bluuebunny/crossref_metadata_2025 huggingface dataset:
Perception of healthcare workers on mobile app-based clinical guideline for the detection and treatment of mental health problems in primary care: a qualitative study in Nepal
Authors: Pokhrel P. , Karmacharya R. , Taylor Salisbury T. , Carswell K. , Kohrt B. A. , Jordans M. J. D. , Lempp H. , Thornicroft G. , Luitel N. P.
Published: January 2021

Background

In recent years, a significant change has taken place in the health care delivery systems due to the availability of smartphones and mobile software applications. The use of mobile technology can help to reduce a number of barriers for mental health care such as providers’ workload, lack of qualified personnel, geographical and attitudinal barriers to seek treatment. This study assessed the perception of Nepali primary healthcare workers about the feasibility, acceptability, and benefits of using a mobile app-based clinical guideline for mental health care.

Method

A qualitative study was conducted in two districts Chitwan and Ramechhap of Nepal with purposively selected medical officers (n = 8) and prescribing primary healthcare workers (n = 35) who were trained in the World Health Organization mental health Gap Action Program Intervention Guide. Semi-structured interviews and focus group discussions were conducted in Nepali, audio recorded, transcribed and translated into English for data analysis. Data were analysed manually using a thematic analysis approach.

Results

The majority of the healthcare workers and medical officers reported a high level of interest, motivation and positive attitudes towards the mobile app-based clinical guidelines for detection and treatment of people with mental disorders in primary care. They respondents suggested that several features and functions should be included in the app: suggestive diagnosis and treatment options; clinical data recording system; sending messages to patients to promote follow-up visits; allow offline functions; minimal typing options and content to be available in Nepali language. The study participants reported that the app could help in bringing uniformity in diagnosis and management of mental disorders across all health facilities, enabling remote supervision, helping verification of health workers’ diagnosis and treatment; and increasing patients’ trust in the treatment. Lack of reliable internet connection in health facilities, possibility of distracting interaction between patient and provider, and confidentiality were the key factors potentially hindering the use of the app.

Conclusion

The suggested functions and features as well as the potential risk factors highlighted by the health workers, will be considered when further developing the mobile app-based clinical guidelines, training modality and materials, and the supervision system.
Palaeoecological differences underlie rare co-occurrence of Miocene European primates
Authors: DeMiguel Daniel , Domingo Laura , Sánchez Israel M. , Casanovas-Vilar Isaac , Robles Josep M. , Alba David M.
Published: January 2021

Background

The two main primate groups recorded throughout the European Miocene, hominoids and pliopithecoids, seldom co-occur. Due to both their rarity and insufficiently understood palaeoecology, it is currently unclear whether the infrequent co-occurrence of these groups is due to sampling bias or reflects different ecological preferences. Here we rely on the densely sampled primate-bearing sequence of Abocador de Can Mata (ACM) in Spain to test whether turnovers in primate assemblages are correlated with palaeoenvironmental changes. We reconstruct dietary evolution through time (ca. 12.6–11.4 Ma), and hence climate and habitat, using tooth-wear patterns and carbon and oxygen isotope compositions of enamel of the ubiquitous musk-deer Micromeryx.

Results

Our results reveal that primate species composition is strongly correlated with distinct environmental phases. Large-bodied hominoids (dryopithecines) are recorded in humid, densely-forested environments on the lowermost portion of the ACM sequence. In contrast, pliopithecoids inhabited less humid, patchy ecosystems, being replaced by dryopithecines and the small-bodied Pliobates toward the top of the series in gallery forests embedded in mosaic environments.

Conclusions

These results support the view that pliopithecoid primates preferred less humid habitats than hominoids, and reveal that differences in behavioural ecology were the main factor underpinning their rare co-occurrence during the European Miocene. Our findings further support that ACM hominoids, like Miocene apes as a whole, inhabited more seasonal environments than extant apes. Finally, this study highlights the importance of high-resolution, local investigations to complement larger-scale analyses and illustrates that continuous and densely sampled fossiliferous sequences are essential for deciphering the complex interplay between biotic and abiotic factors that shaped past diversity.
rs1990622 variant associates with Alzheimer’s disease and regulates TMEM106B expression in human brain tissues
Authors: Hu Yang , Sun Jing-yi , Zhang Yan , Zhang Haihua , Gao Shan , Wang Tao , Han Zhifa , Wang Longcai , Sun Bao-liang , Liu Guiyou
Published: January 2021

Background

It has been well established that the TMEM106B gene rs1990622 variant was a frontotemporal dementia (FTD) risk factor. Until recently, growing evidence highlights the role of TMEM106B in Alzheimer’s disease (AD). However, it remains largely unclear about the role of rs1990622 variant in AD.

Methods

Here, we conducted comprehensive analyses including genetic association study, gene expression analysis, eQTLs analysis, and colocalization analysis. In stage 1, we conducted a genetic association analysis of rs1990622 using large-scale genome-wide association study (GWAS) datasets from International Genomics of Alzheimer’s Project (21,982 AD and 41,944 cognitively normal controls) and UK Biobank (314,278 participants). In stage 2, we performed a gene expression analysis of TMEM106B in 49 different human tissues using the gene expression data in GTEx. In stage 3, we performed an expression quantitative trait loci (eQTLs) analysis using multiple datasets from UKBEC, GTEx, and Mayo RNAseq Study. In stage 4, we performed a colocalization analysis to provide evidence of the AD GWAS and eQTLs pair influencing both AD and the TMEM106B expression at a particular region.

Results

We found (1) rs1990622 variant T allele contributed to AD risk. A sex-specific analysis in UK Biobank further indicated that rs1990622 T allele only contributed to increased AD risk in females, but not in males; (2) TMEM106B showed different expression in different human brain tissues especially high expression in cerebellum; (3) rs1990622 variant could regulate the expression of TMEM106B in human brain tissues, which vary considerably in different disease statuses, the mean ages at death, the percents of females, and the different descents of the selected donors; (4) colocalization analysis provided suggestive evidence that the same variant contributed to AD risk and TMEM106B expression in cerebellum.

Conclusion

Our comprehensive analyses highlighted the role of FTD rs1990622 variant in AD risk. This cross-disease approach may delineate disease-specific and common features, which will be important for both diagnostic and therapeutic development purposes. Meanwhile, these findings highlight the importance to better understand TMEM106B function and dysfunction in the context of normal aging and neurodegenerative diseases.
Cost-effectiveness of GLP-1 receptor agonists versus insulin for the treatment of type 2 diabetes: a real-world study and systematic review
Authors: Yang Chen-Yi , Chen Ying-Ren , Ou Huang-Tz , Kuo Shihchen
Published: January 2021

Background

To conduct a real-word-study-based cost-effectiveness analysis of a GLP-1 receptor agonist (GLP-1RA) versus insulin among type 2 diabetes patients requiring intensified injection therapy and a systematic review of cost-effectiveness studies of GLP-1RAs versus insulin.

Methods

Individual-level analyses incorporating real-world effectiveness and cost data were conducted for a cohort of 1022 propensity-score-matched pairs of GLP-1RA and insulin users from Taiwan’s National Health Insurance Research Database, 2007–2016. Study outcomes included the number needed to treat (NNT) to prevent one case of clinical events, healthcare costs, and cost per case of event prevented. Costs were in 2019 US dollars. Analyses were performed from a third-party payer and healthcare sector perspectives. Structured systematic review procedures were conducted to synthesize updated evidence on the cost-effectiveness of GLP-1RAs versus insulin.

Results

Over a mean follow-up of 2.3 years, the NNT using a GLP-1RA versus insulin to prevent one case of all-cause mortality and hospitalized hypoglycemia was 57 and 30, respectively. Using GLP-1RAs instead of insulin cost US$54,851 and US$29,115 per case of all-cause mortality and hospitalized hypoglycemia prevented, respectively, from the payer perspective, and saved US$19,391 and US$10,293, respectively, from the healthcare sector perspective. Sensitivity analyses showed that the probability of using GLP-1RAs versus insulin being cost-effective for preventing one case of all-cause mortality or hospitalized hypoglycemia ranged from 60 to 100%. The systematic review revealed a cost-effective profile of using GLP-1RAs versus insulin.

Conclusions

Using GLP-1RAs versus insulin for type 2 diabetes patients requiring intensified injection therapy in clinical practice is cost-effective.
Production of biologically active human interleukin-10 by Bifidobacterium bifidum BGN4
Authors: Hong Nayoun , Ku Seockmo , Yuk Kyungjin , Johnston Tony V. , Ji Geun Eog , Park Myeong Soo
Published: January 2021

Background

Bifidobacteriumspp. are representative probiotics that play an important role in the health of their hosts. Among variousBifidobacteriumspp.,B. bifidumBGN4 exhibits relatively high cell adhesion to colonic cells and has been reported to have various in vivo and in vitro bio functionalities (e.g., anti-allergic effect, anti-cancer effect, and modulatory effects on immune cells). Interleukin-10 (IL-10) has emerged as a major suppressor of immune response in macrophages and other antigen presenting cells and plays an essential role in the regulation and resolution of inflammation. In this study, recombinantB. bifidumBGN4 [pBESIL10] was developed to deliver human IL-10 effectively to the intestines.

Results

The vector pBESIL10 was constructed by cloning the human IL-10 gene under agappromoter and signal peptide fromBifidobacteriumspp. into theE. coli-Bifidobacteriumshuttle vector pBES2. The secreted human IL-10 fromB. bifidumBGN4 [pBESIL10] was analyzed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), Western Blotting, and enzyme-linked immunosorbent assay (ELISA). More than 1,473 ± 300 ng/mL (n = 4) of human IL-10 was obtained in the cell free culture supernatant ofB. bifidumBGN4 [pBESIL10]. This productivity is significantly higher than other previously reported human IL-10 level from food grade bacteria. In vitro functional evaluation of the cell free culture supernatant ofB. bifidumBGN4 [pBESIL10] revealed significantly inhibited interleukin-6 (IL-6) production in lipopolysaccharide (LPS)-induced Raw 264.7 cells (n = 6,p < 0.0001) and interleukin-8 (IL-8) production in LPS-induced HT-29 cells (n = 6,p < 0.01) or TNFα-induced HT-29 cells (n = 6,p < 0.001).

Conclusion

B. bifidumBGN4 [pBESIL10] efficiently produces and secretes significant amounts of biologically active human IL-10. The human IL-10 production level in this study is the highest of all human IL-10 production reported to date. Further research should be pursued to evaluateB. bifidumBGN4 [pBESIL10] producing IL-10 as a treatment for various inflammation-related diseases, including inflammatory bowel disease, rheumatoid arthritis, allergic asthma, and cancer immunotherapy.
Efficient whole-cell oxidation of α,β-unsaturated alcohols to α,β-unsaturated aldehydes through the cascade biocatalysis of alcohol dehydrogenase, NADPH oxidase and hemoglobin
Authors: Qiao Yan , Wang Can , Zeng Yin , Wang Tairan , Qiao Jingjing , Lu Chenze , Wang Zhao , Ying Xiangxian
Published: January 2021

Background

α,β-Unsaturated aldehydes are widely used in the organic synthesis of fine chemicals for application in products such as flavoring agents, fragrances and pharmaceuticals. In the selective oxidation of α,β-unsaturated alcohols to the corresponding α,β-unsaturated aldehydes, it remains challenging to overcome poor selectivity, overoxidation and a low atom efficiency in chemical routes.

Results

An E. coli strain coexpressing the NADP+-specific alcohol dehydrogenase YsADH and the oxygen-dependent NADPH oxidase TkNOX was constructed; these components enabled the NADP+ regeneration and catalyzed the oxidation of 100 mM 3-methyl-2-buten-1-ol to 3-methyl-2-butenal with a yield of 21.3%. The oxygen supply was strengthened by introducing the hemoglobin protein VsHGB into recombinant E. coli cells and replacing the atmosphere of the reactor with pure oxygen, which increased the yield to 51.3%. To further improve catalytic performance, the E. coli cells expressing the multifunctional fusion enzyme YsADH-(GSG)-TkNOX-(GSG)-VsHGB were generated, which completely converted 250 mM 3-methyl-2-buten-1-ol to 3-methyl-2-butenal after 8 h of whole-cell oxidation. The reaction conditions for the cascade biocatalysis were optimized, in which supplementation with 0.2 mM FAD and 0.4 mM NADP+ was essential for maintaining high catalytic activity. Finally, the established whole-cell system could serve as a platform for the synthesis of valuable α,β-unsaturated aldehydes through the selective oxidation of various α,β-unsaturated alcohols.

Conclusions

The construction of a strain expressing the fusion enzyme YsADH-(GSG)-TkNOX-(GSG)-VsHGB achieved efficient NADP+ regeneration and the selective oxidation of various α,β-unsaturated alcohols to the corresponding α,β-unsaturated aldehydes. Among the available redox enzymes, the fusion enzyme YsADH-(GSG)-TkNOX-(GSG)-VsHGB has become the most recent successful example to improve catalytic performance in comparison with its separate components.
Long-term efficacy and safety of monotherapy with a single fresh fecal microbiota transplant for recurrent active ulcerative colitis: a prospective randomized pilot study
Authors: Fang Haiming , Fu Lian , Li Xuejun , Lu Chunxia , Su Yuan , Xiong Kangwei , Zhang Lijiu
Published: January 2021

Background

To assess the long-term safety and efficacy of monotherapy with a single fresh fecal microbiota transplant (FMT) for recurrent ulcerative colitis (UC).

Results

Twenty-six eligible patients were enrolled, and 6 patients were excluded. Ultimately, 20 patients were randomized to the FMT group (n = 10) and the control group (n = 10); 80% were females (F/M = 16/4), the mean age was 48 ± 14 years, and the mean duration was 6.4 ± 8.2 years. The mean length of post-FMT follow-up was 19.1 ± 10.1 months (6–38). No statistically significant differences in baseline demographic or clinical characteristics were found between the groups. Ninety percent of patients in the FMT group and 50% of patients in the control group met the primary endpoint at week 8. The Mayo score was significantly decreased compared with that of the control group (n = 10) when reassessed at week 4 (P = 0.001) and week 8 (P = 0.019) after FMT; there was no significant difference 6 months after treatment. The median remission time was 24 months (95% CI 68.26–131.7%) in both the FMT (range 6–38 months) and control groups (range 7–35 months), with no significant difference (P = 0.895). Participants tolerated FMT treatment, and no adverse events occurred during long-term follow-up, with one treatment-related significant adverse event (EBV infection) occurring within 2 weeks after FMT. Stool microbiota composition analysis indicated improved gut microbiota diversity after FMT, with expansion of stool-donor taxa. Bacteroidetes, Firmicutes and Proteobacteria were the dominant bacterial phyla of the gut microbiota in active UC patients. The relative abundance of Bacteroidetes decreased and that of Proteobacteria increased significantly in active UC patients compared with donors, while Firmicutes showed no significant changes. A single fresh FMT could effectively reconstruct the gut microbiota composition in patients with active UC and maintain stability, with increased Bacteroidetes and decreased Proteobacteria abundance. FMT significantly reduced the relative abundance of Escherichia and increased the relative abundance of Prevotella at the genus level. Pyruvate metabolism, glyoxylate and dicarboxylate metabolism, and pantothenate and CoA biosynthesis showed significant differences after transplantation.

Conclusions

Monotherapy with a single fresh FMT is an effective and safe strategy to induce long-term remission without drugs in patients with active UC and may be an alternative induction therapy for recurrent UC or even primary UC.
The causes of holes and loss of physical integrity in long‐lasting insecticidal nets
Authors: Wheldrake Amy , Guillemois Estelle , Arouni Hamidreza , Chetty Vera , Russell Stephen J.
Published: January 2021

Background

Long-lasting insecticidal nets (LLINs) are expected to last for at least 3 years, but whilst this may be achieved from an insecticidal perspective, physical protection is frequently compromised much earlier because of the rapid accumulation of holes during use. To understand why LLINs are so susceptible to loss of physical integrity, thousands of hole damage sites in LLINs retrieved from the field in Africa and Asia were forensically studied to identify the persistent underlying causes.

Methods

A total of 525 LLINs consisting of six different brands from five different countries across Africa and Asia were collected from the field after 1 to 3 years in use. More than 42,000 individual sites of hole damage were analysed based on the morphology and size of each individual hole, aided by optical microscopy (OM) and scanning electron microscopy (SEM). The fracture morphology enabled positive identification of the underlying mechanisms of the damage.

Results

Across all LLINs and geographical settings, mechanical damage is the primary cause of holes and loss of physical integrity in LLINs (63.14% by frequency and 81.52% by area). Snagging is the single most frequent mechanical damage mechanism, whilst the largest sized holes in LLINs result from seam failure and tearing. Abrasion and hole enlargement are also responsible for a progressive loss in the physical integrity of nets. Collectively, these five modes of mechanical damage can be expected to result from normal use of LLINs by households. Evidence of deliberate cutting, burn holes and rodent damage was observed to a lesser degree, which LLINs are not designed to withstand.

Conclusions

Loss of physical integrity in LLINs is an inevitable consequence of using a vector control product that has an inherently low resistance to mechanical damage during normal use. To improve performance, new specifications based on laboratory textile testing is needed, to assess the resistance of LLIN products to the primary causes of mechanical damage when in use, which are snagging, tearing, abrasion and hole enlargement. Seam construction also needs to meet a revised minimum standard to reduce the risk of a rapid loss of physical integrity during use.
Multienzymes activity of metals and metal oxide nanomaterials: applications from biotechnology to medicine and environmental engineering
Authors: Alizadeh Negar , Salimi Abdollah
Published: January 2021

With the rapid advancement and progress of nanotechnology, nanomaterials with enzyme-like catalytic activity have fascinated the remarkable attention of researchers, due to their low cost, high operational stability, adjustable catalytic activity, and ease of recycling and reuse. Nanozymes can catalyze the same reactions as performed by enzymes in nature. In contrast the intrinsic shortcomings of natural enzymes such as high manufacturing cost, low operational stability, production complexity, harsh catalytic conditions and difficulties of recycling, did not limit their wide applications. The broad interest in enzymatic nanomaterial relies on their outstanding properties such as stability, high activity, and rigidity to harsh environments, long-term storage and easy preparation, which make them a convenient substitute instead of the native enzyme. These abilities make the nanozymes suitable for multiple applications in sensing and imaging, tissue engineering, environmental protection, satisfactory tumor diagnostic and therapeutic, because of distinguished properties compared with other artificial enzymes such as high biocompatibility, low toxicity, size dependent catalytic activities, large surface area for further bioconjugation or modification and also smart response to external stimuli. This review summarizes and highlights latest progress in applications of metal and metal oxide nanomaterials with enzyme/multienzyme mimicking activities. We cover the applications of sensing, cancer therapy, water treatment and anti-bacterial efficacy. We also put forward the current challenges and prospects in this research area, hoping to extension of this emerging field. In addition to therapeutic potential of nanozymes for disease prevention, their practical effects in diagnostics, to monitor the presence of SARS-CoV-2 and related biomarkers for future pandemics will be predicted.
Effects of foot massage on relieving pain, anxiety and improving quality of life of patients undergone a cervical spine surgery
Authors: Ren Nana , Yang Guangmin , Ren Xiaofeng , Li Lekun
Published: January 2021

Background

Long-term recovery of patients undergone cervical spine surgery is of paramount importance to improve their quality of life. In this study we aimed to evaluate the effects of foot massage on relieving pain and anxiety of patients with anterior cervical discectomy and fusion (ACDF).

Methods

Enrolled patients undergone ACDF and diagnosed with anxiety disorder at least six months before surgery were treated with 10-min foot massage on a daily basis for four weeks using sweet almond oil. Patients were assessed by neck pain visual analog pain scale (NP-VAS), neck disability index (NDI) and self-rating anxiety scale.

Results

More significant relief in NP-VAS was observed in patients who received foot massage treatment. No significant difference in NDI reduction was seen in patients with or without the treatment. Intervention group demonstrated less anxiety during follow-up (p = 0.021) compared to the control group and more reduction compared to baseline (p = 0.046). In terms of quality of life, while both groups demonstrated improvement in pain relief (p = 0.015 for the intervention group and p = 0.037 for the control group), only the intervention group showed improved mental function (p = 0.031).

Conclusion

This study found that foot massage was effective in alleviating pain and anxiety, while improving quality of life in patients undergone ACDF, indicating that this intervention should be considered in the clinical management of these patients.
Systemic inflammation suppresses spinal respiratory motor plasticity via mechanisms that require serine/threonine protein phosphatase activity
Authors: Tadjalli Arash , Seven Yasin B. , Perim Raphael R. , Mitchell Gordon S.
Published: January 2021

Background

Inflammation undermines multiple forms of neuroplasticity. Although inflammation and its influence on plasticity in multiple neural systems has been extensively studied, its effects on plasticity of neural networks controlling vital life functions, such as breathing, are less understood. In this study, we investigated the signaling mechanisms whereby lipopolysaccharide (LPS)-induced systemic inflammation impairs plasticity within the phrenic motor system—a major spinal respiratory motor pool that drives contractions of the diaphragm muscle. Here, we tested the hypotheses that lipopolysaccharide-induced systemic inflammation (1) blocks phrenic motor plasticity by a mechanism that requires cervical spinal okadaic acid-sensitive serine/threonine protein phosphatase (PP) 1/2A activity and (2) prevents phosphorylation/activation of extracellular signal-regulated kinase 1/2 mitogen activated protein kinase (ERK1/2 MAPK)—a key enzyme necessary for the expression of phrenic motor plasticity.

Methods

To study phrenic motor plasticity, we utilized a well-characterized model for spinal respiratory plasticity called phrenic long-term facilitation (pLTF). pLTF is characterized by a long-lasting, progressive enhancement of inspiratory phrenic nerve motor drive following exposures to moderate acute intermittent hypoxia (mAIH). In anesthetized, vagotomized and mechanically ventilated adult Sprague Dawley rats, we examined the effect of inhibiting cervical spinal serine/threonine PP 1/2A activity on pLTF expression in sham-vehicle and LPS-treated rats. Using immunofluorescence optical density analysis, we compared mAIH-induced phosphorylation/activation of ERK 1/2 MAPK with and without LPS-induced inflammation in identified phrenic motor neurons.

Results

We confirmed that mAIH-induced pLTF is abolished 24 h following low-dose systemic LPS (100 μg/kg, i.p.). Cervical spinal delivery of the PP 1/2A inhibitor, okadaic acid, restored pLTF in LPS-treated rats. LPS also prevented mAIH-induced enhancement in phrenic motor neuron ERK1/2 MAPK phosphorylation. Thus, a likely target for the relevant okadaic acid-sensitive protein phosphatases is ERK1/2 MAPK or its upstream activators.

Conclusions

This study increases our understanding of fundamental mechanisms whereby inflammation disrupts neuroplasticity in a critical population of motor neurons necessary for breathing, and highlights key roles for serine/threonine protein phosphatases and ERK1/2 MAPK kinase in the plasticity of mammalian spinal respiratory motor circuits.
Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis
Authors: Luo Lin , Hu Xianzhen , Dixon Michael L. , Pope Brandon J. , Leavenworth Jonathan D. , Raman Chander , Meador William R. , Leavenworth Jianmei W.
Published: January 2021

Background

Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear.

Methods

To determine the impact of dysregulated regulatory T cells (Tregs), TFR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells.

Results

Mice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased TFH-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE.

Conclusions

Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.
Numerical modeling in arterial hemodynamics incorporating fluid-structure interaction and microcirculation
Authors: He Fan , Hua Lu , Guo Tingting
Published: January 2021

Background

The effects of arterial wall compliance on blood flow have been revealed using fluid-structure interaction in last decades. However, microcirculation is not considered in previous researches. In fact, microcirculation plays a key role in regulating blood flow. Therefore, it is very necessary to involve microcirculation in arterial hemodynamics.

Objective

The main purpose of the present study is to investigate how wall compliance affects the flow characteristics and to establish the comparisons of these flow variables with rigid wall when microcirculation is considered.

Methods

We present numerical modeling in arterial hemodynamics incorporating fluid-structure interaction and microcirculation. A novel outlet boundary condition is employed to prescribe microcirculation in an idealised model.

Results

The novel finding in this work is that wall compliance under the consideration of microcirculation leads to the increase of wall shear stress in contrast to rigid wall, contrary to the traditional result that wall compliance makes wall shear stress decrease when a constant or time dependent pressure is specified at an outlet.

Conclusions

This work provides the valuable study of hemodynamics under physiological and realistic boundary conditions and proves that wall compliance may have a positive impact on wall shear stress based on this model. This methodology in this paper could be used in real model simulations.
Correction to: Required concentration index quantifies effective drug combinations against hepatitis C virus infection
Authors: Kakizoe Yusuke , Koizumi Yoshiki , Ikoma Yukino , Ohashi Hirofumi , Wakita Takaji , Iwami Shingo , Watashi Koichi
Published: January 2021

An amendment to this paper has been published and can be accessed via the original article.
Measuring the paradox of self-stigma: psychometric properties of a brief scale
Authors: Golay Philippe , Moga Mihaela , Devas Celia , Staecheli Mélissa , Poisat Yasmine , Israël Marie , Suter Caroline , Silva Benedetta , Morandi Stéphane , Ferrari Pascale , Favrod Jérôme , Bonsack Charles
Published: January 2021

Background

Exposure to public stigma can lead to stereotype endorsement and resignation, which are constructs related to self-stigma. This latter phenomenon has well-documented deleterious consequences for people living with mental illness. Paradoxically, it can also lead to the empowering reactions of righteous anger and coming out proud.

Aim

The aim of this study was to develop and validate a brief tool to measure stereotype endorsement, righteous anger, and non-disclosure across different groups of stigmatized persons. This process was conducted in collaboration with users.

Method

Using focus groups with mental health professionals and people living with mental illness, 72 items were developed to measure various aspects of self-stigma. The Paradox of Self-Stigma scale (PaSS-24) containing 24 items and three subscores (stereotype endorsement, non-disclosure, and righteous anger) resulted from a calibration phase using factor analysis. This structure was cross-validated on an independent sample. Internal consistency, test–retest reliability, and convergent validity were also evaluated.

Results

202 patients were assessed. The PaSS-24 demonstrated good internal validity. Internal consistency, test–retest reliability, and convergent validity estimates were also good.

Conclusions

The PaSS-24 is a short but psychometrically rigorous tool designed to measure self-stigma and related constructs in French language, developed in collaboration with users. The development and validation of the PaSS-24 represent a first step towards implementing and evaluating programs aimed at reducing negative consequences of self-stigma.
Vulnerable families and costly formula: a qualitative exploration of infant formula purchasing among peri-urban Peruvian households
Authors: Rothstein Jessica D. , Winch Peter J. , Pachas Jessica , Cabrera Lilia Z. , Ochoa Mayra , Gilman Robert H. , Caulfield Laura E.
Published: January 2021

Background

Substantial evidence exists surrounding the health risks of breast milk substitutes (BMS) in place of exclusive breastfeeding among infants < 6 months of age in resource-poor settings. Yet, mothers’ experiences of selecting and purchasing BMS brands have not been well studied to date. This qualitative study explored the factors influencing BMS purchasing practices, along with the consequences of those decisions, in peri-urban Lima, Peru.

Methods

We conducted in-depth interviews (IDIs) with 29 mothers who had begun mixed-feeding their infants during the first 6 months of life. Interviews explored participants’ reasons for initiating infant formula use and their experiences of selecting, purchasing, and providing BMS to their children. Audio recordings were transcribed, coded, and key themes and illustrative vignettes were identified.

Results

The primary reported reasons for initiating infant formula use included having received a recommendation for infant formula from a healthcare provider, concerns about an infant’s weight gain, and the perception of insufficient breast milk. Mothers tended to initially purchase the BMS brand that had been recommended by a doctor, which was often more expensive than the alternatives. The costs of BMS, which escalated as infants grew, often disrupted the household economy and generated significant stress. While some mothers identified alternatives allowing them to continue purchasing the same brand, others chose to switch to less expensive products. Several mothers began to feed their infants follow-on formula or commercial milk, despite their awareness that such practices were not recommended for infants under 6 months of age. The approval of family members and the absence of an infant’s immediate adverse reaction influenced mothers’ decisions to continue purchasing these products.

Conclusions

The high costs of BMS may deepen existing socio-economic vulnerabilities and generate new risks for infant health. The continued dedication of resources towards breastfeeding education and support is critical, and strategies would benefit from underscoring the long-term financial and health consequences of infant formula use, and from strengthening women’s self-efficacy to refuse to initiate infant formula when recommended. In addition, health providers should be trained in counseling to help women to relactate or return to exclusive breastfeeding after cessation.
The lymph node ratio predicts cancer-specific survival of node-positive non-small cell lung cancer patients: a population-based SEER analysis
Authors: Kai Liu , Zhoumiao Chen , Shaohua Xu , Zhao Chen , Zhijun Li , Zhengfu He , Xiujun Cai
Published: January 2021

Background

Lymph node ratio (LNR) has been suggested to be an effective prognostic tool for stratifying non-small cell lung cancer (NSCLC) cases. In this study, we sought to determine cancer-specific survival (CCS) of NSCLC cases from the SEER registry and used the X-tile method to optimize CCS-based LNR cut-off points for prognostic stratification of node-positive NSCLC.

Methods

CSS and other clinicopathologic variables were retrieved from the SEER registry. Kaplan-Meier methods were used to calculate CSS. The optimal cut-off points for LNR classification were determined by the X-tile approach. Multivariate Cox regression analysis was performed to identify independent risks of CSS.

Results

Totally 11,341 lung cancer patients were included. Their median CSS was 22 months (range 0,143). The median LNR was 0.22 (Q1,Q3: 0.11, 0.50). X-tile analysis showed that the optimal LNR cut-off points were 0.28 and 0.81, dividing the cohort into low (LNR1 ≤ 0.28; n = 6580, 58%), middle (0.28 < LNR2 < 0.81; n = 3025, 26.7%), and high (LNR3 > 0.81; n = 1736, 15.3%) subsets. Kaplan-Meier analysis showed that patients with a low LNR had a significantly higher CCS versus patients with middle or high LNR (P < 0.001). Multivariate competing risks regression analysis revealed that LNR was an independent and significant adverse predictor of CSS (LNR2 vs. LNR1: SHR: 1.56, 95%CI: 1.47,1.67, P < 0.001; LNR3 vs. LNR1: SHR: 2.54, 95%CI: 2.30,2.80, P < 0.001).

Conclusions

LNR is an independent prognostic factor of node-positive NSCLC and its optimal cut-off values established using the robust x-tile method effectively define subpopulations of node-positive NSCLC cases, which is important in guiding selection of treatment strategies clinically.
In silico imaging clinical trials: cheaper, faster, better, safer, and more scalable
Authors: Badano Aldo
Published: January 2021

Imaging clinical trials can be burdensome and often delay patient access to novel, high-quality medical devices. Tools for in silico imaging trials have significantly improved in sophistication and availability. Here, I describe some of the principal advantages of in silico imaging trials and enumerate five lessons learned during the design and execution of the first all-in silico virtual imaging clinical trial for regulatory evaluation (the VICTRE study).
Mentoring upcoming researchers for non-communicable diseases’ research and practice in Malawi
Authors: Muula Adamson S. , Hosseinipour Mina C. , Makwero Martha , Kumwenda Johnstone , Lutala Prosper , Mbeba Mary , Rylance Sarah , Mitambo Collins , Nyirenda Moffat
Published: January 2021

The Malawi College of Medicine and its partners are building non-communicable diseases’ (NCDs’) research capacity through a grant from the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health. Several strategies are being implemented including research mentorship for junior researchers interested to build careers in NCDs’ research. In this article, we present the rationale for and our experiences with this mentorship program over its 2 years of implementation. Lessons learned and the challenges are also shared.
The Chinese herbal formula Huoxiang Zhengqi for atopic dermatitis with dampness pattern (CHARM): a study protocol for a double-blinded randomized controlled trial
Authors: Xuan Meiling , Guo Xiaohui , Li Hongyi , Xie Ting , Mo Xiumei , Wen Zehuai
Published: January 2021

Background

Atopic dermatitis (AD) is a complex, common inflammatory skin disease. The Chinese herbal formula Huoxiang Zhengqi (HXZQ) has been a common dermatosis treatment in China for many years, but there is no high-level evidence for its effect on AD/eczema. The aim of this trial is to examine the efficacy and safety of HXZQ treating AD/eczema patients.

Methods

This is a double-blind, multi-center, randomized controlled trial comparing HXZQ to a placebo. It will consist of 4 weeks’ treatment and 4 weeks of follow-up. A total of 218 participants will be randomly allocated into two groups—an HXZQ group and a placebo group, from 7 hospitals in China. Patients diagnosed with AD will be enrolled if they are in accordance with CM dampness pattern, have body surface area (BSA) of 1–10%, have investigator’s global assessment (IGA) of 1–3, have age between 18 and 70 years, and provide signed informed consent. The Eczema Area and Severity Index (EASI) is the primary outcome. The secondary outcomes are the numerical itch rating scale, IGA, BSA, Skindex-29, and EQ-5D-5L score, from baseline to the end of the treatment. Analysis will be on intention-to-treat and per-protocol subject analysis principles.

Discussion

The goal of this trial is to evaluate the efficacy and availability of HXZQ oral liquid in treating AD/eczema in terms of symptoms and eczematous lesions. It will also address whether it has positive effect on QoL.

Trial registration

Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx): Chinese herbal formula Huoxiang Zhengqi for atopic dermatitis with dampness pattern (CHARM): a double-blinded randomized controlled trial, ChiCTR1900026700. Registered on 19 October 2019.
Drug synergy scoring using minimal dose response matrices
Authors: Mäkelä Petri , Zhang Si Min , Rudd Sean G.
Published: January 2021

Objective

Combinations of pharmacological agents are essential for disease control and prevention, offering many advantages over monotherapies, with one of these being drug synergy. The state-of-the-art method to profile drug synergy in preclinical research is by using dose–response matrices in disease-appropriate models, however this approach is frequently labour intensive and cost-ineffective, particularly when performed in a medium- to high-throughput fashion. Thus, in this study, we set out to optimise a parameter of this methodology, determining the minimal matrix size that can be used to robustly detect and quantify synergy between two drugs.

Results

We used a drug matrix reduction workflow that allowed the identification of a minimal drug matrix capable of robustly detecting and quantifying drug synergy. These minimal matrices utilise substantially less reagents and data processing power than their typically used larger counterparts. Focusing on the antileukemic efficacy of the chemotherapy combination of cytarabine and inhibitors of ribonucleotide reductase, we could show that detection and quantification of drug synergy by three common synergy models was well-tolerated despite reducing matrix size from 8 × 8 to 4 × 4. Overall, the optimisation of drug synergy scoring as presented here could inform future medium- to high-throughput drug synergy screening strategies in pre-clinical research.
Development and characterization of thirteen novel microsatellite markers for use in Greenland sharks (Somniosus microcephalus), with cross-amplification in Pacific sleeper sharks (Somniosus pacificus)
Authors: Swintek Meaghan A. , Walter Ryan P.
Published: January 2021

Objective

The objectives of this work are to isolate, develop, and characterize polymorphic microsatellite markers for use in Greenland sharks (Somniosus microcephalus).

Results

Thirteen microsatellite loci were successfully amplified and yielded multi-locus genotypes for 36 S. microcephalus individuals from Grise Fjord (n = 16) and Svalbard (n = 20). Each locus yielded between 2 and 9 alleles and observed heterozygosity ranged from 0.11 to 0.70 when estimated across both sites. One locus and three loci deviated from HWE following Bonferroni correction, for individuals sampled from Grise Fjord and Svalbard, respectively. Cross-amplification was successful at every locus for five of the ten S. pacificus individuals.
Major motor and gait deficits with sexual dimorphism in a Shank3 mutant mouse model
Authors: Matas Emmanuel , Maisterrena Alexandre , Thabault Mathieu , Balado Eric , Francheteau Maureen , Balbous Anais , Galvan Laurie , Jaber Mohamed
Published: January 2021

Background

Contrasting findings were reported in several animal models with a Shank3 mutation used to induce various autism spectrum disorder (ASD) symptoms. Here, we aimed at investigating behavioral, cellular, and molecular consequences of a C-terminal (frameshift in exon 21) deletion in Shank3 protein in mice, a mutation that is also found in clinical conditions and which results in loss of major isoforms of Shank3. A special focus was made on cerebellar related parameters.

Methods

All three genotypes were analyzed [wild type (WT), heterozygote (Shank3+/ΔC) and homozygote (Shank3 ΔC/ΔC)] and males and females were separated into two distinct groups. Motor and social behavior, gait, Purkinje cells (PC) and glutamatergic protein levels were determined. Behavioral and cellular procedures used here were previously validated using two environmental animal models of ASD. ANOVA and post-hoc analysis were used for statistical analysis.

Results

Shank3 ΔC/ΔC mice showed significant impairments in social novelty preference, stereotyped behavior and gait. These were accompanied by a decreased number of PC in restricted cerebellar sub-regions and decreased cerebellar expression of mGluR5. Females Shank3 ΔC/ΔC were less affected by the mutation than males. Shank3+/ΔC mice showed impairments only in social novelty preference, grooming, and decreased mGluR5 expression and that were to a much lesser extent than in Shank3 ΔC/ΔC mice.

Limitations

As Shank3 mutation is a haploinsufficiency, it is of interest to emphasize that Shank3+/ΔC mice showed only mild to no deficiencies compared to Shank3 ΔC/ΔC.

Conclusions

Our findings indicate that several behavioral, cellular, and molecular parameters are affected in this animal model. The reported deficits are more pronounced in males than in females. Additionally, male Shank3 ΔC/ΔC mice show more pronounced alterations than Shank3+/ΔC. Together with our previous findings in two environmental animal models of ASD, our studies indicate that gait dysfunction constitutes a robust set of motor ASD symptoms that may be considered for implementation in clinical settings as an early and quantitative diagnosis criteria.
Human mesenchymal stem cell therapy promotes retinal ganglion cell survival and target reconnection after optic nerve crush in adult rats
Authors: da Silva-Junior Almir Jordão , Mesentier-Louro Louise Alessandra , Nascimento-dos-Santos Gabriel , Teixeira-Pinheiro Leandro Coelho , Vasques Juliana F. , Chimeli-Ormonde Luiza , Bodart-Santos Victor , de Carvalho Luiza Rachel Pinheiro , Santiago Marcelo Felippe , Mendez-Otero Rosalia
Published: January 2021

Background

Optic-nerve injury results in impaired transmission of visual signals to central targets and leads to the death of retinal ganglion cells (RGCs) and irreversible vision loss. Therapies with mesenchymal stem cells (MSCs) from different sources have been used experimentally to increase survival and regeneration of RGCs.

Methods

We investigated the efficacy of human umbilical Wharton’s jelly-derived MSCs (hWJ-MSCs) and their extracellular vesicles (EVs) in a rat model of optic nerve crush.

Results

hWJ-MSCs had a sustained neuroprotective effect on RGCs for 14, 60, and 120 days after optic nerve crush. The same effect was obtained using serum-deprived hWJ-MSCs, whereas transplantation of EVs obtained from those cells was ineffective. Treatment with hWJ-MSCs also promoted axonal regeneration along the optic nerve and reinnervation of visual targets 120 days after crush.

Conclusions

The observations showed that this treatment with human-derived MSCs promoted sustained neuroprotection and regeneration of RGCs after optic nerve injury. These findings highlight the possibility to use cell therapy to preserve neurons and to promote axon regeneration, using a reliable source of human MSCs.