bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapy of chronic hepatitis C in people who inject drugs: focus on adherence
Authors: Frankova Sona , Jandova Zuzana , Jinochova Gabriela , Kreidlova Miluse , Merta Dusan , Sperl Jan
Published: June 2021

Background

Intravenous drug use (IVDU) represents the major factor of HCV transmission, but the treatment uptake among people who inject drugs (PWID) remains low owing to a false presumption of low efficacy. The aim of our study was to assess treatment efficacy in PWID and factors determining adherence to therapy.

Methods

A total of 278 consecutive patients starting DAA (direct-acting antivirals) therapy were included, divided into two groups: individuals with a history of IVDU, PWID group (N = 101) and the control group (N = 177) without a history of IVDU.

Results

Sustained virological response 12 weeks after the end of therapy (SVR12) was achieved by 99/101 (98%) and 172/177 (98%) patients in the PWID and control group, respectively; in PWID group, two patients were lost to follow-up, and in the control group, four patients relapsed and one was lost to follow-up. PWID patients postponed appointments significantly more often, 29 (28.7%) in PWID versus 7 (4%) in the control group, p = 0.001. Thirteen of 101 (12.9%) and six of 177 (3.4%) patients in the PWID and in the control group, respectively, missed at least one visit (p < 0.01). However, postponing visits led to a lack of medication in only one PWID. In the PWID group, older age (p < 0.05; OR 1.07, 95% CI 1.00–1.20) and stable housing (p < 0.01; OR 9.70, 95% CI 2.10–56.20) were factors positively contributing to adherence. Contrarily, a stable job was a factor negatively influencing adherence (p < 0.05; OR 0.24, 95% CI 0.06–0.81). In the control group, none of the analyzed social and demographic factors had an impact on adherence to therapy.

Conclusions

In PWID, treatment efficacy was excellent and was comparable with SVR of the control group. Stable housing and older age contributed to a better adherence to therapy.
STAT3/HIF-1α signaling activation mediates peritoneal fibrosis induced by high glucose
Authors: Yang Xiaoxiao , Bao Manchen , Fang Yi , Yu Xiaofang , Ji Jun , Ding Xiaoqiang
Published: June 2021

Background

Epithelial-mesenchymal transition (EMT) of mesothelial cells is a key step in the peritoneal fibrosis (PF). Recent evidence indicates that signal transducer and activator of transcription 3 (STAT3) might mediate the process of renal fibrosis, which could induce the expression of hypoxia-inducible factor-1α (HIF-1α). Here, we investigated the effect of STAT3 activation on HIF-1α expression and the EMT of mesothelial cells, furthermore the role of pharmacological blockade of STAT3 in the process of PF during peritoneal dialysis (PD) treatment.

Methods

Firstly, we investigated the STAT3 signaling in human peritoneal mesothelial cells (HPMCs) from drained PD effluent. Secondly, we explored the effect of STAT3 signaling activation on the EMT and the expression of HIF-1α in human mesothelial cells (Met-5A) induced by high glucose. Finally, peritoneal fibrosis was induced by daily intraperitoneal injection with peritoneal dialysis fluid (PDF) so as to explore the role of pharmacological blockade of STAT3 in this process.

Results

Compared with the new PD patient, the level of phosphorylated STAT3 was up-regulated in peritoneal mesothelial cells from long-term PD patients. High glucose (60 mmol/L) induced over-expression of Collagen I, Fibronectin, α-SMA and reduced the expression of E-cadherin in Met-5A cells, which could be abrogated by STAT3 inhibitor S3I-201 pretreatment as well as by siRNA for STAT3. Furthermore, high glucose-mediated STAT3 activation in mesothelial cells induced the expression of HIF-1α and the profibrotic effect of STAT3 signaling was alleviated by siRNA for HIF-1α. Daily intraperitoneal injection of high-glucose based dialysis fluid (HG-PDF) induced peritoneal fibrosis in the mice, accompanied by the phosphorylation of STAT3. Immunostaining showed that phosphorylated STAT3 was expressed mostly in α-SMA positive cells in the peritoneal membrane induced by HG-PDF. Administration of S3I-201 prevented the progression of peritoneal fibrosis, angiogenesis, macrophage infiltration as well as the expression of HIF-1α in the peritoneal membrane induced by high glucose.

Conclusions

Taken together, these findings identified a novel mechanism linking STAT3/HIF-1α signaling to peritoneal fibrosis during long-term PD treatment. It provided the first evidence that pharmacological inhibition of STAT3 signaling attenuated high glucose-mediated mesothelial cells EMT as well as peritoneal fibrosis.
Molecular subtype identification and prognosis stratification by a metabolism-related gene expression signature in colorectal cancer
Authors: Lin Dagui , Fan Wenhua , Zhang Rongxin , Zhao Enen , Li Pansong , Zhou Wenhao , Peng Jianhong , Li Liren
Published: June 2021

Background

Metabolic reprograming have been associated with cancer occurrence and progression within the tumor immune microenvironment. However, the prognostic potential of metabolism-related genes in colorectal cancer (CRC) has not been comprehensively studied. Here, we investigated metabolic transcript-related CRC subtypes and relevant immune landscapes, and developed a metabolic risk score (MRS) for survival prediction.

Methods

Metabolism-related genes were collected from the Molecular Signatures Database and metabolic subtypes were identified using an unsupervised clustering algorithm based on the expression profiles of survival-related metabolic genes in GSE39582. The ssGSEA and ESTIMATE methods were applied to estimate the immune infiltration among subtypes. The MRS model was developed using LASSO Cox regression in the GSE39582 dataset and independently validated in the TCGA CRC and GSE17537 datasets.

Results

We identified two metabolism-related subtypes (cluster-A and cluster-B) of CRC based on the expression profiles of 539 survival-related metabolic genes with distinct immune profiles and notably different prognoses. The cluster-B subtype had a shorter OS and RFS than the cluster-A subtype. Eighteen metabolism-related genes that were mostly involved in lipid metabolism pathways were used to build the MRS in GSE39582. Patients with higher MRS had worse prognosis than those with lower MRS (HR 3.45, P < 0.001). The prognostic role of MRS was validated in the TCGA CRC (HR 2.12, P = 0.00017) and GSE17537 datasets (HR 2.67, P = 0.039). Time-dependent receiver operating characteristic curve and stratified analyses revealed the robust predictive ability of the MRS in each dataset. Multivariate Cox regression analysis indicted that the MRS could predict OS independent of TNM stage and age.

Conclusions

Our study provides novel insight into metabolic heterogeneity and its relationship with immune landscape in CRC. The MRS was identified as a robust prognostic marker and may facilitate individualized therapy for CRC patients.
SRPK1/AKT axis promotes oxaliplatin-induced anti-apoptosis via NF-κB activation in colon cancer
Authors: Huang Jing-Qiang , Li He-Feng , Zhu Jing , Song Jun-Wei , Zhang Xian-Bin , Gong Peng , Liu Qiu-Yu , Zhou Chun-Hui , Wang Liang , Gong Li-Yun
Published: June 2021

Background

Colorectal cancer is the third most common diagnosis. Oxaliplatin is used as first-line treatment of colon cancer. However, oxaliplatin resistance greatly reduces its therapeutic effect. SRPK1 involves in pre-mRNA splicing and tumorigenesis. How SRPK1 mediates drug resistance in colon cancer is unknown.

Methods

The expression of SRPK1 was analyzed in the TCGA and the CPTAC pan-cancer samples and detected in colon cancer cell lines and tissues by IHC and western blot. The MTT and TUNEL assay were used to verify the anti-apoptosis ability of colon cancer cell. The activation of NF-κB was determined by luciferase assay and qRT-PCR. AKT, IKK, IκB and their phosphorylation level were verified by western blot.

Results

We found that SRPK1 expression was the second highest in TCGA and the CPTAC pan-cancer samples. The mRNA and protein levels of SRPK1 were increased in tissues from patients with colon cancer. SRPK1 was associated with clinical stage and TNM classifications in 148 cases of colon cancer patients. High SRPK1 levels correlated with poor prognosis (p < 0.001). SRPK1 overexpression enhanced the anti-apoptosis ability of colon cancer cells, whereas SRPK1 silencing had the opposite effect under oxaliplatin treatment. Mechanistically, SRPK1 enhances IKK kinase and IκB phosphorylation to promote NF-κB nuclear translocation to confer oxaliplatin resistance.

Conclusions

Our findings suggest that SRPK1 participates in colon cancer progression and enhances the anti-apoptosis capacity to induce drug resistance in colon cancer cells via NF-κB pathway activation, and thus might be a potential pharmaceutically target for colon cancer treatment.
Association between serum advanced oxidation protein products and mortality risk in maintenance hemodialysis patients
Authors: Zhou Chun , Zhang Yuanyuan , Chen Jianghua , Mei Changlin , Xiong Fei , Shi Wei , Zhou Wei , Liu Xusheng , Sun Shiren , Tian Jianwei , Ye Ziliang , Wu Qimeng , Qin Xianhui , Jiang Jianping , Hou Fan Fan ,   CCSD (China Collaborative Study on Dialysis) group
Published: June 2021

Background

The association between serum advanced oxidation protein products (AOPP) and mortality risk remains equivocal. We aimed to assess the correlation of serum AOPP levels with the risk of all-cause mortality in hemodialysis (HD) patients.

Methods

A total of 1394 maintenance HD patients with complete data on AOPP and related parameters were included from China Collaborative Study on Dialysis (CCSD), a multi-center, prospective cohort study. The primary outcome was all-cause mortality, the secondary outcome was cardiovascular disease (CVD) mortality.

Results

During a median follow-up duration of 5.2 years (IQR, 2.1–5.4), all-cause mortality occurred in 492 (31.4%) participants. Overall, there was a reversed L-shaped association between serum AOPP and all-cause mortality in HD patients (Pfor nonlinearity = 0.04), with an inflection point at 87 µmol/L. Accordingly, there was no significant association between serum AOPP and all-cause mortality (per SD increment; HR, 0.94; 95%CI, 0.84, 1.05) in participants with AOPP < 87 µmol/L. However, there was a positive relationship of serum AOPP and all-cause mortality (per SD increment; HR, 1.24; 95%CI, 1.08, 1.42) in those with AOPP ≥ 87 µmol/L. Moreover, a similar trend was found for CVD mortality.

Conclusions

Elevated serum AOPP levels were associated with higher risk of all-cause mortality in Chinese maintenance HD patients.
A case of dermatomyositis in a patient with central core disease: unusual association with autoimmunity and genetic muscle disease
Authors: Kim Min Jung , Kim Mi Hyeon , Park Sung-Hye , Song Yeong Wook
Published: June 2021

Background

Dermatomyositis is an inflammatory muscle disease caused by immune-mediated muscle injury, and central core disease (CCD) is a congenital myopathy associated with disturbed intracellular calcium homeostasis and excitation-contraction coupling. To date, CCD has not been reported to have autoantibodies or coexist with inflammatory myopathy.

Case presentation

Here, we described the case of a 25-year-old woman who had progressive proximal muscle weakness, myalgia, pruritic macular rash, skin ulcers, and calcinosis. Dermatomyositis was initially suspected based on the clinical symptoms accompanied by elevated muscle enzyme levels, electromyography abnormalities, and a positive antinuclear antibody test. However, the patient’s muscle biopsy revealed the characteristic findings of both dermatomyositis and CCD, suggesting that dermatomyositis occurred in this patient with previously asymptomatic CCD. The patient did not have any pathogenic gene mutations associated with congenital myopathy, including RYR1 and SEPN1 in targeted next-generation sequencing. She received high-dose glucocorticoid therapy and azathioprine with a significant improvement in muscle strength.

Conclusions

We present a case of rare coexistence of dermatomyositis and CCD. Clinicians should be aware that patients with CCD may have inflammatory myopathy that responds well to immunosuppressive therapy.
Spatial heterogeneity in discontinuation of modern spacing method in districts of India
Authors: Nayak Soumya Ranjan , Mohanty Sanjay K. , Mahapatra Bidhubhusan , Sahoo Umakanta
Published: June 2021

Background

Despite six decades of official family planning programme, the use of modern contraceptive method remained low in India. The discontinuation of modern spacing method (DMSM) has also increased from 42.3% in 2005−06 to 43.6% during 2015–16. Discontinuation rate is higher for Injectable (51%), followed by condom (47%), pill (42%) and lowest in IUD (26%).

Methods

Data from NFHS-4 (2015–16) comprising of 601,509 households, 699,686 women and a sample of 119,548 episode of modern spacing method was used for the analysis. Multiple decrement life table has used to estimate 12-month discontinuation rate of modern spacing methods (DMSM). Moran’s I statistics, Bivariate LISA cluster map has used to understand the spatial correlates and clustering the DMSM. OLS model and impact analysis has used to assess the significant associated covariates with discontinuation.

Result

The 12-month DMSM in India is 43.5%; largely due to desire for becoming pregnant and method failure. The high discontinuation rate was observed in most of the southern (62%) and central (46%) regions of India. DMSM has significantly and spatially associated with neighbouring districts of India (Moran’s I = 0.47, p-value = 0.00). The prevalence of modern spacing method is negatively associated with discontinuation in the neighbouring districts of India. The unmet need (β = 0.84, 95% CI 0.55–1.14), desire of children (β = 0.26, 95% CI − 0.05–0.57) and female sterilization (β = 0.54, 95% CI 0.14–0.95) were three main contributing factor to DMSM.

Conclusion

Districts of high DMSM need programmatic intervention. More attention for counselling to client, health worker outreach to user and better quality care services will stimulate non-user of contraception.
Metabolomic signatures for liver tissue and cecum contents in high-fat diet-induced obese mice based on UHPLC-Q-TOF/MS
Authors: Cai Hongying , Wen Zhiguo , Meng Kun , Yang Peilong
Published: June 2021

Background

The incidence of obesity is increasing worldwide, and it is a risk factor for diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Our previous study had demonstrated that high-fat diet induced increased weight gain, fat weight, serum cholesterol, triglyceride, and ATL levels in liver, and influenced the diversity and composition of cecal microbiota in mice. Hence, this study aimed to investigate the roles of the gut microbially derived metabolites and liver metabolites between the obese and lean mice, focusing on their association with the progression of obesity induced by high-fat diet (HFD).

Methods

An obesity model in mice was established with HFD for 16 weeks. Cecal contents and liver tissues metabolomics based on ultraperformance liquid chromatography-quadrupole-time-of-flight mass spectrometry and orthogonal partial least squares discriminant analyses (OPLS-DA) was performed to identify the alterations in metabolites associated with obese mice.

Results

Obese and lean groups were clearly discriminated from each other on OPLS-DA score plot and major metabolites contributing to the discrimination were mainly involved in glycerophospholipid metabolism, primary bile acid biosynthesis, and biosynthesis of unsaturated fatty acids pathways. HFD-induced alterations of 19 metabolites in liver and 43 metabolites in cecum contents were identified as potential biomarkers related to obesity. Specifically, chenodeoxycholic acid, taurochenodeoxycholate, and tauroursodeoxycholic acid in liver were elevated 35.94, 24.36, and 18.71-fold, respectively. PI(P-16:0/18:1(9Z)), PG(19:0/16:0), PS(P-16:0/20:2(11Z,14Z)), PI(22:1(11Z)/12:0), and PE(21:0/0:0) in cecum were enhanced 884, 640.96, 226.63, 210.10, 45.13-fold in comparison with the lean mice. These metabolites were the most important biomarkers for discriminating between the obese and lean mice. In addition, cecum contents metabolites were strongly correlated with hepatic metabolites through gut-liver axis analysis.

Conclusions

HFD increased lipid profiles (i.e. glycerophospholipids, PC, PE, PI, PG, and PS) and total bile acid (primary and secondary bile acid) in liver and cecum, suggesting that they may play an important role in the progression of obesity. These metabolites can be used to better understand obesity and related disease induced by HFD. Furthermore, the level alterations of these metabolites can be used to assess the risk of obesity and the therapeutic effect of obesity management.
On the arts and humanities in medical education
Authors: Rabinowitz Danielle G.
Published: June 2021

This paper aims to position the birth of the Medical Humanities movement in a greater historical context of twentieth century American medical education and to paint a picture of the current landscape of the Medical Humanities in medical training. It first sheds light on the model of medical education put forth by Abraham Flexner through the publishing of the 1910 Flexner Report, which set the stage for defining physicians as experimentalists and rooting the profession in research institutions. While this paved the way for medical advancements, it came at the cost of producing a patriarchal approach to medical practice. By the late 1960s, the public persona of the profession was thus devoid of humanism. This catalyzed the birth of the Medical Humanities movement that helped lay the framework for what has perpetuated as the ongoing incorporation of humanistic subjects into medical training. As we enter a time in medicine in which rates of burnout are ever-increasing and there are growing concerns about a concomitant reduction in empathy among trainees, the need for instilling humanism remains important. We must consequently continue to consider how to ensure the place of the Medical Humanities in medical education moving forward.
Insufficient blood supply of fovea capitis femoris, a risk factor of femoral head osteonecrosis
Authors: Zhao Keyang , Zhang Fangfang , Quan Kun , Zhu Bin , Li Guangyi , Mei Jiong
Published: June 2021

Background

A defective nutrient foramen in the fovea capitis femoris was hypothesized to reflect the blood circulation pattern of the femoral head, leading to insufficient blood supply and causing osteonecrosis of the femoral head.

Methods

Normal and necrotic femoral head specimens were collected. The necrotic femoral head group was divided into a non-traumatic and traumatic subgroup. 3D scanning was applied to read the number, the diameter, and the total cross-sectional area of the nutrient foramina in the fovea capitis femoris. Chi-squared tests and independent t-tests were used to detect any differences in the categorical and continuous demographic variables. Logistic regression models were used to estimate the odds ratio (OR) for non-traumatic and traumatic osteonecrosis in different characteristic comparisons.

Results

A total of 249 femoral head specimens were collected, including 100 normal femoral heads and 149 necrotic femoral heads. The necrotic femoral head group revealed a significantly higher percentage of no nutrient foramen (p < 0.001), a smaller total area of nutrient foramina (p < 0.001), a smaller mean area of nutrient foramina (p = 0.014), a lower maximum diameter of the nutrient foramen (p < 0.001), and a lower minimum diameter of the nutrient foramen (p < 0.001) than the normal femoral head group. The logistic regression model demonstrated an increasing number of nutrient foramina (crude OR, 0.51; p < 0.001), a larger total area of nutrient foramina (crude OR, 0.58; p < 0.001), a larger mean area of nutrient foramina (crude OR, 0.52; p = 0.023), a greater maximum diameter of the nutrient foramen (crude OR, 0.26; p < 0.001), and greater minimum diameter of the nutrient foramen (crude OR, 0.20; p < 0.001) significantly associated with reduced odds of osteonecrosis of the femoral head (ONFH). The necrotic femoral head group was further divided into 118 non-traumatic and 31 traumatic necrotic subgroups, and no significant difference was observed in any characteristics between them.

Conclusions

Characteristics of the nutrient foramen in the fovea capitis femoris showed a significant defect of necrotic than normal femoral heads, and significantly reduced odds were associated with the higher abundance of the nutrient foramen in ONFH. Therefore, the condition of the nutrient foramen might be the indicator of ONFH.
Interplay between Epstein-Barr virus infection and environmental xenobiotic exposure in cancer
Authors: Aguayo Francisco , Boccardo Enrique , Corvalán Alejandro , Calaf Gloria M. , Blanco Rancés
Published: June 2021

Epstein-Barr virus (EBV) is a herpesvirus associated with lymphoid and epithelial malignancies. Both B cells and epithelial cells are susceptible and permissive to EBV infection. However, considering that 90% of the human population is persistently EBV-infected, with a minority of them developing cancer, additional factors are necessary for tumor development. Xenobiotics such as tobacco smoke (TS) components, pollutants, pesticides, and food chemicals have been suggested as cofactors involved in EBV-associated cancers. In this review, the suggested mechanisms by which xenobiotics cooperate with EBV for carcinogenesis are discussed. Additionally, a model is proposed in which xenobiotics, which promote oxidative stress (OS) and DNA damage, regulate EBV replication, promoting either the maintenance of viral genomes or lytic activation, ultimately leading to cancer. Interactions between EBV and xenobiotics represent an opportunity to identify mechanisms by which this virus is involved in carcinogenesis and may, in turn, suggest both prevention and control strategies for EBV-associated cancers.
Aversive emotion rapidly activates orexin neurons and increases heart rate in freely moving mice
Authors: Yamashita Akira , Moriya Shunpei , Nishi Ryusei , Kaminosono Jun , Yamanaka Akihiro , Kuwaki Tomoyuki
Published: June 2021

The perifornical area of the hypothalamus has been known as the center for the defense response, or fight-or-flight response, which is characterized by a concomitant rise in arterial blood pressure, heart rate, and respiratory frequency. It is well established that orexin neurons, which are located in this region, play a critical role in this response. In this study, we further examined this role by recording orexin neuronal activity and heart rate in freely moving mice using an original dual-channel fiber photometry system in vivo. Analysis of orexin neuron activity in relation to autonomic responses to aversive stimuli revealed a rapid increase in neuronal activity just prior to changes in heart rate. In addition, we examined whether orexin neurons would be activated by a conditioned neutral sound that was previously associated with aversive stimulus. We show that the memory of the aversive stimulus activated orexin neurons and increased heart rate. Our data suggest that orexin neurons are a key component linking aversive emotions to autonomic defense response. Our data also suggest that targeting orexin neurons may enable treatment of psychiatric disorders associated with chronic stress and traumatic memories.
Evolving therapeutic landscape in follicular lymphoma: a look at emerging and investigational therapies
Authors: Hanel Walter , Epperla Narendranath
Published: June 2021

Follicular Lymphoma (FL) is the most common subtype of indolent B cell non-Hodgkin lymphoma. The clinical course can be very heterogeneous with some patients being safely observed over many years without ever requiring treatment to other patients having more rapidly progressive disease requiring multiple lines of treatment for disease control. Front-line treatment of advanced FL has historically consisted of chemoimmunotherapy but has extended to immunomodulatory agents such as lenalidomide. In the relapsed setting, several exciting therapies that target the underlying biology and immune microenvironment have emerged, most notable among them include targeted therapies such as phosphoinositide-3 kinase and Enhancer of Zeste 2 Polycomb Repressive Complex 2 inhibitors and cellular therapies including chimeric antigen receptor T cells and bispecific T cell engagers. There are several combination therapies currently in clinical trials that appear promising. These therapies will likely reshape the treatment approach for patients with relapsed and refractory FL in the coming years. In this article, we provide a comprehensive review of the emerging and investigational therapies in FL and discuss how these agents will impact the therapeutic landscape in FL.
Molecular pathogenesis of the myeloproliferative neoplasms
Authors: Greenfield Graeme , McMullin Mary Frances , Mills Ken
Published: June 2021

The Philadelphia negative myeloproliferative neoplasms (MPN) compromise a heterogeneous group of clonal myeloid stem cell disorders comprising polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Despite distinct clinical entities, these disorders are linked by morphological similarities and propensity to thrombotic complications and leukaemic transformation. Current therapeutic options are limited in disease-modifying activity with a focus on the prevention of thrombus formation. Constitutive activation of the JAK/STAT signalling pathway is a hallmark of pathogenesis across the disease spectrum with driving mutations in JAK2, CALR and MPL identified in the majority of patients. Co-occurring somatic mutations in genes associated with epigenetic regulation, transcriptional control and splicing of RNA are variably but recurrently identified across the MPN disease spectrum, whilst epigenetic contributors to disease are increasingly recognised. The prognostic implications of one MPN diagnosis may significantly limit life expectancy, whilst another may have limited impact depending on the disease phenotype, genotype and other external factors. The genetic and clinical similarities and differences in these disorders have provided a unique opportunity to understand the relative contributions to MPN, myeloid and cancer biology generally from specific genetic and epigenetic changes. This review provides a comprehensive overview of the molecular pathophysiology of MPN exploring the role of driver mutations, co-occurring mutations, dysregulation of intrinsic cell signalling, epigenetic regulation and genetic predisposing factors highlighting important areas for future consideration.
Evolution of inspiratory muscle function in children during mechanical ventilation
Authors: Crulli Benjamin , Kawaguchi Atsushi , Praud Jean-Paul , Petrof Basil J. , Harrington Karen , Emeriaud Guillaume
Published: June 2021

Background

There is no universally accepted method to assess the pressure-generating capacity of inspiratory muscles in children on mechanical ventilation (MV), and no study describing its evolution over time in this population.

Methods

In this prospective observational study, we have assessed the function of the inspiratory muscles in children on various modes of MV. During brief airway occlusion maneuvers, we simultaneously recorded airway pressure depression at the endotracheal tube (ΔPaw, force generation) and electrical activity of the diaphragm (EAdi, central respiratory drive) over five consecutive inspiratory efforts. The neuro-mechanical efficiency ratio (NME, ΔPaw/EAdimax) was also computed. The evolution over time of these indices in a group of children in the pediatric intensive care unit (PICU) was primarily described. As a secondary objective, we compared these values to those measured in a group of children in the operating room (OR).

Results

In the PICU group, although median NMEoccl decreased over time during MV (regression coefficient − 0.016, p = 0.03), maximum ΔPawmax remained unchanged (regression coefficient 0.109, p = 0.50). Median NMEoccl at the first measurement in the PICU group (after 21 h of MV) was significantly lower than at the only measurement in the OR group (1.8 cmH2O/µV, Q1–Q3 1.3–2.4 vs. 3.7 cmH2O/µV, Q1–Q3 3.5–4.2; p = 0.015). Maximum ΔPawmax in the PICU group was, however, not significantly different from the OR group (35.1 cmH2O, Q1–Q3 21–58 vs. 31.3 cmH2O, Q1–Q3 28.5–35.5; p = 0.982).

Conclusions

The function of inspiratory muscles can be monitored at the bedside of children on MV using brief airway occlusions. Inspiratory muscle efficiency was significantly lower in critically ill children than in children undergoing elective surgery, and it decreased over time during MV in critically ill children. This suggests that both critical illness and MV may have an impact on inspiratory muscle efficiency.
Plasticity engineering of plant monoterpene synthases and application for microbial production of monoterpenoids
Authors: Lei Dengwei , Qiu Zetian , Qiao Jianjun , Zhao Guang-Rong
Published: June 2021

Plant monoterpenoids with structural diversities have extensive applications in food, cosmetics, pharmaceuticals, and biofuels. Due to the strong dependence on the geographical locations and seasonal annual growth of plants, agricultural production for monoterpenoids is less effective. Chemical synthesis is also uneconomic because of its high cost and pollution. Recently, emerging synthetic biology enables engineered microbes to possess great potential for the production of plant monoterpenoids. Both acyclic and cyclic monoterpenoids have been synthesized from fermentative sugars through heterologously reconstructing monoterpenoid biosynthetic pathways in microbes. Acting as catalytic templates, plant monoterpene synthases (MTPSs) take elaborate control of the monoterpenoids production. Most plant MTPSs have broad substrate or product properties, and show functional plasticity. Thus, the substrate selectivity, product outcomes, or enzymatic activities can be achieved by the active site mutations and domain swapping of plant MTPSs. This makes plasticity engineering a promising way to engineer MTPSs for efficient production of natural and non-natural monoterpenoids in microbial cell factories. Here, this review summarizes the key advances in plasticity engineering of plant MTPSs, including the fundamental aspects of functional plasticity, the utilization of natural and non-natural substrates, and the outcomes from product isomers to complexity-divergent monoterpenoids. Furthermore, the applications of plasticity engineering for improving monoterpenoids production in microbes are addressed.
Screening and characterization of cellulolytic molds from empty fruit bunches and soils in palm oil plantation area in Indonesia
Authors: Miller Tracy , Waturangi Diana Elizabeth , Purwadaria Tresnawati
Published: June 2021

Objective

This research was aimed to isolate cellulolytic molds in empty fruit bunches of oil palm (EFBOP) and soils from palm oil plantation area and identify their enzyme activities to digest EFBOP.

Results

A total of seven molds were successfully isolated and screened for their enzyme activities from EFBOP and the soils. The enzymes from each isolate were produced in submerged culture using Mineral Mandels and 3% of alkali pretreated pollard in triplicates. The results indicated that all of the isolates were able to hydrolyze Carboxymethyl Cellulose (CMC), Whatmann No. 1 filter paper, and also EFBOP to sugars with reducing ends that reacted to 3,5-Dinitrosalicylic acid (DNS). The CMCase activity of isolate X showed the highest while the lowest was found for isolate MT8. Filter paperase (FPase) activity of isolate X performed the highest wile the lowest were found from isolate MT3 and MT6. The saccharification activity of isolate P showed the highest while MT6 performed the lowest activity
Structure and function of capsid protein in flavivirus infection and its applications in the development of vaccines and therapeutics
Authors: Zhang Xingcui , Zhang Yanting , Jia Renyong , Wang Mingshu , Yin Zhongqiong , Cheng Anchun
Published: June 2021

Flaviviruses are enveloped single positive-stranded RNA viruses. The capsid (C), a structural protein of flavivirus, is dimeric and alpha-helical, with several special structural and functional features. The functions of the C protein go far beyond a structural role in virions. It is not only responsible for encapsidation to protect the viral RNA but also able to interact with various host proteins to promote virus proliferation. Therefore, the C protein plays an important role in infected host cells and the viral life cycle. Flaviviruses have been shown to affect the health of humans and animals. Thus, there is an urgent need to effectively control flavivirus infections. The structure of the flavivirus virion has been determined, but there is relatively little information about the function of the C protein. Hence, a greater understanding of the role of the C protein in viral infections will help to discover novel antiviral strategies and provide a promising starting point for the further development of flavivirus vaccines or therapeutics.
Smoking cessation using preference-based tools: a mixed method pilot study of a novel intervention among smokers with low socioeconomic position
Authors: Héron Mégane , Le Faou Anne-Laurence , Ibanez Gladys , Métadieu Brigitte , Melchior Maria , El-Khoury Lesueur Fabienne
Published: June 2021

Background

Compared to smokers with favorable socio-economic position (SEP), those with low SEP are less likely to have a successful smoking cessation attempt. Tailored approaches are therefore needed, and general practitioners could help reaching and assisting usually hard-to-reach population.

Method

STOP (Sevrage Tabagique à l’aide d’Outils dédiés selon la Préférence) is a pilot study, examining the feasibility, acceptability and potentiality of a smoking cessation intervention centered on smoker’s preference. Smokers with low SEP, wishing to quit, were recruited in six healthcare centers in the Greater Paris area. They were asked to choose between different types of nicotine replacement therapy (NRT) products and/or e-cigarette with liquids delivered free of charge to aid their smoking cessation attempt. We describe the characteristics of recruited participants, their perception of smoking cessation aids, and the evolution of their smoking status 4 to 6 weeks after recruitment.

Results

We recruited 49 participants, of which 29% chose an e-cigarette, 29% chose NRT and 42% chose both an e-cigarette and NRT. The intervention was shown to be acceptable by participants and health professionals. Among the 24 participants followed for at least one month, 14 (28% of all participants) stopped smoking, and 9 (18%) considerably reduced their consumption.

Conclusion

The STOP intervention is feasible and acceptable, even if more efforts should be made to limit lost-to-follow-up. This preference-based intervention also shows interesting prospect in helping smokers with low SEP quit smoking. We will test the efficacy of this preference-based intervention in a randomized controlled trial.
Transcription factor 7-like 2 gene- smoking interaction on the risk of diabetic nephropathy in Chinese Han population
Authors: Xue Peng , Cao Haihong , Ma Zhimin , Zhou Ying , Wang Nian
Published: June 2021

Objectives

To evaluate the relationship between transcription factor 7-like 2 (TCF7L2) gene polymorphism and diabetic nephropathy (DN) risk, as well as the effect of gene-environment interactions on DN risk in Chinese Han population.

Methods

The Hardy-Weinberg equilibrium (HWE) and the relationship between TCF7L2 gene single nucleotide polymorphism (SNPs) and DN susceptibility were evaluated by SNPStats. The interaction among four SNPs and environmental factors were tested by generalized multifactor dimensionality reduction (GMDR). The consistency of cross validation, accuracy of test balance and sign test were calculated to evaluate the interaction of each selection. The logistic regression was used to test the interaction between rs7903146 and current smoking by stratified analysis.

Results

Logistic regression analysis indicated that the DN risk of rs7903146-T allele carriers were obviously higher than that in CC genotype carriers (CT + TT versus CC), adjusted OR (95 %CI) = 1.64 (1.24–2.06). However, we also discovered that people with rs12255372, rs11196205 and rs290487 minor allele had non-significant difference risk of DN compared with people with major allele. The GMDR model found a significant two-locus model (p = 0.0100) including rs7903146 and current smoking, suggesting a potential gene–environment interaction between rs7903146 and current smoking. Compared with never smokers with rs7903146- CC genotype, current smokers with rs7903146- CT or TT genotype had the highest DN risk. After covariate adjustment, OR (95 %CI) was 2.15 (1.58–2.78).

Conclusions

We found a significant relationship of rs7903146-T alleles, and the interaction between rs7903146-T and current smoking with increased DN risk.
Assessment about Luneberg integrals and application to digital in-line holography
Authors: Coëtmellec S. , Lebrun D. , Brunel M. , E. M. Janssen A. J.
Published: June 2021

In this publication, the Luneberg integrals are revisited and the conditions of the using of such integrals have been recalled. Additivity law of Luneberg’s integrals and the link with the Frenel kernel for the propagation are discussed. By means of the definition of the Luneberg’s integrals, the propagation of a vectorial electromagnetic field (Hertz potentials) is developed and a new approach of the computation have been proposed based on Zernike polynomials. With this new approach simulations of holograms is illustrated in the case of the digital in-line holography with an opaque disk.
Design of a phosphor-converted LED based lighting system considering both the lighting and color uniformity
Authors: Yan Jinren
Published: June 2021

In this work, a scheme of combining an aspheric reflector and a primary packaging freeform lens in phosphor-converted lighting-emitting diode (pc-LED) based lighting system design was developed. In contrast to most of previous works in which the color and illumination uniformity of the pc-LED lighting systems were improved one by one, the developed scheme can improve both indicators simultaneously. To demonstrate the feasibility of the developed design scheme, an initially designed pc-LED optical model, with an average correlated color temperature (CCT) of about 5000 K, was constructed as the light source of the illumination system. The key ingredient to the color uniformity of the illumination system was investigated at first, and then several instances with the cut-off angle ranging from 40 to 60 degrees were further discussed. Detailed analysis shows: for each case, the CCT variation decreases from over 4000 K to smaller than 300 K and the illumination uniformity increases from a very low level to better than 80% on the target region.
Acceptance and completion of rifapentine-based TB preventive therapy (3HP) among people living with HIV (PLHIV) in Kampala, Uganda—patient and health worker perspectives
Authors: Semitala Fred C. , Musinguzi Allan , Ssemata Jackie , Welishe Fred , Nabunje Juliet , Kadota Jillian L. , Berger Christopher A. , Katamba Achilles , Kiwanuka Noah , Kamya Moses R. , Dowdy David , Cattamanchi Adithya , Katahoire Anne R.
Published: June 2021

Background

A 12-dose, once-weekly regimen of isoniazid and rifapentine (3HP) is effective in preventing tuberculosis (TB) among people living with HIV (PLHIV). We sought to identify potential barriers to and facilitators of acceptance and completion of 3HP treatment from the perspective of people living with HIV (PLHIV) and health workers in a routine HIV care setting in Kampala, Uganda.

Methods

We conducted semi-structured interviews with 25 PLHIV and 10 health workers at an HIV/AIDS clinic in Kampala, Uganda. For both groups, we explored their understanding and interpretations of TB and TB preventive therapy (TPT), and perceptions about social and contextual factors that might influence the willingness of PLHIV to initiate and complete 3HP. We analyzed the data using an inductive thematic approach and aligned the emergent themes to the Behavior Change Wheel framework to identify sources of behavior and targeted behavior change interventions.

Results

Facilitators of acceptance and completion of 3HP treatment among PLHIV were fear of contracting TB, awareness of being at risk of getting TB, willingness to take TPT, trust in health workers, and the perceived benefits of directly observed therapy (DOT) and self-administered therapy (SAT) 3HP delivery strategies. Barriers included inadequate understanding of TPT, fear of potential side effects, concerns about the effectiveness of 3HP, and the perceived challenges of DOT or SAT. Among health workers, perceived facilitators included knowledge that TB is a common cause of mortality for PLHIV, fear of getting TB, and trust in the health workers by PLHIV, the advantages of once-weekly 3HP dosing, and the benefits of DOT and SAT 3HP delivery strategies. Health worker-reported barriers for PLHIV included inadequate understanding of TB and benefits of TPT, TB-associated stigma, potential side effects pill burden, and challenges of DOT and SAT 3HP delivery strategies. Lack of experience in the use of digital technology to monitor patient care was identified as a health worker-specific barrier. Identified intervention functions to address the facilitators or barriers included education, persuasion, environmental restructuring, enablement, and training.

Conclusions

Using a formative qualitative and comprehensive theoretical approach, we identified key barriers, facilitators, and appropriate interventions, including patient education, enhancing trust, and patient-centered treatment support that could be used to optimize the delivery of 3HP to PLHIV in our setting. These interventions are likely generalizable to other clinical interventions in similar populations in sub-Saharan Africa and other TB high-burden settings.
Intact Fasting Insulin Identifies Nonalcoholic Fatty Liver Disease in Patients Without Diabetes
Authors: Bril Fernando , McPhaul Michael J , Kalavalapalli Srilaxmi , Lomonaco Romina , Barb Diana , Gray Meagan E , Shiffman Dov , Rowland Charles M , Cusi Kenneth
Published: June 2021

Context

Patients with nonalcoholic fatty liver disease (NAFLD) are characterized by insulin resistance and hyperinsulinism. However, insulin resistance measurements have not been shown to be good diagnostic tools to predict NAFLD in prior studies.

Objective

We aimed to assess a newly validated method to measure intact molecules of insulin by mass spectrometry to predict NAFLD.

Methods

Patients underwent a 2-hour oral glucose tolerance test (OGTT), a liver magnetic resonance spectroscopy (1H-MRS), and a percutaneous liver biopsy if they had a diagnosis of NAFLD. Mass spectrometry was used to measure intact molecules of insulin and C-peptide.

Results

A total of 180 patients were recruited (67% male; 52 ± 11 years of age; body mass index [BMI] 33.2 ± 5.7 kg/m2; 46% with diabetes and 65% with NAFLD). Intact fasting insulin was higher in patients with NAFLD, irrespective of diabetes status. Patients with NAFLD without diabetes showed ~4-fold increase in insulin secretion during the OGTT compared with all other subgroups (P = 0.008). Fasting intact insulin measurements predicted NAFLD in patients without diabetes (area under the receiver operating characteristic curve [AUC] of 0.90 [0.84-0.96]). This was significantly better than measuring insulin by radioimmunoassay (AUC 0.80 [0.71-0.89]; P = 0.007). Intact fasting insulin was better than other clinical variables (eg, aspartate transaminase, triglycerides, high-density lipoprotein, glucose, HbA1c, and BMI) to predict NAFLD. When combined with alanine transaminase (ALT) (intact insulin × ALT), it detected NAFLD with AUC 0.94 (0.89-0.99) and positive and negative predictive values of 93% and 88%, respectively. This newly described approach was significantly better than previously validated noninvasive scores such as NAFLD-LFS (P = 0.009), HSI (P < 0.001), and TyG index (P = 0.039).

Conclusion

In patients without diabetes, accurate measurement of fasting intact insulin levels by mass spectrometry constitutes an easy and noninvasive strategy to predict presence of NAFLD.
Rescue of Cell Surface Expression and Signaling of Mutant Follicle-Stimulating Hormone Receptors
Authors: Hanyroup Sharika , Anderson Ross C , Nataraja Selvaraj , Yu Henry N , Millar Robert P , Newton Claire L
Published: June 2021

Mutations in G protein-coupled receptors (GPCRs) underlie numerous diseases. Many cause receptor misfolding and failure to reach the cell surface. Pharmacological chaperones are cell-permeant small molecules that engage nascent mutant GPCRs in the endoplasmic reticulum, stabilizing folding and “rescuing” cell surface expression. We previously demonstrated rescue of cell surface expression of luteinizing hormone receptor mutants by an allosteric agonist. Here we demonstrate that a similar approach can be employed to rescue mutant follicle-stimulating hormone receptors (FSHRs) with poor cell surface expression using a small-molecule FSHR agonist, CAN1404. Seventeen FSHR mutations described in patients with reproductive dysfunction were expressed in HEK 293T cells, and cell surface expression was determined by enzyme-linked immunosorbent assay of epitope-tagged FSHRs before/after treatment with CAN1404. Cell surface expression was severely reduced to ≤18% of wild-type (WT) for 11, modestly reduced to 66% to 84% of WT for 4, and not reduced for 2. Of the 11 with severely reduced cell surface expression, restoration to ≥57% of WT levels was achieved for 6 by treatment with 1 µM CAN1404 for 24 h, and a corresponding increase in FSH-induced signaling was observed for 4 of these, indicating restored functionality. Therefore, CAN1404 acts as a pharmacological chaperone and can rescue cell surface expression and function of certain mutant FSHRs with severely reduced cell surface expression. These findings aid in advancing the understanding of the effects of genetic mutations on GPCR function and provide a proof of therapeutic principle for FSHR pharmacological chaperones.
Inhibition of miR-29 Activity in the Myeloid Lineage Increases Response to Calcitonin and Trabecular Bone Volume in Mice
Authors: Shin Bongjin , Hrdlicka Henry C , Delany Anne M , Lee Sun-Kyeong
Published: June 2021

The miR-29-3p family (miR-29a, miR-29b, miR-29c) of microRNAs is increased during receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis. In vivo, activation of a miR-29-3p tough decoy inhibitor in Cre recombinase under the control of the lysozyme 2 promoter-expressing cells (myeloid lineage) resulted in mice displaying enhanced trabecular and cortical bone volume because of decreased bone resorption. Calcitonin receptor (Calcr) is a miR-29 target that negatively regulates bone resorption. CALCR was significantly increased in RANKL-treated miR-29-decoy osteoclasts, and these cells were more responsive to the inhibitory effect of calcitonin on osteoclast formation. Further, cathepsin K (Ctsk), which is critical for resorption, was decreased in miR-29-decoy cells. CALCR is a Gs-coupled receptor and its activation raises cAMP levels. In turn, cAMP suppresses cathepsin K, and cAMP levels were increased in miR-29-decoy cells. siRNA-mediated knock-down of Calcr in miR-29 decoy osteoclasts allowed recovery of cathepsin K levels in these cells. Overall, using a novel knockin tough decoy mouse model, we identified a new role for miR-29-3p in bone homeostasis. In RANKL-driven osteoclastogenesis, as seen in normal bone remodeling, miR-29-3p promotes resorption. Consequently, inhibition of miR-29-3p activity in the myeloid lineage leads to increased trabecular and cortical bone. Further, this study documents an interrelationship between CALCR and CTSK in osteoclastic bone resorption, which is modulated by miR-29-3p.