bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved Posterolateral Lumbar Spinal Fusion Using a Biomimetic, Nanocomposite Scaffold Augmented by Autologous Platelet-Rich Plasma
Authors: Van Eps Jeffrey L. , Fernandez-Moure Joseph S. , Cabrera Fernando J. , Taraballi Francesca , Paradiso Francesca , Minardi Silvia , Wang Xin , Aghdasi Bayan , Tasciotti Ennio , Weiner Bradley K.
Published: August 2021

Remodeling of the human bony skeleton is constantly occurring with up to 10% annual bone volume turnover from osteoclastic and osteoblastic activity. A shift toward resorption can result in osteoporosis and pathologic fractures, while a shift toward deposition is required after traumatic, or surgical injury. Spinal fusion represents one such state, requiring a substantial regenerative response to immobilize adjacent vertebrae through bony union. Autologous bone grafts were used extensively prior to the advent of advanced therapeutics incorporating exogenous growth factors and biomaterials. Besides cost constraints, these applications have demonstrated patient safety concerns. This study evaluated the regenerative ability of a nanostructured, magnesium-doped, hydroxyapatite/type I collagen scaffold (MHA/Coll) augmented by autologous platelet-rich plasma (PRP) in an orthotopic model of posterolateral lumbar spinal fusion. After bilateral decortication, rabbits received either the scaffold alone (Group 1) or scaffold with PRP (Group 2) to the anatomic right side. Bone regeneration and fusion success compared to internal control were assessed by DynaCT with 3-D reconstruction at 2, 4, and 6 weeks postoperatively followed by comparative osteogenic gene expression and representative histopathology. Both groups formed significantly more new bone volume than control, and Group 2 subjects produced significantly more trabecular and cortical bone than Group 1 subjects. Successful fusion was seen in one Group 1 animal (12.5%) and 6/8 Group 2 animals (75%). This enhanced effect by autologous PRP treatment appears to occurviaastounding upregulation of key osteogenic genes. Both groups demonstrated significant gene upregulation compared to vertebral bone controls for all genes. Group 1 averaged 2.21-fold upregulation of RUNX2 gene, 3.20-fold upregulation of SPARC gene, and 3.67-fold upregulation of SPP1 gene. Depending on anatomical subgroup (cranial, mid, caudal scaffold portions), Group 2 had significantly higher average expression of all genes than both control and Group 1–RUNX2 (8.23–19.74 fold), SPARC (18.67–55.44 fold), and SPP1 (46.09–90.65 fold). Our data collectively demonstrate the osteoinductive nature of a nanostructured MHA/Coll scaffold, a beneficial effect of augmentation with autologous PRP, and an ability to achieve clinical fusion when applied together in an orthotopic model. This has implications both for future study and biomedical innovation of bone-forming therapeutics.
Cell-Free Glycoengineering of the Recombinant SARS-CoV-2 Spike Glycoprotein
Authors: Ruhnau Johannes , Grote Valerian , Juarez-Osorio Mariana , Bruder Dunja , Mahour Reza , Rapp Erdmann , Rexer Thomas F. T. , Reichl Udo
Published: August 2021

The baculovirus-insect cell expression system is readily utilized to produce viral glycoproteins for research as well as for subunit vaccines and vaccine candidates, for instance against SARS-CoV-2 infections. However, the glycoforms of recombinant proteins derived from this expression system are inherently different from mammalian cell-derived glycoforms with mainly complex-type N-glycans attached, and the impact of these differences in protein glycosylation on the immunogenicity is severely under investigated. This applies also to the SARS-CoV-2 spike glycoprotein, which is the antigen target of all licensed vaccines and vaccine candidates including virus like particles and subunit vaccines that are variants of the spike protein. Here, we expressed the transmembrane-deleted human β-1,2 N-acetlyglucosamintransferases I and II (MGAT1ΔTM and MGAT2ΔTM) and the β-1,4-galactosyltransferase (GalTΔTM) in E. coli to in-vitro remodel the N-glycans of a recombinant SARS-CoV-2 spike glycoprotein derived from insect cells. In a cell-free sequential one-pot reaction, fucosylated and afucosylated paucimannose-type N-glycans were converted to complex-type galactosylated N-glycans. In the future, this in-vitro glycoengineering approach can be used to efficiently generate a wide range of N-glycans on antigens considered as vaccine candidates for animal trials and preclinical testing to better characterize the impact of N-glycosylation on immunity and to improve the efficacy of protein subunit vaccines.
Critical View of Novel Treatment Strategies for Glioblastoma: Failure and Success of Resistance Mechanisms by Glioblastoma Cells
Authors: Burster Timo , Traut Rebecca , Yermekkyzy Zhanerke , Mayer Katja , Westhoff Mike-Andrew , Bischof Joachim , Knippschild Uwe
Published: August 2021

According to the invasive nature of glioblastoma, which is the most common form of malignant brain tumor, the standard care by surgery, chemo- and radiotherapy is particularly challenging. The presence of glioblastoma stem cells (GSCs) and the surrounding tumor microenvironment protects glioblastoma from recognition by the immune system. Conventional therapy concepts have failed to completely remove glioblastoma cells, which is one major drawback in clinical management of the disease. The use of small molecule inhibitors, immunomodulators, immunotherapy, including peptide and mRNA vaccines, and virotherapy came into focus for the treatment of glioblastoma. Although novel strategies underline the benefit for anti-tumor effectiveness, serious challenges need to be overcome to successfully manage tumorigenesis, indicating the significance of developing new strategies. Therefore, we provide insights into the application of different medications in combination to boost the host immune system to interfere with immune evasion of glioblastoma cells which are promising prerequisites for therapeutic approaches to treat glioblastoma patients.
Pharmacokinetics and Pharmacodynamics of a Novel Virulent Klebsiella Phage Kp_Pokalde_002 in a Mouse Model
Authors: Dhungana Gunaraj , Nepal Roshan , Regmi Madhav , Malla Rajani
Published: August 2021

Phage therapy is one of the most promising alternatives to antibiotics as we face global antibiotic resistance crisis. However, the pharmacokinetics (PK) and pharmacodynamics (PD) of phage therapy are largely unknown. In the present study, we aimed to evaluate the PK/PD of a locally isolated virulent novel øKp_Pokalde_002 (Podoviridae, C1 morphotype) that infects carbapenem-resistantKlebsiella pneumoniae(Kp56) using oral and intraperitoneal (IP) route in a mouse model. The result showed that the øKp_Pokalde_002 rapidly distributed into the systemic circulation within an hourviaboth oral and IP routes. A higher concentration of phage in plasma was found after 4 h (2.3 x 105PFU/ml) and 8 h (7.3 x 104PFU/ml) of administration through IP and oral route, respectively. The phage titer significantly decreased in the blood and other tissues, liver, kidneys, and spleen after 24 h and completely cleared after 72 h of administration. In the Kp56 infection model, the bacterial count significantly decreased in the blood and other organs by 4–7 log10CFU/ml after 24 h of øKp_Pokalde_002 administration. Elimination half-life of øKp_Pokalde_002 was relatively shorter in the presence of host-bacteria Kp56 compared to phage only, suggesting rapid clearance of phage in the presence of susceptible host. Further, administration of the øKp_Pokalde_002 alone in healthy mice (viaIP or oral) did not stimulate pro-inflammatory cytokines (TNF-α and IL-6). Also, treatment with øKp_Pokalde_002 resulted in a significant reduction of pro-inflammatory cytokines (TNF-α and IL-6) caused by bacterial infection, thereby reducing the tissue inflammation. In conclusion, the øKp_Pokalde_002 possess good PK/PD properties and can be considered as a potent therapeutic candidate for future phage therapy in carbapenem-resistantK. pneumoniaeinfections.
Oral Microbiota Composition and Function Changes During Chronic Erythematous Candidiasis
Authors: Lyu Xin , Zheng Hui , Wang Xu , Zhang Heyu , Gao Lu , Xun Zhe , Zhang Qian , He Xuesong , Hua Hong , Yan Zhimin , Chen Feng
Published: August 2021

Oral microbiota is constantly changing with the host state, whereas the oral microbiome of chronic erythematous candidiasis remains poorly understood. The aim of this study was to compare oral microbial signatures and functional profiling between chronic erythematous candidiasis and healthy subjects. Using shotgun metagenomic sequencing, we analyzed the microbiome in 12 chronic erythematous candidiasis, 12 healthy subjects, and 2 chronic erythematous candidiasis cured by antifungal therapy. We found that the salivary microbiota of chronic erythematous candidiasis was significantly different from that of healthy subjects. Among them, Rothia mucilaginosa and Streptococcus mitis were the most abundant disease-enriched species (Mann-Whitney U-test, P < 0.05). In addition, co-occurrence network analysis showed that C. albicans formed densely connected modules with oral bacterial species and was mainly positive connected to Streptococcus species. Furthermore, we investigated the functional potentials of the microbiome and identified a set of microbial marker genes associated with chronic erythematous candidiasis. Some of these genes enriching in chronic erythematous candidiasis are involved in eukaryotic ribosome, putative glutamine transport system, and cytochrome bc1 complex respiratory unit. Altogether, this study revealed the changes of oral microbial composition, the co-occurrence between C. albicans and oral bacteria, as well as the changes of microbial marker genes during chronic erythematous candidiasis, which provides evidence of oral microbiome as a target for the treatment and prevention of chronic erythematous candidiasis.
Characterization of Coxsackievirus A6 Strains Isolated From Children With Hand, Foot, and Mouth Disease
Authors: Liu Hongbo , Zhang Ming , Feng Changzeng , Cong Shanri , Xu Danhan , Sun Hao , Yang Zhaoqing , Ma Shaohui
Published: August 2021

Coxsackievirus A6 (CVA6) is a key pathogen causing hand, foot and mouth disease (HFMD). However, there are currently no specific antiviral drugs or vaccines for treating infections caused by CVA6. In this study, human rhabdomyosarcoma (RD), African green monkey kidney (Vero), and human embryonic lung diploid fibroblast (KMB17) cells were used to isolate CVA6 from 327 anal swab and fecal samples obtained during HFMD monitoring between 2009 and 2017. The VP1 genes of the isolates were sequenced and genotyped, and the biological characteristics of the representative CVA6 strains were analyzed. A total of 37 CVA6 strains of the D3 gene subtypes were isolated from RD cells, all of which belonged to the epidemic strains in mainland China. Using the adaptive culture method, 10 KMB17 cell-adapted strains were obtained; however, no Vero cell-adapted strains were acquired. Among the KMB17 cell-adapted strains, only KYN-A1205 caused disease or partial death in suckling mice, and its virulence was stronger than its RD cell-adapted strain. The pathogenic KYN-A1205 strain caused strong tropism to the muscle tissue and led to pathological changes, including muscle necrosis and nuclear fragmentation in the forelimb and hindlimb. Sequence analysis demonstrated that the KYN-A1205 strain exhibited multiple amino acid mutations after KMB17 cell adaptation. Moreover, it showed strong pathogenicity, good immunogenicity and genetic stability, and could be used as an experimental CVA6 vaccine candidate.
Past, Present, and Future of Multisensory Wearable Technology to Monitor Sleep and Circadian Rhythms
Authors: Lujan Matthew R. , Perez-Pozuelo Ignacio , Grandner Michael A.
Published: August 2021

Movement-based sleep-wake detection devices (i.e., actigraphy devices) were first developed in the early 1970s and have repeatedly been validated against polysomnography, which is considered the “gold-standard” of sleep measurement. Indeed, they have become important tools for objectively inferring sleep in free-living conditions. Standard actigraphy devices are rooted in accelerometry to measure movement and make predictions,viascoring algorithms, as to whether the wearer is in a state of wakefulness or sleep. Two important developments have become incorporated in newer devices. First, additional sensors, including measures of heart rate and heart rate variability and higher resolution movement sensing through triaxial accelerometers, have been introduced to improve upon traditional, movement-based scoring algorithms. Second, these devices have transcended scientific utility and are now being manufactured and distributed to the general public. This review will provide an overview of: (1) the history of actigraphic sleep measurement, (2) the physiological underpinnings of heart rate and heart rate variability measurement in wearables, (3) the refinement and validation of both standard actigraphy and newer, multisensory devices for real-world sleep-wake detection, (4) the practical applications of actigraphy, (5) important limitations of actigraphic measurement, and lastly (6) future directions within the field.
Characteristics of the Precipitation Diurnal Variation and Underlying Mechanisms Over Jiangsu, Eastern China, During Warm Season
Authors: Mu Xiyu , Huang Anning , Wu Yang , Xu Qi , Zheng Yuanyuan , Lin Huijuan , Fang Dexian , Zhang Xindan , Tang Yong , Cai Shuxin
Published: August 2021

Based on the hourly precipitation observed from ∼1800 automatic rain gauges during 2013–2017, characteristics of precipitation diurnal variation and underlying mechanisms over Jiangsu Province, eastern China, during the warm season (May to September) have been revealed in this study. Results show that the precipitation amount (PA), frequency (PF), and intensity (PI) are zonally distributed over Jiangsu. The precipitation shows distinct diurnal cycle and zonal distribution. The large precipitation is located over the southwest side of the Jiangsu section of Yangtze River (JSYR). From midnight to noon, the precipitation expands northeastward, but the precipitation shrinks southeastward from noon to midnight. Meanwhile, the PA is larger during the daytime than that during the nighttime over most Jiangsu. In addition, the PA shows two diurnal peaks, with one in the early morning mainly resulting from the long-duration rainfall and the other in the afternoon resulting from the short-duration rainfall. The total rainfall is largely contributed by the long-duration rainfall. During the whole warm season, water vapor convergence (divergence) and ascending (sinking) movements are consistent, corresponding to the long-duration precipitation diurnal cycles. The contribution of rainfall with long (short) duration to the total rainfall over most areas shows very distinct sub-seasonal variations with a clear decreasing (increasing) trend from pre-Meiyu through Meiyu to post-Meiyu. Among the three subperiods in a warm season, the PA and diurnal cycle of the total rainfall are mostly contributed by those during the Meiyu period. The long-duration precipitation is closely related to the enhancement of the water vapor convergence during the pre-Meiyu period. However, during the Meiyu and post-Meiyu periods, the long-duration precipitation is more consistent with the dynamic lift since the water vapor is abundant. Concluded from the cluster analysis, precipitation spatial distributions are closely associated with the underlying surface, such as the Yangtze River, big cities, Lake Taihu, Lake Hongze, and complex coastal lines. The diurnal variation of the rainfall over different underlying surfaces shows respective diurnal cycle features.
COVID-19 and Obesity: Role of Ectopic Visceral and Epicardial Adipose Tissues in Myocardial Injury
Authors: Lasbleiz Adèle , Gaborit Bénédicte , Soghomonian Astrid , Bartoli Axel , Ancel Patricia , Jacquier Alexis , Dutour Anne
Published: August 2021

In March 2020, the WHO declared coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global pandemic. Obesity was soon identified as a risk factor for poor prognosis, with an increased risk of intensive care admissions and mechanical ventilation, but also of adverse cardiovascular events. Obesity is associated with adipose tissue, chronic low-grade inflammation, and immune dysregulation with hypertrophy and hyperplasia of adipocytes and overexpression of pro-inflammatory cytokines. However, to implement appropriate therapeutic strategies, exact mechanisms must be clarified. The role of white visceral adipose tissue, increased in individuals with obesity, seems important, as a viral reservoir for SARS-CoV-2 via angiotensin-converting enzyme 2 (ACE2) receptors. After infection of host cells, the activation of pro-inflammatory cytokines creates a setting conducive to the “cytokine storm” and macrophage activation syndrome associated with progression to acute respiratory distress syndrome. In obesity, systemic viral spread, entry, and prolonged viral shedding in already inflamed adipose tissue may spur immune responses and subsequent amplification of a cytokine cascade, causing worse outcomes. More precisely, visceral adipose tissue, more than subcutaneous fat, could predict intensive care admission; and lower density of epicardial adipose tissue (EAT) could be associated with worse outcome. EAT, an ectopic adipose tissue that surrounds the myocardium, could fuel COVID-19-induced cardiac injury and myocarditis, and extensive pneumopathy, by strong expression of inflammatory mediators that could diffuse paracrinally through the vascular wall. The purpose of this review is to ascertain what mechanisms may be involved in unfavorable prognosis among COVID-19 patients with obesity, especially cardiovascular events, emphasizing the harmful role of excess ectopic adipose tissue, particularly EAT.
Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis
Authors: Sharan Riti , Singh Dhiraj Kumar , Rengarajan Jyothi , Kaushal Deepak
Published: August 2021

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious disease killer worldwide with 1.4 million TB deaths in 2019. While the majority of infected population maintain an active control of the bacteria, a subset develops active disease leading to mortality. Effective T cell responses are critical to TB immunity with CD4+ and CD8+ T cells being key players of defense. These early cellular responses to TB infection have not yet been studied in-depth in either humans or preclinical animal models. Characterizing early T cell responses in a physiologically relevant preclinical model can provide valuable understanding of the factors that control disease development. We studied Mtb-specific T cell responses in the lung compartment of rhesus macaques infected with either a low- or a high-dose of Mtb CDC1551 via aerosol. Relative to baseline, significantly higher Mtb-specific CD4+IFN-γ+ and TNF-α+ T cell responses were observed in the BAL of low dose infected macaques as early as week 1 post TB infection. The IFN-γ and TNF-a response was delayed to week 3 post infection in Mtb-specific CD4+ and CD8+T cells in the high dose group. The manifestation of earlier T cell responses in the group exposed to the lower Mtb dose suggested a critical role of these cytokines in the antimycobacterial immune cascade, and specifically in the granuloma formation to contain the bacteria. However, a similar increase was not reflected in the CD4+ and CD8+IL-17+ T cells at week 1 post infection in the low dose group. This could be attributed to either a suppression of the IL-17 response or a lack of induction at this early stage of infection. On the contrary, there was a significantly higher IL-17+ response in Mtb-specific CD4+ and CD8+T cells at week 3 in the high dose group. The results clearly demonstrate an early differentiation in the immunity following low dose and high dose infection, largely represented by differences in the IFN-γ and TNF-α response by Mtb-specific T cells in the BAL. This early response to antigen expression by the bacteria could be critical for both bacterial growth control and bacterial containment.
Contaminants and Where to Find Them: Microbiological Quality Control in Axenic Animal Facilities
Authors: Lebeuf Maria , Turgeon Nathalie , Faubert Cynthia , Pleau Alexandre , Robillard Justin , Paradis Éric , Marette André , Duchaine Caroline
Published: August 2021

The use of axenic animal models in experimental research has exponentially grown in the past few years and the most reliable way for confirming their axenic status remains unclear. It is especially the case when using individual ventilated positive-pressure cages such as the Isocage. This type of cage are at a greater risk of contamination and expose animals to a longer handling process leading to more potential stress when opened compared to isolators. The aim of this study was to propose simple ways to detect microbial contaminants with Isocages type isolator resulting by developing, validating and optimizing three different methods (culture, microscopy, and molecular). These three approaches were also testedin situby spiking 21 axenic mice with different microorganisms. Our results suggest that the culture method can be used for feces and surface station (IBS) swabs exclusively (in Brain Heart Infusion for 7 days at 25°C and 37°C in aerobic conditions, and at 30°C in anaerobic conditions), while microscopy (wet mounts) and molecular method (quantitative PCR) were only suitable for fecal matter analyses.In situresults suggests that the culture and molecular methods can detect up to 100% of bacterial contamination events while the microscopy approach generates many erroneous results when not performed by a skilled microscopist.In situresults also suggest that when an axenic mouse is contaminated by a microbial agent, the microorganism will colonize the mouse to such an extent that detection is obvious in 4 days, in average. This report validates simple but complimentary tests that can be used for optimal detection of contaminants in axenic animal facilities using Isocage type isolators.
Modeling Nonlinear Dendritic Processing of Facilitation in a Dragonfly Target-Tracking Neuron
Authors: Bekkouche Bo M. B. , Shoemaker Patrick A. , Fabian Joseph M. , Rigosi Elisa , Wiederman Steven D. , O’Carroll David C.
Published: August 2021

Dragonflies are highly skilled and successful aerial predators that are even capable of selectively attending to one target within a swarm. Detection and tracking of prey is likely to be driven by small target motion detector (STMD) neurons identified from several insect groups. Prior work has shown that dragonfly STMD responses are facilitated by targets moving on a continuous path, enhancing the response gain at the present and predicted future location of targets. In this study, we combined detailed morphological data with computational modeling to test whether a combination of dendritic morphology and nonlinear properties of NMDA receptors could explain these observations. We developed a hybrid computational model of neurons within the dragonfly optic lobe, which integrates numerical and morphological components. The model was able to generate potent facilitation for targets moving on continuous trajectories, including a localized spotlight of maximal sensitivity close to the last seen target location, as also measured during in vivo recordings. The model did not, however, include a mechanism capable of producing a traveling or spreading wave of facilitation. Our data support a strong role for the high dendritic density seen in the dragonfly neuron in enhancing non-linear facilitation. An alternative model based on the morphology of an unrelated type of motion processing neuron from a dipteran fly required more than three times higher synaptic gain in order to elicit similar levels of facilitation, despite having only 20% fewer synapses. Our data support a potential role for NMDA receptors in target tracking and also demonstrate the feasibility of combining biologically plausible dendritic computations with more abstract computational models for basic processing as used in earlier studies.
Widespread Disruptions of White Matter in Familial Multiple Sclerosis: DTI and NODDI Study
Authors: Gharaylou Zeinab , Sahraian Mohammad Ali , Hadjighassem Mahmoudreza , Kohanpour Mohsen , Doosti Rozita , Nahardani Shima , Moghadasi Abdorreza Naser
Published: August 2021

Diffusion tensor imaging (DTI) is a noninvasive, quantitative MRI technique that measures white matter (WM) integrity. Many brain dimensions are heritable, including white matter integrity measured with DTI. Family studies are valuable to provide insights into the interactive effects of non-environmental factors on multiple sclerosis (MS). To examine the contribution of familial factors to the diffusion signals across WM microstructure, we performed DTI and calculated neurite orientation dispersion plus density imaging (NODDI) diffusion parameters in two patient groups comprising familial and sporadic forms of multiple sclerosis and their unaffected relatives. We divided 111 subjects (49 men and 62 women: age range 19–60) into three groups conforming to their MS history. The familial MS group included 30 participants (patients; n = 16, healthy relatives; n = 14). The sporadic group included 41 participants (patients; n = 10, healthy relatives; n = 31). Forty age-matched subjects with no history of MS in their families were defined as the control group. To study white matter integrity, two methods were employed: one for calculating the mean of DTI, FA, and MD parameters on 18 tracts using Tracts Constrained by Underlying Anatomy (TRACULA) and the other for whole brain voxel-based analysis using tract-based spatial statistics (TBSS) on NDI and ODI parameters derived from NODDI and DTI parameters. Voxel-based analysis showed considerable changes in FA, MD, NDI, and ODI in the familial group when compared with the control group, reflecting widespread impairment of white matter in this group. The analysis of 18 tracts with TRACULA revealed increased MD and FA reduction in more tracts (left and right ILF, UNC, and SLFT, forceps major and minor) in familial MS patients vs. the control group. There were no significant differences between the patient groups. We found no consequential changes in healthy relatives of both patient groups in voxel-based and tract analyses. Considering the multifactorial etiology of MS, familial studies are of great importance to clarify the effects of certain predisposing factors on demyelinating brain pathology.
Association of Hearing Acuity and Cognitive Function Among a Low-Income Elderly Population in Rural China: A Population-Based Cross-Sectional Study
Authors: Xu Yi , Li Yan , Guo Dandan , Zhang Xin , Guo Huiying , Cao Hui , Li Xin , Zhang Jing , Tu Jun , Wang Jinghua , Ning Xianjia , Yang Dong
Published: August 2021

Hearing loss is a modifiable risk factor for dementia and cognitive decline. However, the association between cognition and hearing acuity at different frequencies is unknown. We aimed to assess the relationships between hearing acuity at different frequencies with global cognitive function and five domains of cognition among a low-income elderly population in northern rural China. A population-based cross-sectional study was conducted to collect basic information from elderly residents aged 60 years and older in rural areas of Tianjin, China from April 2012 to November 2013. Pure tone averages (PTAs) at different frequencies in the ear with better hearing and Mini-Mental State Examination (MMSE) scores were measured, and the relationships between these variables were assessed. A total of 737 residents aged 60 years or more were enrolled in this study, and the prevalence of hearing impairment was 60.7%. After adjusting for sex, age, education, income, smoking, drinking, systolic blood pressure (SBP), total cholesterol (TC), and low-density lipoprotein cholesterol level (LDL-C), MMSE score and immediate recall score were negatively associated with overall PTA (OPTA) at four frequencies (0.5, 1, 2, and 4 kHz), PTA at low frequencies (LPTA; 0.5, 1, and 2 kHz), and PTA at high frequencies (HPTA; 3, 4, and 8 kHz) in the ear with better hearing. Moreover, orientation score was negatively associated with OPTA and LPTA, and the attention and calculation scores were negatively associated with OPTA and HPTA. Each 10-dB increase in OPTA was associated with a MMSE score decrease of 0.464. Each 10-dB increase in LPTA or HPTA was associated with a MMSE score decrease of 0.441 (95% CI: −0.795, −0.086) and 0.351 (95% CI: −0.592, −0.110), respectively. The present study demonstrated significant but weak relationships between OPTA, LPTA, and HPTA with global cognitive function, as defined using MMSE scores; these relationships were independent of age, education, lifestyle factors, and laboratory test values. These results indicated that hearing was associated with cognitive decline among older individuals, who should be screened routinely to identify risk for cognitive decline.
Mainstreaming Local Food Species for Nutritional and Livelihood Security: Insights From Traditional Food Systems of Adi Community of Arunachal Pradesh, India
Authors: Singh Ranjay K. , Bhardwaj Rakesh , Singh Anamika , Payum Temin , Rai Arvind K. , Singh Anshuman , Wangchu Lobsang , Upadhyay Sanjay
Published: August 2021

This study brings out the critical role of lesser-known local plant species in the food, nutrition and livelihood security of Adi community in Arunachal Pradesh, India. Considering women as a major custodian in knowledge and practices on foods, a total of 90 Adi women and 60 key knowledgeable community members (thus a total of 150 participants) were selected from East Siang and Upper Siang districts of Arunachal Pradesh. Data were collected using combination of methods including recipe contest, focus group discussion, personal interviews and laboratory analyses. The results indicated that Adi women were able to identify 39 bioculturally important species from a range of locally available plant species. Used alone or with other foods, these plants remain central to the Adi people's cultural identity and livelihood security. In addition to improving food and nutritional security, these species accessed from different land use systems, are also sold on the local markets to generate decent incomes. Of the species identified by Adi women, 28 were culturally shared and used frequently in food and ethnomedicine. Laboratory analyses of the selected 22 species revealed exceptionally high levels of minerals and other nutrients, such as proteins and anti-oxidants, supporting their traditional use for health benefits. Our study results provide valuable insights to the researchers to explore the vast hidden potential of these and other similar species for improving nutritional well-being of local communities in marginal areas. Adequate policy support is needed to enable Adi and other such marginalized communities to cope with challenges being posed to traditional food systems.
Longitudinal Changes in CT Body Composition in Patients Undergoing Surgery for Colorectal Cancer and Associations With Peri-Operative Clinicopathological Characteristics
Authors: Dolan Ross D. , Abbass Tanvir , Sim Wei M. J. , Almasaudi Arwa S. , Dieu Ly B. , Horgan Paul G. , McSorley Stephen T. , McMillan Donald C.
Published: August 2021

There is evidence for the direct association between body composition, the magnitude of the systemic inflammatory response, and outcomes in patients with colorectal cancer. Patients with a primary operable disease with and without follow-up CT scans were examined in this study. CT scans were used to define the presence and changes in subcutaneous fat, visceral fat, skeletal muscle mass, and skeletal muscle density (SMD). In total, 804 patients had follow-up scans and 83 patients did not. Furthermore, 783 (97%) patients with follow-up scans and 60 (72%) patients without follow-up scans were alive at 1 year. Patients with follow-up scans were younger (p < 0.001), had a lower American Society of Anaesthesiology Grade (p < 0.01), underwent a laparoscopic surgery (p < 0.05), had a higher BMI (p < 0.05), a higher skeletal muscle index (SMI) (p < 0.01), a higher SMD (p < 0.01), and a better 1-year survival (p < 0.001). Overall only 20% of the patients showed changes in their SMI (n = 161) and an even lower percentage of patients showed relative changes of 10% (n = 82) or more. In conclusion, over the period of ~12 months, a low–skeletal muscle mass was associated with a systemic inflammatory response and was largely maintained following surgical resection.
Downregulation of miR-181b-5p Inhibits the Viability, Migration, and Glycolysis of Gallbladder Cancer by Upregulating PDHX Under Hypoxia
Authors: Qin Yiyu , Zheng Yongliang , Huang Cheng , Li Yuanyuan , Gu Min , Wu Qin
Published: August 2021

Background

Gallbladder cancer (GBC) is a malignant cancer with poor prognosis. Evidences have shown that miRNAs are closely related to the occurrence of GBC; thus, we aimed to explore miRNAs, which plays an important role in the occurrence and development of GBC.

Methods

Microarray analysis was performed to investigate the differentially expressed miRNAs between five non-neoplastic gallbladder tissues (normal tissues) and five gallbladder tumor tissues (tumor tissues). RT-qPCR was performed to detect the level of miR-181b-5p in cells, and CCK-8 was performed to detect cell viability. Then, glucose assay kit or lactic acid assay kit was performed to detect the level of glucose consumption or lactate production. Next, transwell and wound healing assays were used to assess cell migration. In addition, dual-luciferase reporter assay was used to verify the relationship between miR-181b-5p and PDHX. At last, Western blotting was performed to determine the protein level of PDHX.

Results

Microarray analysis suggested miR-181b-5p was significantly upregulated in GBC tumor tissue. KEGG analysis for the protein targets of miR-181b-5p indicates a close relationship existed between miR-181b-5p and glycolysis. In addition, the level of miR-181b-5p was notably increased in GBC-SD or G415 cells, compared with HIBEpiC cells. GBC cell viability was significantly decreased under hypoxia, and these decreases were exacerbated by miR-181b-5p antagomir. Moreover, glucose consumption or lactate production of GBC cells was significantly upregulated under hypoxia, whereas these increases were completely revered by miR-181b-5p antagomir. Further investigation revealed that PDHX was a direct target of miR-181b-5p.

Conclusion

In this study, downregulation of miR-181b-5p inhibits the viability, migration, and glycolysis of GBC by upregulating PDHX under hypoxia. This finding suggested that miR-181b-5p might be considered as a novel therapeutic target for the treatment of GBC.
Ultrasound Elastography for the Evaluation of Lymph Nodes
Authors: Wang Bin , Guo Qi , Wang Jia-Yu , Yu Yang , Yi Ai-Jiao , Cui Xin-Wu , Dietrich Christoph F.
Published: August 2021

The differential diagnosis of lymphadenopathy is important for predicting prognosis, staging, and monitoring the treatment, especially for cancer patients. Conventional computed tomography and magnetic resonance imaging characterize lymph node (LN) with disappointing sensitivity and specificity. Conventional ultrasound with the advantage of high resolution has been widely used for the LN evaluation. Ultrasound elastography (UE) using color map or shear wave velocity can non-invasively demonstrate the stiffness and homogeneity of both the cortex and medulla of LNs and can detect early circumscribed malignant infiltration. There is a need of a review to comprehensively discuss the current knowledge of the applications of various UE techniques in the evaluation of LNs. In this review, we discussed the principles of strain elastography and shear wave-based elastography, and their advantages and limitations in the evaluation of LNs. In addition, we comprehensively introduced the applications of various UE techniques in the differential diagnosis of reactive LNs, lymphoma, metastatic LNs, and other lymphadenopathy. Moreover, the applications of endoscopic UE and endobronchial UE are also discussed, including their use for improving the positive rate of diagnosis of fine-needle aspiration biopsy.
Immune Check Point Inhibitors in Primary Cutaneous T-Cell Lymphomas: Biologic Rationale, Clinical Results and Future Perspectives
Authors: Roccuzzo Gabriele , Giordano Silvia , Fava Paolo , Pileri Alessandro , Guglielmo Alba , Tonella Luca , Sanlorenzo Martina , Ribero Simone , Fierro Maria Teresa , Quaglino Pietro
Published: August 2021

Primary cutaneous T-cell lymphomas (PCTCL) are the most common types of cutaneous lymphomas, with Mycosis fungoides as the most frequent subtype. Besides early stages which usually have a good prognosis, advanced stages remain a great therapeutic challenge with low survival rates. To date, none of the currently available therapeutic options have significantly improved the outcomes of advanced cutaneous lymphomas. Recent studies have demonstrated that immune-checkpoint molecules, such as PD-1 and CTLA-4, play part in the proliferation pathways of neoplastic T-cells, as well as in other tumors. Hence, the potential role of immune-checkpoint-inhibitors in treating cutaneous lymphomas has been investigated in the last years. Herein, we outline the current knowledge regarding the role of immune-checkpoint molecules in PCTCL, their signaling pathways, microenvironment and therapeutic inhibition rationale. Moreover, we review the published data on immunotherapies in PCTCL and summarize the currently ongoing clinical trials in this field.
Higher Serum Lysophosphatidic Acids Predict Left Ventricular Reverse Remodeling in Pediatric Dilated Cardiomyopathy
Authors: Wen Haichu , You Hongzhao , Li Yulin , Ma Ke , Jiao Meng , Wu Shaowei , You Shijie , Huang Jie , Su Junwu , Gu Yan , Wang Zhiyuan , Zheng Ping , Shui Guanghou , Wang Yuan , Jin Mei , Du Jie
Published: August 2021

Background: The prognosis of pediatric dilated cardiomyopathy (PDCM) is highly variable, ranging from death to cardiac function recovery. Left ventricular reverse remodeling (LVRR) represents a favorable prognosis in PDCM. Disturbance of lipid metabolism is associated with the change of cardiac function, but no studies have examined lipidomics data and LVRR.

Methods: Discovery analyses were based on 540 targeted lipids in an observational, prospective China—AOCC (An Integrative-Omics Study of Cardiomyopathy Patients for Diagnosis and Prognosis in China) study. The OPLS-DA and random forest (RF) analysis were used to screen the candidate lipids. Associations of the candidate lipids were examined in Cox proportional hazards regression models. Furthermore, we developed a risk score comprising the significant lipids, with each attributed a score of 1 when the concentration was above the median. All significant findings were replicated in a validation set of the China-AOCC study.

Results: There were 59 patients in the discovery set and 24 patients in the validation set. LVRR was observed in 27 patients (32.5%). After adjusting for age, left ventricular ejection fraction (LVEF), and left ventricular end-diastolic dimension (LVEDD) z-score, lysophosphatidic acids (LysoPA) 16:0, LysoPA 18:2, LysoPA 18:1, and LysoPA 18:0 were significantly associated with LVRR in the discovery set, and hazard ratios (HRs) were 2.793 (95% CI, 1.545–5.048), 2.812 (95% CI, 1.542–5.128), 2.831 (95% CI, 1.555–5.154), and 2.782 (95% CI, 1.548-5.002), respectively. We developed a LysoPA score comprising the four LysoPA. When the LysoPA score reached 4, LVRR was more likely to be observed in both sets. The AUC increased with the addition of the LysoPA score to the LVEDD z-score (from 0.693 to 0.875 in the discovery set, from 0.708 to 0.854 in the validation set) for prediction of LVRR.

Conclusions: Serum LysoPA can predict LVRR in PDCM patients. When the LysoPA score was combined with the LVEDD z-score, it may help in ascertaining the prognosis and monitoring effects of anti-heart failure pharmacotherapy.
Early Prediction of Multiple Organ Dysfunction in the Pediatric Intensive Care Unit
Authors: Bose Sanjukta N. , Greenstein Joseph L. , Fackler James C. , Sarma Sridevi V. , Winslow Raimond L. , Bembea Melania M.
Published: August 2021

Objective:The objective of the study is to build models for early prediction of risk for developing multiple organ dysfunction (MOD) in pediatric intensive care unit (PICU) patients.

Design:The design of the study is a retrospective observational cohort study.

Setting:The setting of the study is at a single academic PICU at the Johns Hopkins Hospital, Baltimore, MD.

Patients:The patients included in the study were <18 years of age admitted to the PICU between July 2014 and October 2015.

Measurements and main results:Organ dysfunction labels were generated every minute from preceding 24-h time windows using the International Pediatric Sepsis Consensus Conference (IPSCC) and Proulx et al. MOD criteria. Early MOD prediction models were built using four machine learning methods: random forest, XGBoost, GLMBoost, and Lasso-GLM. An optimal threshold learned from training data was used to detect high-risk alert events (HRAs). The early prediction models from all methods achieved an area under the receiver operating characteristics curve ≥0.91 for both IPSCC and Proulx criteria. The best performance in terms of maximum F1-score was achieved with random forest (sensitivity: 0.72, positive predictive value: 0.70, F1-score: 0.71) and XGBoost (sensitivity: 0.8, positive predictive value: 0.81, F1-score: 0.81) for IPSCC and Proulx criteria, respectively. The median early warning time was 22.7 h for random forest and 37 h for XGBoost models for IPSCC and Proulx criteria, respectively. Applying spectral clustering on risk-score trajectories over 24 h following early warning provided a high-risk group with ≥0.93 positive predictive value.

Conclusions:Early predictions from risk-based patient monitoring could provide more than 22 h of lead time for MOD onset, with ≥0.93 positive predictive value for a high-risk group identified pre-MOD.
Drug-Related Problems of Patients in Primary Health Care Institutions: A Systematic Review
Authors: Ni Xiao-Feng , Yang Chun-Song , Bai Yu-Mei , Hu Zi-Xian , Zhang Ling-Li
Published: August 2021

Introduction: Drug-related problems (DRPs) are not only detrimental to patients' physical health and quality of life but also lead to a serious waste of health care resources. The condition of DRPs might be more severe for patients in primary health care institutions.

Objective: This systematic review aims to comprehensively review the characteristics of DRPs for patients in primary health care institutions, which might help find effective strategies to identify, prevent, and intervene with DRPs in the future.

Methods: We searched three English databases (Embase, The Cochrane Library, and PubMed) and four Chinese databases (CNKI, CBM, VIP, and Wanfang). Two of the researchers independently conducted literature screening, quality evaluation, and data extraction. Qualitative and quantitative methods were combined to analyze the data.

Results: From the 3,368 articles screened, 27 met the inclusion criteria and were included in this review. The median (inter-quartile range, IQR) of the incidences of DRPs was 70.04% (59%), and the median (IQR) of the average number of DRPs per patient was 3.4 (2.8). The most common type of DRPs was “treatment safety.” The causes of DRPs were mainly in the prescribing section, including “drug selection” and “dose selection”, while patients' poor adherence in the use section was also an important cause of DRPs. Risk factors such as the number of medicines, age, and disease condition were positively associated with the occurrence of DRPs. In addition, the medians (IQR) of the rate of accepted interventions, implemented interventions, and solved DRPs were 78.8% (22.3%), 64.15% (16.85%), and 76.99% (26.09%), respectively.

Conclusion: This systematic review showed that the condition of DRPs in primary health care institutions was serious. In pharmaceutical practice, the patients with risk factors of DRPs should be monitored more closely. Pharmacists could play important roles in the identification and intervention of DRPs, and more effective intervention strategies need to be established in the future.
Comparison Between Decitabine and Azacitidine for Patients With Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndrome: A Systematic Review and Network Meta-Analysis
Authors: Ma Jiale , Ge Zheng
Published: August 2021

Background: The hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) have been widely used in patients with acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (HR-MDS). However, few direct clinical trials have been carried out to compare the efficacy and adverse events (AEs) between these two agents. The clinical choice between them is controversial. A systematic review and network meta-analysis (NMA) was performed to compare the efficacy, safety, and survival of DAC and AZA in AML and HR-MDS patients.

Methods: We systematically searched MEDLINE, Embase, Web of Science, and Cochrane Library through March 15, 2021. Randomized controlled trials (RCTs) on AML or HR-MDS patients comparing the efficacy and safety between DAC and AZA or comparing one of HMAs to conventional care regimens (CCR) were selected.

Results: Eight RCTs (n = 2,184) were identified in the NMA. Four trials compared AZA to CCR, and four compared DAC to CCR. Direct comparisons indicated that, compared to CCR, both AZA and DAC were associated with higher overall response (OR) rate (AZA vs. CCR: relative risk (RR) = 1.48, 95% CI 1.05–2.1; DAC vs. CCR: RR = 2.14, 95% CI 1.21–3.79) and longer overall survival (OS) (AZA vs. CCR: HR = 0.64, 95% CI 0.50–0.82; DAC vs. CCR: HR = 0.84, 95% CI 0.72–0.98), and AZA showed higher rate of complete remission with incomplete blood count recovery (CRi) (HR = 2.52, 95% CI 1.27–5). For the indirect method, DAC showed a higher complete remission (CR) rate than AZA in patients with both AML (RR = 2.28, 95% CI 1.12–4.65) and MDS (RR = 7.57, 95% CI 1.26–45.54). Additionally, DAC significantly increased the risk of 3/4 grade anemia (RR = 1.61, 95% CI: 1.03–2.51), febrile neutropenia (RR = 4.03, 95% CI: 1.41–11.52), and leukopenia (RR = 3.43, 95% CI 1.64–7.16) compared with AZA. No statistical significance was found for the other studied outcomes.

Conclusion: Compared to CCR, both AZA and DAC can promote outcomes in patients with AML and HR-MDS. DAC showed higher efficacy especially CR rate than AZA (low-certainty evidence), while AZA experienced lower frequent grade 3/4 cytopenia than patients receiving DAC treatment.
Case Report: Low Hematocrit Leading to Tacrolimus Toxicity
Authors: Piletta-Zanin Alexandre , De Mul Aurélie , Rock Nathalie , Lescuyer Pierre , Samer Caroline F. , Rodieux Frédérique
Published: August 2021

Tacrolimus is a calcineurin inhibitor characterized by a narrow therapeutic index and high intra- and inter-individual pharmacokinetic variability. Therapeutic drug monitoring in whole-blood is the standard monitoring procedure. However, tacrolimus extensively binds to erythrocytes, and tacrolimus whole-blood distribution and whole-blood trough concentrations are strongly affected by hematocrit. High whole-blood tacrolimus concentrations at low hematocrit may result in high unbound plasma concentrations and increased toxicity. We present the case of a 16-year-old girl with kidney and liver transplant in whom low concentrations of tacrolimus in the context of low hematocrit led to significant increase in the dosage of tacrolimus and participate, along with a genetic polymorphism of ABCB1, in nephrotoxicity.