension. 68 patients were randomly rolled into two groups, 34 cases in the control group (group A) received routine nursing and remaining 34 cases in the experimental group (group B) received INHE. The disease knowledge mastery (DKM) and the effect of rehabilitation nursing of patients were compared. The results suggested that DKM of patients in group B was obviously greater (P < 0.05). The total effective rate (TER) in group B was 91.45%, which was observably greater than that (76.35%) in group A (P < 0.05). After nursing, the fasting plasma glucose (FPG), 2-hour postprandial glucose (2h PG), systolic blood pressure (SBP), and diastolic blood pressure (DBP) levels of all patients decreased, and those in group B were much lower (P < 0.05). Scores of the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) of the two groups were 56.34 ± 8.12 points and 56.33 ± 8.01 points in group A, respectively; and those in group B were 42.52 ± 6.77 points and 41.71 ± 7.23 points, respectively; and they were all decreased and those in the group B were obviously smaller (P < 0.05). In summary, INHE can effectively improve the psychological cognition of patients with T2DM and hypertension and strengthen the control of blood pressure and blood sugar.
First Assessment of Mercury (Hg) Concentrations in Skin and Carapace of Flatback Turtles (Natator depressus) (Garman) From Western Australia
Authors: Schneider Larissa , Tucker Anton D. , Vincent Kathryn , Fossette Sabrina , Young Erina J. , Whiting Scott D.
Published: March 2022

Mercury pollution in the surface ocean has more than doubled over the past century. Within oceanic food webs, sea turtles have life history characteristics that make them especially vulnerable to mercury (Hg) accumulation. In this study we investigated Hg concentrations in the skin and carapace of nesting flatback turtles (Natator depressus) from two rookeries in Western Australia. A total of 50 skin samples and 52 carapace samples were collected from nesting turtles at Thevenard Island, and 23 skin and 28 carapace samples from nesting turtles at Eighty Mile Beach. We tested the influence of turtle size on Hg concentrations, hypothesising that larger and likely older adult turtles would exhibit higher concentrations due to more prolonged exposure to Hg. We compared the rookeries, hypothesising that the turtles from the southern rookery (Thevenard Island) were more likely to forage and reside in the Pilbara region closer to industrial mining activity and loading ports (potential exposure to higher environmental Hg concentrations) with turtles from the northern rookery (Eighty Mile Beach) more likely to reside and feed in the remote Kimberley. Turtles from the Eighty Mile Beach rookery had significantly higher skin Hg concentrations (x̄ = 19.4 ± 4.8 ng/g) than turtles from Thevenard Island (x̄ = 15.2 ± 5.8 ng/g). There was no significant difference in carapace Hg concentrations in turtles between Eighty Mile Beach (x̄ = 48.4 ± 21.8 ng/g) and Thevenard Island (x̄ = 41.3 ± 16.5 ng/g). Turtle size did not explain Hg concentrations in skin samples from Eighty Mile Beach and Thevenard Island, but turtle size explained 43.1% of Hg concentrations in the carapace of turtles from Eighty Mile Beach and 44.2% from Thevenard Island. Mercury concentrations in the flatback turtles sampled in this study are relatively low compared to other sea turtles worldwide, likely a result of the generally low concentrations of Hg in the Australian environment. Although we predicted that mining activities would influence flatback turtle Hg bioaccumulations, our data did not support this effect. This may be a result of foraging ground overlap between the two rookeries, or the predominant wind direction carrying atmospheric Hg inland rather than seaward. This is the first Hg study in skin and carapace of flatback turtles and represents a baseline to compare Hg contamination in Australia’s surrounding oceans.
Urbanization’s Effects on Problem Solving Abilities: A Meta-Analysis
Authors: Vincze Ernő , Kovács Bálint
Published: March 2022

Cognitive abilities are often assumed to be advantageous in urban habitats, but relatively few studies tested this assumption. In a meta-analysis, we tested whether urban animals have better problem-solving abilities compared to their less urbanized conspecifics. After screening 210 papers we collected by keyword search and forward search, we found 12 studies that compared the ability to solve food-extraction or obstacle-removal problems between urban and non-urban populations of the same animal species. These studies were published between 2009 and 2021, and were performed mostly on birds, whereas a quarter of them used mammals as study species. We found a statistically non-significant trend that urban animals are more successful and faster problem-solvers compared to their less urbanized conspecifics. However, both solving success and solving latency effect sizes were highly heterogeneous, therefore hard to generalize. Though the sample was too low to test the factors explaining this high heterogeneity, we suggest that it may be explained by variation in task types, study species, definitions of urbanization, whether the study was performed on captive or free-living animals, geographical location, or publication bias in both directions. Altogether, more studies are needed to either confirm or disprove this trend.
Case Report: Novel Mutations in the PCCB Gene Causing Late-Onset Propionic Acidemia
Authors: Ji Guang , Liu Yaling , Song Xueqin , Li Zhenfei
Published: March 2022

Introduction: Propionic acidemia is an autosomal recessive metabolic disorder and the patients with adult onset are very rare.

Methods: Two PCCB mutations were identified. Clinical data were collected from a patient, and metabolic screening and clinical exome sequencing analysis were performed.

Results: Two novel mutations were identified in the PCCB gene: M1:c.404_406del:p.G135del and M2:c.632C>T:p.T211I.

Conclusion: Late-onset propionic acidemia should be taken into account, and metabolic screening as well as gene analysis should be performed to make a definite diagnosis timely.
Long Non-coding RNA HOXA11-AS Facilitates Proliferation of Lung Adenocarcinoma Cells via Targeting the Let-7c-5p/IGF2BP1 Axis
Authors: Lv Xiaodong , Fang Zhixian , Qi Weibo , Xu Yufen , Chen Wenyu
Published: March 2022

Objective: This study investigates the relationship between the HOXA11-AS/let-7c-5p/IGF2BP1 regulatory axis and lung adenocarcinoma.

Methods: The expression levels of HOXA11-AS, let-7c-5p, and IGF2BP1 were evaluated in LUAD tissue and cell lines. Subcellular fractionation detection assay was adopted to verify the HOXA11-AS distribution in LUAD cells. The interaction relationship between let-7c-5p and HOXA11-AS or IGF2BP1 was validated by dual-luciferase reporter detection. In RNA binding protein immunoprecipitation assay, the binding relationship between HOXA11-AS and let-7c-5p was identified. The cell viability of transfected cells was tested by the Cell Counting Kit-8 assay. The mouse xenograft model was used to identify the effect of HOXA11-AS on tumor growth in vivo.

Results: Upregulation of lncRNA HOXA11-AS was found in LUAD, and suppression of HOXA11-AS could suppress the proliferative ability of LUAD cells. The let-7c-5p was expressed to be downregulated, which played an inhibitory role in LUAD cell proliferation. Let-7c-5p was negatively regulated by HOXA11-AS. HOXA11-AS promoted LUAD cell proliferation, while let-7c-5p had an inverse effect. Besides, IGF2BP1, regulated by let-7c-5p, had a positive relation with HOXA11-AS, while overexpression of IGF2BP1 could suppress the inhibition of silencing HOXA11-AS on LUAD cell proliferation. Experiments on mice confirmed that HOXA11-AS facilitated LUAD cell growth in vivo through regulating the let-7c-5p/IGF2BP1 axis.

Conclusion: HOXA11-AS promoted LUAD cell proliferation by targeting let-7c-5p/IGF2BP1, which could be potential molecular targets for LUAD.
Model-Based Meta-Analysis on the Efficacy of Biologics and Small Targeted Molecules for Crohn’s Disease
Authors: Yu Boran , Zhao Libo , Jin Siyao , He Huan , Zhang Jing , Wang Xiaoling
Published: March 2022

Information on comparative drug efficacy is of great importance for drug development as well as clinical practice. Up to now, the relative efficacy of biologics and small targeted molecules for Crohn’s disease (CD) remains unclear. The objective of this study was to quantify the relative efficacy of investigational and approved biological treatments for CD measured in Crohn’s Disease Activity Index (CDAI), Inflammatory Bowel Disease Questionnaire (IBDQ), and C-reactive protein (CRP). The analysis dataset was composed of summary-level data from 46 trials, containing 12,846 patients, with treatment of 24 drugs. Six mathematical models with non-parametric placebo estimations were developed to describe the time course and dose–response of six efficacy measures. The effects of covariate were further evaluated. Time–response relationships were found in outcomes measured in CDAI. The patients’ age, disease duration, baseline CDAI, and CRP showed an impact on the efficacy. Model simulations were performed to compare the efficacies across different drugs. The most achievement in clinical remission (defined as CDAI less than 150) and clinical response (defined as the reduction in CDAI for 100 or 70) was observed in the simulation for PF-04236921 and infliximab, respectively. The most improvement in IBDQ was shown in tofacitinib. In general, tumor necrosis factor (TNF)-α inhibitors were the most effective biologics, and the highest efficacy of small targeted molecules was observed in janus kinase (JAK) inhibitors. These findings have important implications for clinical practice in CD.
Case Report: Severe Rhabdomyolysis and Multiorgan Failure After ChAdOx1 nCoV-19 Vaccination
Authors: Cirillo Emilia , Esposito Ciro , Giardino Giuliana , Azan Gaetano , Fecarotta Simona , Pittaluga Stefania , Ruggiero Lucia , Barretta Ferdinando , Frisso Giulia , Notarangelo Luigi Daniele , Pignata Claudio
Published: March 2022

Background

Severe skeletal muscle damage has been recently reported in patients with SARS-CoV-2 infection and as a rare vaccination complication.

Case summary

On Apr 28, 2021 a 68-year-old man who was previously healthy presented with an extremely severe rhabdomyolysis that occurred nine days following the first dose of SARS-CoV-2 ChAdOx1 nCov-19 vaccination. He had no risk factors, and denied any further assumption of drugs except for fermented red rice, and berberine supplement. The clinical scenario was complicated by a multi organ failure involving bone marrow, liver, lung, and kidney. For the rapid increase of the inflammatory markers, a cytokine storm was suspected and multi-target biologic immunosuppressive therapy was started, consisting of steroids, anakinra, and eculizumab, which was initially successful resulting in close to normal values of creatine phosphokinase after 17 days of treatment. Unfortunately, 48 days after the vaccination an accelerated phase of deterioration, characterized by severe multi-lineage cytopenia, untreatable hypotensive shock, hypoglycemia, and dramatic increase of procalcitonin (PCT), led to patient death.

Conclusion

Physicians should be aware that severe and fatal rhabdomyolysis may occur after SARS-CoV2 vaccine administration.
AC-X: Characteristic Antinuclear Antibody Patterns of Two Anti-Mi-2 Autoantibody-Positive Dermatomyositis Patients—A Case Report
Authors: Wu Ziyan , Xu Honglin , Zhang Shulan
Published: March 2022

Here we reported two anti-Mi-2 autoantibody-positive dermatomyositis (DM) patients with a characteristic antinuclear antibody (ANA) immunofluorescence pattern. Autoantibodes were screened by indirect immunofluorescence (IIF) on HEp-2 cells (Euroimmun, Lübeck, Germany) and confirmed by line immunoblot (ANA Profile 3—Euroimmun, Germany). These two patients were positive for ANA (speckled, titer 1:320), followed by confirmation of positive anti-Mi-2α and anti-Mi-2β positive and negative for all other antibodies. We found a characteristic ANA pattern of the anti-Mi-2 antibody that differed from the AC-4 pattern, especially in the morphology of mitotic cells (metaphase, anaphase, and telophase). Thus, we would like to suggest reporting this characteristic antinuclear antibody pattern as a new AC type, as AC-X.
Role of Interleukin-17A in the Pathomechanisms of Periodontitis and Related Systemic Chronic Inflammatory Diseases
Authors: Feng Yi , Chen Zheng , Tu Shao-Qin , Wei Jia-Ming , Hou Yu-Luan , Kuang Zhi-Li , Kang Xiao-Ning , Ai Hong
Published: March 2022

Periodontitis is a chronic inflammatory and destructive disease caused by periodontal microbial infection and mediated by host immune response. As the main cause of loosening and loss of teeth in adults, it is considered to be one of the most common and serious oral diseases in the world. The co-existence of periodontitis and systemic chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, diabetes and so on is very common. It has been found that interleukin-17A (IL-17A) secreted by various innate and adaptive immune cells can activate a series of inflammatory cascade reactions, which mediates the occurrence and development of periodontitis and related systemic chronic inflammatory diseases. In this work, we review the role of IL-17A in the pathomechanisms of periodontitis and related systemic chronic inflammatory diseases, and briefly discuss the therapeutic potential of cytokine targeted agents that modulate the IL-17A signaling. A deep understanding of the possible molecular mechanisms in the relationship between periodontitis and systemic diseases will help dentists and physicians update their clinical diagnosis and treatment ideas.
Comparison of Efficacy and Safety Between Standard, Accelerated Epithelium-Off and Transepithelial Corneal Collagen Crosslinking in Pediatric Keratoconus: A Meta-Analysis
Authors: Li Yuanjun , Lu Ying , Du Kaixuan , Yin Yewei , Hu Tu , Fu Yanyan , Xiang Aiqun , Fu Qiuman , Wu Xiaoying , Wen Dan
Published: March 2022

Purpose

The purpose of the study is to compare the efficacy of standard epithelium-off CXL (SCXL), accelerated epithelium-off CXL (ACXL), and transepithelial crosslinking CXL (TECXL) for pediatric keratoconus.

Methods

A literature search on the efficacy of SCXL, ACXL, and TECXL [including accelerated TECXL (A-TECXL)] for keratoconus patients younger than 18 years was conducted using PubMed, Cochrane Library, ClinicalTrials.gov, and EMBASE up to 2021. Primary outcomes were changes in uncorrected visual acuity (UCVA) and maximum keratometry (Kmax) after CXL. Secondary outcomes were changes in best-corrected visual acuity (BCVA), mean refractive spherical equivalent (MRSE), and central corneal thickness (CCT). Estimations were analyzed by weighted mean difference (WMD) and 95% confidence interval (CI).

Results

A number of eleven identified studies enrolled 888 eyes (SCXL: 407 eyes; ACXL: 297 eyes; TECXL: 28 eyes; A-TECXL: 156 eyes). For pediatric keratoconus, except for a significant greater improvement in BCVA at 24-month follow-up in SCXL (WMD = –0.08, 95%CI: –0.14 to –0.01, p = 0.03, I2 = 71%), no significant difference was observed in other outcomes between the SCXL and ACXL groups. SCXL seems to provide greater changes in UCVA (WMD = –0.24, 95% CI: –0.34 to –0.13, p < 0.00001, I2 = 89%), BCVA (WMD = –0.09, 95% CI: –0.15 to –0.04, p = 0.0008, I2 = 94%), and Kmax (WMD = –1.93, 95% CI: –3.02 to –0.85, p = 0.0005, I2 = 0%) than A-TECXL, with higher incidence of adverse events.

Conclusion

For pediatric keratoconus, both SCXL and ACXL appear to be comparable in the efficacy of visual effects and keratometric outcomes; SCXL seems to provide greater changes in visual and pachymetric outcomes than A-TECXL.
The Discovery, Validation, and Function of Hypoxia-Related Gene Biomarkers for Obstructive Sleep Apnea
Authors: Wu Xiaofeng , Pan Zhou , Liu Wei , Zha Shiqian , Song Yan , Zhang Qingfeng , Hu Ke
Published: March 2022

While there is emerging evidence that hypoxia critically contributes to the pathobiology of obstructive sleep apnea (OSA), the diagnostic value of measuring hypoxia or its surrogates in OSA remains unclear. Here we investigated the diagnostic value of hypoxia-related genes and explored their potential molecular mechanisms of action in OSA. Expression data from OSA and control subjects were downloaded from the Gene Expression Omnibus database. Differentially-expressed genes (DEGs) between OSA and control subjects were identified using the limma R package and their biological functions investigated with the clusterProfiler R package. Hypoxia-related DEGs in OSA were obtained by overlapping DEGs with hypoxia-related genes. The diagnostic value of hypoxia-related DEGs in OSA was evaluated by receiver operating curve (ROC) analysis. Random forest (RF) and lasso machine learning algorithms were used to construct diagnostic models to distinguish OSA from control. Geneset enrichment analysis (GSEA) was performed to explore pathways related to key hypoxia-related genes in OSA. Sixty-three genes associated with hypoxia, transcriptional regulation, and inflammation were identified as differentially expressed between OSA and control samples. By intersecting these with known hypoxia-related genes, 17 hypoxia-related DEGs related to OSA were identified. Protein-protein interaction network analysis showed that 16 hypoxia-related genes interacted, and their diagnostic value was further explored. The 16 hypoxia-related genes accurately predicted OSA with AUCs >0.7. A lasso model constructed using AREG, ATF3, ZFP36, and DUSP1 had a better performance and accuracy in classifying OSA and control samples compared with an RF model as assessed by multiple metrics. Moreover, GSEA revealed that AREG, ATF3, ZFP36, and DUSP1 may regulate OSA via inflammation and contribute to OSA-related cancer risk. Here we constructed a reliable diagnostic model for OSA based on hypoxia-related genes. Furthermore, these transcriptional changes may contribute to the etiology, pathogenesis, and sequelae of OSA.
Cone Photoreceptors in Diabetic Patients
Authors: Elsner Ann E. , Walker Brittany R. , Gilbert Robert N. , Parimi Vamsi , Papay Joel A. , Gast Thomas J. , Burns Stephen A.
Published: March 2022

Purpose

Cones in diabetic patients are at risk due to metabolic and vascular changes. By imaging retinal vessel modeling at high magnification, we reduced its impact on cone distribution measurements. The retinal vessel images and retinal thickness measurements provided information about cone microenvironment.

Methods

We compared cone data in 10 diabetic subjects (28–78 yr) to our published norms from 36 younger and 10 older controls. All subjects were consented and tested in a manner approved by the Indiana University Institutional Review Board, which adhered to the Declaration of Helsinki. Custom adaptive optics scanning laser ophthalmoscopy (AOSLO) was used to image cones and retinal microcirculation. We counted cones in a montage of foveal and temporal retina, using four non-contiguous samples within 0.9–7 deg that were selected for best visibility of cones and least pathology. The data were fit with a two parameter exponential model: ln(cone density) = a * microns eccentricity + b. These results were compared to retinal thickness measurements from SDOCT.

Results

Diabetic cone maps were more variable than in controls and included patches, or unusually bright and dark cones, centrally and more peripherally. Model parameters and total cones within the central 14 deg of the macula differed across diabetic patients. Total cones fell into two groups: similar to normal for 5 vs. less than normal for 2 of 2 younger diabetic subjects and 3 older subjects, low but not outside the confidence limits. Diabetic subjects had all retinal vascular remodeling to varying degrees: microaneurysms; capillary thickening, thinning, or bends; and vessel elongation including capillary loops, tangles, and collaterals. Yet SD-OCT showed that no diabetic subject had a Total Retinal Thickness in any quadrant that fell outside the confidence limits for controls.

Conclusions

AOSLO images pinpointed widespread retinal vascular remodeling in all diabetic eyes, but the SDOCT showed no increased retinal thickness. Cone reflectivity changes were found in all diabetic patients, but significantly low cone density in only some. These results are consistent with early changes to neural, glial, or vascular components of the retinal without significant retinal thickening due to exudation.
Safety and Efficacy of Spironolactone in Dialysis-Dependent Patients: Meta-Analysis of Randomized Controlled Trials
Authors: Liu Jing , Jia WanYu , Yu Chen
Published: March 2022

Background

Patients with end-stage renal disease (ESRD) are characterized with high risk of heart failure. Although mineralocorticoid receptor antagonists have beneficial effect on relieving cardiac fibrosis and, thus, reduce the incidence of cardiovascular disease and cardiac death, the therapeutic benefits and adverse effects are still controversial. We conducted a meta-analysis to measure the safety and efficacy of spironolactone in patients undergoing dialysis.

Methods

A systematic search for randomized controlled trials (RCTs) was performed in PubMed, Embase, and Cochrane databases. Primary outcomes included changes in all-cause mortality (ACM), serum potassium concentration, incidence of hyperkalemia and gynecomastia (GYN). Secondary outcomes included changes in blood pressure (BP), left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF). Subgroup analysis and sensitivity analysis were further conducted. This research was registered with PROSPERO (International Prospective Register of Systematic Reviews; No. CRD42021287493).

Results

Fifteen RCTs with 1,258 patients were enrolled in this pooled-analysis. Spironolactone treatment significantly decreased ACM (RR = 0.42, P < 0.0001), CCV (RR = 0.54, P = 0.008) and LVMI (MD = −6.28, P = 0.002), also increased occurrence of GYN (RR = 4.36, P = 0.0005). However, LVEF (MD = 2.63, P = 0.05), systolic BP (MD = −4.61, P = 0.14) and diastolic BP (MD = −0.12, P = 0.94) did not change between two groups after treatment. Although serum potassium concentration was increased (MD = 0.22, P < 0.0001) after spironolactone supplement, the risk of hyperkalemia remained unchanged (RR = 1.21, P = 0.31). Further subgroup analysis found more obvious advantageous as well as disadvantageous effects in Asian subjects than European or American ones. Also, with more than 9 months of treatment duration, patients achieved more favorable influence than shorter duration.

Conclusions

These results highlight the therapeutic effects of spironolactone on cardiovascular indexes, including ACM, CCV, and LVMI. However, the unignorable increase of GYN incidence and serum potassium level indicate that close monitor in dialysis-dependent patients, especially Asian patients, is essential.
Age-Associated Risk of Liver-Related Adverse Drug Reactions
Authors: Han Yan-zhong , Guo Yu-ming , Xiong Peng , Ge Fei-lin , Jing Jing , Niu Ming , Zhao Xu , Bai Zhao-fang , Song Hai-bo , Xiao Xiao-he , Wang Jia-bo
Published: March 2022

Objective

Aging population is generally considered more sensitive to adverse drug reactions (ADRs). Yet, big data-based quantitative evidence currently does not exist to support this concept. This study aims to investigate age-associated risks of liver-related ADR (L-ADR).

Methods

Spontaneous reporting data from 2012 to 2016 were retrieved from the China National ADR Monitoring System. The risk ratio (RR) was used to quantify the relative risk of L-ADR of each age group. The reporting odds ratio (ROR) was used to quantify the correlation with the risk of L-ADR of each drug category or drug in older adults.

Results

Totally, 64,702 L-ADR reports were retrieved, covering ages from 1 to 116, with a median age of 49. The RR values increased exponentially with the increase of age, which indicates that the relative risk of L-ADR increased by 33% for every 10-year increase in age. The age cutoff point for relative high risk of L-ADR was estimated at 52.0 years old (RR = 1). In 17 categories composed of 270 drugs, the top 3 drug categories with a high correlation to the risk of L-ADR in older adults were antiarrhythmic (ROR, 5.75; 95% CI: 4.45–7.42), antilipemic (ROR, 4.77; 95% CI: 4.53–5.02), and antihypertensive (ROR, 2.97; 95% CI: 2.59–3.41).

Conclusions

This research illustrates quantitatively that aging is a potential risk factor for L-ADR, with a 33% increase in relative risk for every 10-year increase in age. Risk management should be addressed for older adults when those drugs with a high correlation to the risk of L-ADR are used.