bluuebunny/crossref_metadata_2025 huggingface dataset:
P451 Efficacy and safety of tofacitinib in the treatment of patients with active, moderate to severe, Ulcerative Colitis: a systematic review and meta-analysis
Authors: Khorshid Fasge M , Dorgham D , Sharobim A , Attia M , Hussein M , Dorgham N
Published: May 2021

Background

To perform a systematic review and meta-analysis to discuss the efficacy and safety of tofacitinib in patients with moderate to severe ulcerative colitis (UC).

Methods

We searched PubMed, Scopus, Web of Science, in addition to Cochrane Central, until May 2020 using relevant keywords. We included randomized controlled trials (RCTs) in addition to cohort studies that compared tofacitinib oral treatment versus placebo in patients with active UC, with a moderate to severe degree. Quality of included RCTs was assessed by the Cochrane risk of bias assessment tool, whereas the Newcastle-Ottawa scale was applied to assess for bias sources in included cohort studies. Data were pooled, after being extracted, from eligible articles in the review manager software, or the open meta-analyst software. Dichotomous outcomes were pooled as risk ratios (RR) under the fixed effect model, while continuous outcomes were pooled as standardized mean difference (SMD) under the random-effects model.

Results

pooling data from seven RCTs and four cohort studies, 2728 patients, showed that tofacitinib therapy was superior to placebo in inducing a clinical response in UC patients after eight weeks (p = 0.0001) and 26 weeks, in a proportion 0.4 of patients who took tofacitinib 10 mg BID. Additionally, tofacitinib treatment was associated with significantly higher events of clinical remission of UC, after eight weeks (RR= 3.12, 95% CI [2.34, 4.16], p < 0.0001). Likewise, endoscopic, deep, in addition to symptomatic remission rates were higher in the tofacitinib group, compared to the group of placebo (p ≤ 0.008). Most of the drug-related adverse events were comparable between tofacitinib and placebo groups. However, tofacitinib treatment was associated with fewer serious adverse events (RR= 0.68, 95% CI [0.48, 0.98], p = 0.04); adverse events that led to drug discontinuation (RR= 0.53, 95% CI [0.39, 0.73], p< 0.0001); and worsening of UC (RR= 0.48, 95% CI [0.38, 0.61], p < 0.00001). On the other hand, the placebo group had fewer overall infections (p = 0.002); and elevation in laboratory parameters, including LDL cholesterol, total cholesterol, and triglycerides.

Conclusion

Our systematic review and meta-analysis showed that, in patients with active moderate to severe UC, tofacitinib treatment was superior to placebo in inducing clinical response and remission, with less adverse reactions. Additionally, treatment with tofacitinib showed beneficial quality of life and survival benefits for UC patients. Future clinical trials should study the effect of higher doses of tofacitinib in larger RCTs, with longer follow up periods.
P530 Proactive therapeutic drug monitoring of anti-TNF agents is associated with higher mucosal healing rates in Crohn’s disease
Authors: Brinar M , Sabic M , Turk N , Grgic D , Domislovic V , Cukovic Cavka S , Kozmar A , Krznaric Z
Published: May 2021

Background

Reactive therapeutic drug monitoring (TDM) is routinely used in managing secondary loss of response to anti-TNF agents. Proactive TDM use has been associated with better clinical outcomes but its use in routine practice is still controversial. We aimed to investigate whether using proactive TDM strategy will result in higher mucosal healing and clinical remission rates.

Methods

After review of electronic case files, all patients that received anti-TNF treatment for active disease from 01.01.2017-01.02.2021. and responded to induction were included. Patients starting treatment for postoperative prophylaxis were excluded from the study. In the proactive group TDM was performed in week 14 and patients with subtherapeutic trough levels were dose optimized and underwent subsequent TDM measurments until the target trough level was reached. In the reactive group TDM was performed in the case of loss of response. Mucosal healing was defined as SES CD 3 for patients with CD and Mayo endoscopic score of £ 1 for UC patients. Clinical remission after 52 weeks was defined by the attending physician.

Results

A total of 161 IBD patients were included, 109 patients with CD and 52 patients with UC. There were 69 patients in the proactive group and 92 patients in the reactive group. No significant difference regarding age at diagnosis, age at treatment initiation, disease duration , prior immunomodulator use and time do endoscopy was observed between groups. A higher proportion of patients in the proactive group achieved mucosal healing but the difference between groups was not significant in the total cohort (proactive 52.4% vs reactive 42.2%; p=0.250). A significantly higher proportion of CD patients (n=109) in the proactive group achieved mucosal healing compared to the reactive group (56.8% vs 34.8%; p=0.039). No significant difference in mucosal healing rates between the groups was observed in UC cases. No significant difference in clinical remission rates was observed between the proactive and reactive group in the total cohort, CD and UC patients respectively.

Conclusion

Proactive TDM strategy is a valuable tool in managing CD patients resluting in higher rates of mucosal healing. Further studies are needed to define the optimal timepoints for proactive TDM.
P551 Lack of adherence to infliximab in inflammatory bowel disease patients contributes to loss of response in Crohn’s disease
Authors: Ferreiro Iglesias R , Gonzalez-Lopez J , Calvino-Suarez C , Mauriz-Barreiro V , Baston-Rey I , Cruz R , Dominguez-Munoz J E , Barreiro-de Acosta M
Published: May 2021

Background

Lack of adherence in patients with inflammatory bowel disease (IBD) is a relevant problem in our clinical practice. Non-adherence to anti-TNF increases healthcare costs. The aim of this study was both to measure adherence and also to study the factors and consequences related to non-adherence in patients with IBD under maintenance treatment with infliximab (IFX).

Methods

A prospective, observational cohort study was designed and patients with IBD under treatment with IFX were consecutively included. Adherence was measured with pharmacy refills and Morisky Medication Adherence Scale-8 (MMAS-8). Patients were systematically asked about adherence and the mean displacement days, the accumulated delay, the mean delay and the medication possession ratio (MPR) were calculated. MPR was calculated by dividing the number of days supplied within the refill interval by the number of days in the actual refill interval over 24 months. Potencial risk factors for non-adherence were evaluated: age, gender, disease duration, site of disease, behaviour of Crohn’s disease (CD), smoking status, educational level, marital status, type of housing, extraintestinal manifestations, previous surgery, concomitant treatments, anxiety and depression. Relapse was defined as a Harvey Bradshaw score > 4 in CD and a partial Mayo > 2 in ulcerative colitis (UC). The Mann-Whitney Wilcoxon U Test was used to distinguish the intergroup differences. Correlations were evaluated with Spearman rank correlation coefficients.

Results

Ninety patients with mean age 46 years (range: 22–85) were included. 49 (54.4%) were women and 63 (70%) had CD. Anxiety occurred in 38.9% of patients and depression in 78.9%. Three quarters of the patients were in clinical remission at inclusion. After 24 months of follow-up, 82 (91.1%) had delayed some dose of treatment, 35 (38.9%) had delayed on at least 7 days some dose of treatment, and 11 (12.2%) had not received some of the scheduled doses. The MPR was 87% (range 46–100). Lack of adherence was related to loss of response to IFX in CD (p = 0.035), but not in UC (p=0.078). In UC, lack of adherence was related with anxiety (p=0.046). The Spearman’s correlation between older age and non-adherence was 0.53 (p=0.006) in UC and 0.1 (p=0.308) in CD.

Conclusion

Lack of adherence is related to loss of response to IFX in CD. Non-adherence to IFX is high and strongly associated with age in UC. Older patients with UC are more prone to lack of adherence.
P603 Patient characteristics and adverse effects in biologic treatment of Crohn’s Disease and Ulcerative Colitis: A nationwide Danish cohort study years 2015–2018
Authors: Bjørn Jensen C , Jarlov Jensen K , Wennerström C , Sommer K J , Burisch J , Petersen J
Published: May 2021

Background

Biological therapies have demonstrated effectiveness in the treatment of Crohn’s Disease (CD) and Ulcerative Colitis (UC), but comparative analyses of the various treatments remain limited.

Methods

Using Danish national registries, we performed a nationwide cohort study including all bio-naïve individuals diagnosed with UC or CD initiating treatment with infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ), golimumab (GOL), or ustekinumab (UST) during 2015–2018. The hazard ratios (HR) of hospitalization, surgery, and start of corticosteroid therapy were explored using Cox regression adjusted for health-related and socio-economic parameters at treatment initiation.

Results

More than 90% of 1,836 CD and 1,886 UC patients had IFX as first-line treatment. Patients with ADA, VDZ, UST or GOL as first-line treatment were older at diagnosis and start of biologic treatment. A larger proportion were women, had higher education, and had previously had IBD surgery.

We observed a higher risk of all-cause hospitalization (HR: 1.56 (95% CI: 1.16; 2.10)) among CD patients with ADA as first-line treatment compared to IFX. No risk difference was observed of IBD hospitalization, IBD related surgery, or use of corticosteroids between ADA- and IFX-treated CD patients. We observed no risk difference between ADA- and IFX-treated UC patients for any outcomes. For both CD and UC patients, analyses of VDZ were based on very low number of cases and the results were inconclusive. Analyses of GOL and UST were not possible because of low numbers.

Second-line treatment with VDZ compared to ADA among CD patients previously treated with IFX showed no risk difference of all-cause hospitalization (1.32 (0.91; 1.92)), IBD hospitalization (1.27 (0.68; 2.35)), IBD related surgery (1.41 (0.69; 2.85)), or use of corticosteroids (0.70 (0.27; 1.82)). Among UC patients, second-line VDZ was associated with an increased risk of IBD related surgery (1.94 (1.01; 3.71)), but not of all-cause hospitalization (0.77 (0.48; 1.24)), IBD hospitalization (0.75 (0.38; 1.46)), or corticosteroid use (0.92 (0.37; 2.28)) compared to ADA.

Conclusion

We observed increased risk of hospitalization among CD patients treated with ADA compared to IFX, and increased risk of IBD-related surgery in UC patients receiving VDZ as second line treatment compared to ADA. The differences in key baseline characteristics patients initiating biologic treatment with ADA, VDZ, UST or GOL compared to IFX might reflect differences in disease state, that justify deviations from treatment guideline. It should be further investigated if the associations are an effect of differences in treatment efficacy and safety or confounding by differences in disease state at treatment start.
P656 Epidemiology and outcomes associated with local surgical and intersphincteric ligation procedures for complex cryptoglandular fistulas: A systematic literature review
Authors: Iglay K , Bennett D , Kappelman M , Karki C , Cook S
Published: May 2021

Background

Studies suggest that complex cryptoglandular fistulas (CCF) are difficult to treat, resulting in higher intervention failure rates and functional disability. This systematic literature review (SLR) assessed the epidemiology of cryptoglandular fistula and outcomes associated with local, surgical and intersphincteric ligation procedures for treatment of CCF.

Methods

PubMed and Embase were searched to identify articles published in the past 5 years (2015–2020) relating to incidence or prevalence of cryptoglandular fistula and outcomes of surgical interventions for CCF (PROSPERO registration number CRD42020177732). Outcomes of interest included fistula closure/healing, recurrence, surgery failure, post-operative pain and faecal incontinence. The interventions included anal flap procedures, fistulectomy, fistulotomy, primary sphincteroplasty, modified Park’s technique, LIFT or BIOLIFT, and TROPIS. Two trained reviewers used pre-specified eligibility criteria to identify studies for inclusion and evaluate risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. Data were extracted for a range of variables, including study type and design, population, outcomes and limitations.

Results

In total, 148 studies were identified that met a priori eligibility criteria for all cryptoglandular fistulas and all intervention types. Of these, two reported incidence or prevalence of cryptoglandular fistulas and 18 reported outcomes for the interventions of interest in CCF. Prevalence of cryptoglandular fistulas was reported as 1.35 per 10 000 patients without Crohn’s disease, and 52.6% of patients without IBD were found to progress from anorectal abscess to fistula over 12 months. Studies examining the clinical outcomes reported primary healing rates of 57.4–100.0%, recurrence rates of 4.9–61.0% and failure rates of 2.8–18.0% of patients. Only five studies reported post-operative pain as a clinical outcome. Overall, these studies suggest patients experience no or minimal longer-term post-operative pain. In studies reporting post-operative faecal incontinence following anal mucosal flap procedures, observed incontinence rates were low, as measured using Wexner or Miller scoring. None of the studies involving fistulectomy measured faecal incontinence.

Conclusion

This SLR provides a summary of outcomes from a selected group of surgical interventions for CCF. Healing rates vary according to surgery type; however, differences in study design and heterogenous definitions prevent direct comparison. Overall, the published literature indicates low to modest rates of CCF recurrence and limited data on faecal incontinence and longer-term post-operative pain.

Sponsor: Takeda Pharmaceuticals USA, Inc.
P669 Effect of vedolizumab therapy on whole blood transcriptional profiles in patients with Inflammatory Bowel Disease
Authors: Haglund S , Söderman J , Almer S
Published: May 2021

Background

Vedolizumab (VDZ) is one of many new biological drugs used in patients with inflammatory bowel disease who fail more conventional therapy. Despite proven efficacy, subgroups of patients show limited clinical benefit from VDZ. Here, we hypothesized that differences in clinical response to VDZ therapy might be reflected in changes in gene expression in whole blood which potentially could serve as easy accessible candidate biomarkers.

Methods

Transcriptional profiles of 20 patients (Crohn’s disease 13, ulcerative colitis 7) were established by sequencing of RNA isolated from stabilized whole blood collected at baseline (T0), and at follow-up at week 10–12 (T1) following three infusions of VDZ. Clinical response was defined as a decrease of > 3 in the simplified Harvey Bradshaw Index or in the Simple Clinical Colitis Activity Index at T1 compared with T0. Differently expressed genes were identified by using the R packages Rsubread, edgeR and limma with hg38 as reference genome. Pathway analyses were done by gene set enrichment analysis (GSEA, Broad Institute) using Reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Routine laboratory parameters were obtained.

Results

Overall, two genes were down-regulated (IGLV2-23 > 2-fold) and four genes were up-regulated (ADAMTS5 > 2-fold) at follow up (FDR < 0.05). This was attributed to regulation in responders (n=9), but not in non-responder (n=11). In responders, 55 genes were down-regulated (25 genes > 2-fold, e.g. IGHV3-74) and 146 genes were up-regulated (8 genes > 2-fold, e.g. OLFM1) at T1 vs. T0. However, at T0 there were no differences between responders and non-responders suitable as predictive biomarkers. Nevertheless, 89 KEGG pathways were differently enriched between study groups at baseline, and up to 44 pathways within the groups when studying the transcriptional profiles over time (FDR < 0.075). The plasma-concentration of VDZ was not associated with the clinical outcome, and was not correlated with the dose of VDZ (mg/kg bodyweight).

Conclusion

There is a strong need for reliable and predictive biomarkers in decision making for personalised medicine. Our study shows that VDZ affects the transcriptional profile in blood of patients responding to treatment, whereas no gene regulation was noticed in non-responders. It also suggests that whole blood is not optimal for identifying predictive pre-treatment biomarkers based on individual genes in patients with need for this integrin inhibitor. However, treatment outcome may depend on several interacting genes, illustrated by the identification of significant pathway differences between study groups, both at baseline (T0) as well as in response to treatment (T1). Further studies are needed to confirm our findings.
P670 Identification of two additional susceptibility loci for Crohn’s disease in Koreans
Authors: Lee H S , Jung S , Ye B D , Baek J , Park D , Park S H , Yang S K , Song K
Published: May 2021

Background

Genome-wide association studies (GWAS) have identified more than 240 susceptibility loci associated with IBD mainly in Caucasians, however, there are limited studies in other populations.

Methods

To identify additional susceptibility loci in Asians, we expanded our previous study design (comprising a total of 1,621 patients with Crohn’s disease [CD] and 4,419 controls), followed by replication in an additional 582 patients with CD and 845 controls. To determine biological processes associated with candidate genes for CD, we conducted pathway analyses by MAGMA using the results obtained through the current meta-analyses and the summary statistics of the largest meta-analysis in the European population as input.

Results

The meta-analysis of Korean GWAS identified two novel susceptibility loci for CD at rs2240751 in the MFSD12-C19orf71-FZR1-DOHH region on 19p13 (pcombined = 3.03 × 10–8) and rs6936629 in the RFX6-GPRC6A-FAM162B region on 6q22 (pcombined = 3.63 × 10–8), of which rs6936629 showed significant association in European population (p = 1.88 × 10–4). Comparisons of the top 10 pathways for CD between the Korean and European data showed that MHC class Ⅱ protein complex, antigen binding, and response to antigenic stimulus-related pathways were more significant in the Korean population (Figure 1A), whereas cytokine and transcription factor-related pathways were more significant in the European population (Figure 1B).

Conclusion

Our findings provide additional biological insight into CD pathogenesis and support the importance of studying IBD genetics in diverse populations.
P679 The keystone bacterium Christensenella minuta improves colitis in in vivo preclinical Inflammatory Bowel Disease models
Authors: Kropp C , Le Corf K , Relizani K , Tambosco K , Martinez C , Chain F , Rawadi G , Langella P , Claus S , Martin R
Published: May 2021

Background

There is increasing evidence that microbiome-based therapies can correct dysbiosis and reduce inflammation associated with Inflammatory Bowel Diseases (IBD). In particular, the human commensal family of Christensenellaceae bacteria has been reported as missing in several cohorts of Crohn’s disease patients, indicating that it may have a role in maintaining microbial symbiosis in this population. To assess its potential for IBD management, we used the reference type species Christensenella minuta DSM 22607 to examine its anti-inflammatory properties.

Methods

We first performed two distinct independent preclinical colitis models: i) a moderate DNBS-induced colitis model in mice and ii) a severe TNBS-induced colitis model in rats. To decipher the mechanisms of action of C. minuta underlying the observed effects, we determined its ability to produce short chain fatty acids (SCFA) at different growth phases and we assessed its capacity to modulate the inflammatory response of human colonic cells.

Results

Our results showed that in both rodent models, C. minuta prevented intestinal damages by decreasing macroscopic scores, reduced colonic inflammation by limiting neutrophils infiltration in the colon and stimulated mucosal healing. We also confirmed that C. minuta is a high acetate and moderate butyrate producer. Finally, we showed that C. minuta displayed potent anti-inflammatory properties by decreasing the secretion of the pro-inflammatory cytokine IL-8 through NF-kB inhibition in HT-29 cells.

Conclusion

Together, these results revealed for the first time the strong anti-inflammatory properties of C. minuta and confirm its high potential as an innovative microbiome-based biotherapy for IBD.
P682 Antibiotic resistome profiles of fecal Escherichia coli isolates in association with Crohn’s disease
Authors: Siniagina M , Markelova M , Boulygina E , Laikov A , Khusnutdinova D , Abdulkhakov S , Grigoryeva T
Published: May 2021

Background

In recent years, there was a growing interest in the modulation and manipulation of the intestinal flora to treat patients through fecal microbiota transplantation (FMT). Unfortunately, 2 cases of bacteremia via FMT in 2019 occurred in patients due to extended-spectrum beta–lactamase–producing E. coli from the same stool donor. However, one of the recipients did not get an active infection. So, the association between health status and bacterial ability to resist chemicals requires further investigations.

Methods

Totally, 63 E. coli strains from 32 fecal samples (14 CD patients and 18 controls) were whole-genome sequenced on the Miseq platform (project #0671-2020-0058). The strains were tested against 15 antibiotics by a disc-diffusion assay according to EUCAST guidelines. E. coli ATCC 25922 was used as a control. Antibiotic resistance genes were predicted by the Resistance Gene Identifier and CARD database.

Results

All strains tested were susceptible only to meropenem (Figure 1). The proportion of multidrug-resistant strains in CD patients and controls did not differ significantly. Strains from both groups differed in sensitivity to amikacin and levofloxacin (Fisher’s exact test, p<0.1). Ciprofloxacin, widely used in therapy, was less effective against CD-derived strains (15%) compared to controls (3%). The inefficiency of fluoroquinolones could be due to plasmid-associated genes (qnrS1, qnrB19) and mutations in chromosome genes (gyrA, parC). Several strains carried aminoglycoside transferase genes, but only 1 CD-derived strain was non-sensitive. Susceptibility to tetracyclines did not differ between groups, and almost all strains, growing on the antibiotic, contained efflux pump genes (tetA, tetB, tetD, tetR). About half of the strains from both groups were active against penicillins carrying genes for class A (TEM-1, TEM-150) and D beta-lactamases (OXA-1). TEM-150 was only in control strains. Cephalosporin-resistant strains were in both groups and harbored AmpC type β-lactamases. Almost all strains had multidrug efflux systems (MdtEF-TolC, EmrAB-TolC, EmrKY-TolC, AcrAB-TolC), MdtG and AcrD efflux pumps, and their regulators. Although all strains contained pmrF and pmrC genes, only 1 CD-derived strain was non-sensitive to polymyxin.

Figure 1. Antibiotic resistance of E. coli strains (in %, * - p < 0.1)

Conclusion

Thus, the differences in susceptibility between CD- and control-derived strains were revealed. However, E. coli strains from healthy subjects contained antibiotic resistance genes and demonstrated activity against antibiotics of various categories, which might be crucial and should be taken into account for a safe and effective therapy in the treatment of CD.
Randomized Controlled Trial Substudy of Cell-specific Mechanisms of Janus Kinase 1 Inhibition With Upadacitinib in the Crohn’s Disease Intestinal Mucosa: Analysis From the CELEST Study
Authors: Aguilar Daniel , Revilla Lluís , Garrido-Trigo Alba , Panés Julian , Lozano Juan J , Planell Núria , Esteller Miriam , Lacerda Ana P , Guay Heath , Butler James , Davis Justin Wade , Salas Azucena
Published: May 2021

Background

Janus kinase (JAK) inhibition shows promise for treatment of patients with moderate to severe Crohn’s disease. We aimed to provide mechanistic insights into the JAK1-selective inhibitor upadacitinib through a transcriptomics substudy on biopsies from patients with Crohn's disease from CELEST.

Methods

Seventy-four patients consented to this optional substudy. Ileal and colonic biopsies were collected during endoscopy at screening and week 12 or 16. RNA isolated from 226 samples was analyzed by RNAseq, with additional qPCR analysis. Additional biopsies from patients with Crohn's disease receiving anti-tumor necrosis factor (anti-TNF; n = 34) and healthy controls (n = 10) were used for qPCR. Single-cell RNAseq public profiles were used to evaluate treatment effects on specific cellular subsets, associations with endoscopic improvement, and indirect comparisons with the anti-TNF-treated cohort.

Results

In involved areas of mucosa with endoscopic remission after upadacitinib treatment, 1156 and 76 protein-coding genes were significantly regulated (false discovery rate < 0.05) at week 12/16 in colonic and ileal biopsies, respectively (60 overlapped), compared with baseline. Upadacitinib did not significantly affect transcriptomes of noninvolved intestinal areas. CELEST patients (mostly anti-TNF-refractory) showed baseline differences in gene expression compared with a separate cohort of biologic-naïve patients. Notably, upadacitinib reversed overexpression of inflammatory fibroblast and interferon-γ effector signature markers.

Conclusions

Upadacitinib modulates inflammatory pathways in mucosal lesions of patients with anti-TNF-refractory Crohn's disease, including inflammatory fibroblast and interferon-γ-expressing cytotoxic T cell compartments. This substudy is the first to describe the molecular response to JAK1 inhibition in inflammatory bowel disease and differential effects relative to anti-TNF treatment. (Clinical trial identifier: NCT02365649)
ISDS Reform in the Context of China’s IIAs
Authors: Kong Qingjiang , Chen Kaiyuan
Published: May 2021

The investor–state dispute settlement mechanism enables investors to seek remedies in the face of a violation of related international investment agreements, which are crucial to maintaining the standards of investor protection that have been consented to by the contracting parties. On the other hand, more and more problems in the system have been exposed as the number of investor–state dispute settlement cases has increased. These range from substantive issues, such as the treatment granted to investors, to procedural ones, such as cost management and related procedures. Debates on investor–state dispute settlement reform have led to various options for reshaping the relevant mechanisms. Amid the new trend of investment liberalization and facilitation, China is undergoing a new round of bilateral investment treaty revision and free trade agreement negotiation. How the investor–state dispute settlement process is to be framed boils down to how China assesses its own interest vis-à-vis its partners and how it prioritises its objectives in international investment agreement negotiation with its partners. It is submitted that China should take a calculated risk on the investor–state dispute settlement provisions in international investment agreements with adequate consideration of competing interests.
Nitrate-responsive NIN-like protein transcription factors perform unique and redundant roles in Arabidopsis
Authors: Konishi Mineko , Okitsu Takayuki , Yanagisawa Shuichi
Published: May 2021

Upon sensing nitrate, NODULE INCEPTION (NIN)-like protein (NLP) transcription factors alter gene expression to promote nitrate uptake and utilization. Of the nine NLPs in Arabidopsis, the physiological roles of only three NLPs (NLP6–NLP8) have been characterized to date. To evaluate the unique and redundant roles of Arabidopsis NLPs, we assessed the phenotypes of single and higher order nlp mutants. Unlike other nlp single mutants, nlp2 and nlp7 single mutants showed a reduction in shoot fresh weight when grown in the presence of nitrate as the sole nitrogen source, indicating that NLP2, like NLP7, plays a major role in vegetative growth. Interestingly, the growth defect of nlp7 recovered upon the supply of ammonium or glutamine, whereas that of nlp2 did not. Furthermore, complementation assays using chimeric constructs revealed that the coding sequence, but not the promoter region, of NLP genes was responsible for the differences between nlp2 and nlp7 single mutant phenotypes, suggesting differences in protein function. Importantly, nitrate utilization was almost completely abolished in the nlp septuple mutant (nlp2 nlp4 nlp5 nlp6 nlp7 nlp8 nlp9), suggesting that NLPs other than NLP2 and NLP7 also assist in the regulation of nitrate-inducible gene expression and nitrate-dependent promotion of vegetative growth in Arabidopsis.
RNA-regulatory exosome complex confers cellular survival to promote erythropoiesis
Authors: Mehta Charu , Fraga de Andrade Isabela , Matson Daniel R , Dewey Colin N , Bresnick Emery H
Published: May 2021

Cellular differentiation requires vast remodeling of transcriptomes, and therefore machinery mediating remodeling controls differentiation. Relative to transcriptional mechanisms governing differentiation, post-transcriptional processes are less well understood. As an important post-transcriptional determinant of transcriptomes, the RNA exosome complex (EC) mediates processing and/or degradation of select RNAs. During erythropoiesis, the erythroid transcription factor GATA1 represses EC subunit genes. Depleting EC structural subunits prior to GATA1-mediated repression is deleterious to erythroid progenitor cells. To assess the importance of the EC catalytic subunits Dis3 and Exosc10 in this dynamic process, we asked if these subunits function non-redundantly to control erythropoiesis. Dis3 or Exosc10 depletion in primary murine hematopoietic progenitor cells reduced erythroid progenitors and their progeny, while sparing myeloid cells. Dis3 loss severely compromised erythroid progenitor and erythroblast survival, rendered erythroblasts hypersensitive to apoptosis-inducing stimuli and induced γ-H2AX, indicative of DNA double-stranded breaks. Dis3 loss-of-function phenotypes were more severe than those caused by Exosc10 depletion. We innovated a genetic rescue system to compare human Dis3 with multiple myeloma-associated Dis3 mutants S447R and R750K, and only wild type Dis3 was competent to rescue progenitors. Thus, Dis3 establishes a disease mutation-sensitive, cell type-specific survival mechanism to enable a differentiation program.
Impact of COVID-19 on lifestyle habits and mental health symptoms in children with attention-deficit/hyperactivity disorder in Canada
Authors: Swansburg Rose , Hai Tasmia , MacMaster Frank P , Lemay Jean-François
Published: May 2021

Objectives

The COVID-19 pandemic created an environment of restricted access to health and recreation services. Lifestyle habits including sleep, eating, exercise, and screen use were modified, potentially exacerbating adverse mental health outcomes. This study investigates the impact of COVID-19 on lifestyle habits and mental health symptoms in paediatric attention-deficit/hyperactivity disorder (ADHD) in Canada.

Methods

An online survey was distributed across Canada to caregivers of children with ADHD (children aged 5 to 18 years) assessing depression (PHQ-9), anxiety (GAD-7), ADHD (SNAP-IV), and lifestyle behaviours. Data were analyzed by gender (male/female) and age category (5 to 8, 9 to 12, and 13 to 18 years). Spearman’s correlations between lifestyle habits and mental health outcomes were conducted.

Results

A total of 587 surveys were completed. Mean child age was 10.14 years (SD 3.06), including 166 females (28.3%). The PHQ-9 and GAD-7 indicated that 17.4% and 14.1% of children met criteria for moderately severe to severe depression and anxiety symptoms respectively. Children met SNAP-IV cut-off scores for inattention (73.7%), hyperactivity/impulsivity (66.8%), and oppositional defiant disorder (38.6%) behaviours. Caregivers reported changes in sleep (77.5%), eating (58.9%), exercise (83.7%), and screen use (92.9%) in their ADHD child, greatly impacting youth. Sleeping fewer hours/night, eating more processed foods, and watching TV/playing videogames >3.5 hours/day correlated with greater depression, anxiety and ADHD symptoms, and exercising <1 hour/day further correlated with depression symptoms (P<0.01).

Conclusions

The COVID-19 pandemic has resulted in less healthy lifestyle habits and increased mental health symptoms in Canadian children with ADHD. Longitudinal studies to better understand the relationship between these factors are recommended.
SmBICs Inhibit Anthocyanin Biosynthesis in Eggplant (Solanum melongena L.)
Authors: He Yongjun , Li DaLu , Li ShaoHang , Liu Yang , Chen Huoying
Published: May 2021

Eggplant is rich in anthocyanins, which are thought to be highly beneficial for human health. It has been reported that blue light inhibitors of cryptochromes (BICs) act as negative regulators in light signal transduction, but little is known about their role in anthocyanin biosynthesis. In this study, yeast one-hybrid analysis showed that SmBICs could bind to the promoter of SmCHS, indicating that they could directly participate in eggplant anthocyanin biosynthesis. In SmBICs-silenced eggplants, more anthocyanins were accumulated, while SmBIC1-overexpression (OE) and SmBIC2-OE Arabidopsis and eggplants synthesized less anthocyanin. Quantitative real-time polymerase chain reaction also revealed that the anthocyanin structural genes, which were downregulated in SmBIC1-OE and SmBIC2-OE lines, were upregulated in SmBICs-silenced eggplants. In addition, transcriptome analysis further confirmed that differentially expressed genes of SmBICs-OE plants were enriched mainly in the pathways related to anthocyanin biosynthesis and the key transcription factors and structural genes for anthocyanin biosynthesis, such as SmMYB1, SmTT8, SmHY5, SmCHS, SmCHI, SmDFR and SmANS, were suppressed significantly. Finally, bimolecular fluorescence complementation and blue-light-dependent degradation assay suggested that SmBICs interacted with photo-excited SmCRY2 to inhibit its photoreaction, thereby inhibiting the expression of genes related to anthocyanin biosynthesis and reducing anthocyanin accumulation. Collectively, our study suggests that SmBICs repress anthocyanin biosynthesis by inhibiting photoactivation of SmCRY2. This study provides a new working model for anthocyanin biosynthesis in eggplant.
Prevalence and Characteristics of Advocacy Curricula in U.S. Medical Schools
Authors: Brender Teva D. , Plinke Wesley , Arora Vineet M. , Zhu Jane M.
Published: May 2021

Purpose

Recent national events, including the COVID-19 pandemic and protests of racial inequities, have drawn attention to the role of physicians in advocating for improvements in the social, economic, and political factors that affect health. Characterizing the current state of advocacy training in U.S. medical schools may help set expectations for physician advocacy and predict future curricular needs.

Method

Using the member school directory provided by the Association of American Medical Colleges, the authors compiled a list of 154 MD-granting medical schools in the United States in 2019–2020. They used multiple search strategies to identify online course catalogues and advocacy-related curricula using variations of the terms “advocacy,” “policy,” “equity,” and “social determinants of health.” They used an iterative process to generate a preliminary coding schema and to code all course descriptions, conducting content analysis to describe the structure of courses and topics covered.

Results

Of 134 medical schools with any online course catalogue available, 103 (76.9%) offered at least 1 advocacy course. Required courses were typically survey courses focused on general content in health policy, population health, or public health/epidemiology, whereas elective courses were more likely to focus specifically on advocacy skills building and to feature field experiences. Of 352 advocacy-specific courses, 93 (26.4%) concentrated on a specific population (e.g., children or persons with low socioeconomic status). Few courses (n = 8) focused on racial/ethnic minorities and racial inequities.

Conclusions

Findings suggest that while most U.S. medical schools offer at least 1 advocacy course, the majority are elective rather than required, and the structure and content of advocacy-related courses vary substantially. Given the urgency to address social, economic, and political factors affecting health and health equity, this study provides an important and timely overview of the prevalence and content of advocacy curricula at U.S. medical schools.
ETS1 promoted cell growth, metastasis and epithelial–mesenchymal transition process in melanoma by regulating miR-16-mediated SOX4 expression
Authors: Yang Ling-Xia , Guo Hu-Bing , Liu Sui-Yuan , Feng Hong-Ping , Shi Jin
Published: May 2021

Melanoma is a malignant tumor with high metastasis and mortality. Epithelial–mesenchymal transition (EMT) was reported to be involved in the growth and metastasis of melanoma. To investigate these sections further, we showed that E26 transformation specific 1 (ETS1) could regulate growth, metastasis and EMT process of melanoma by regulating microRNA(miR)-16/SRY-related HMG box (SOX) 4 expression. MiR-16, ETS1, SOX4 and nuclear factor κB (NF-κB) expression levels in melanoma cells were examined using qPCR. ETS1, SOX4, EMT-related proteins and NF-κB signaling pathway-related proteins were examined using western blot. Cell counting kit-8 assay, transwell assay were applied to evaluate the cell proliferation, migration and invasion of melanoma cells, respectively. Besides, a dual-luciferase reporter assay was employed to verify the binding relationship between ETS1 and miR-16, miR-16 and SOX4, miR-16 and NF-κB1. We showed that ETS1 and SOX4 were upregulated in melanoma cells, while miR-16 was downregulated. MiR-16 overexpression suppressed growth, metastasis and EMT process of melanoma. We found ETS1 could bind to the promoter region of miR-16 and inhibited its transcription. ETS1 silence could inhibit growth, metastasis and EMT process of melanoma, and inhibition of miR-16 could reverse the effects. Besides, miR-16 is directly bound to SOX4 and downregulated its expression. Rescued experiments confirmed that SOX4 overexpression abolished the inhibition effect of miR-16 mimics on growth, metastasis and EMT process of melanoma. Finally, NF-κB1 as the target of miR-16 mediated downstream biological responses. ETS1 activated NF-κB signaling pathway through miR-16 via targeting SOX4, thus promoting growth, metastasis and EMT of melanoma.
Adjuvant Temozolomide for the Treatment of Glioblastoma: A Meta-analysis of Randomized Controlled Studies
Authors: Zhao Yan , Wu Jie , Shi Lunbo
Published: May 2021

Introduction

The efficacy of adjuvant temozolomide to radiotherapy for glioblastoma remained elusive. This meta-analysis aimed to explore the influence of radiotherapy plus adjuvant temozolomide on the efficacy and safety for glioblastoma.

Methods

We have searched several databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through November 2020 and included randomized controlled trials assessing the efficacy and safety of adjuvant temozolomide to radiotherapy for glioblastoma.

Results

Seven randomized controlled trials and 1900 patients were included in the meta-analysis. Overall, compared with radiotherapy for glioblastoma, adjuvant temozolomide was associated with significantly increased survival rate [odds ratio (OR), 4.04; 95% confidence interval (CI), 2.61–6.24; P < 0.00001], median progression-free survival (mean difference, 0.55; 95% CI, 0.03–1.07; P = 0.04), and hematological complications (OR, 4.12; 95% CI, 1.43–11.88; P = 0.009), but revealed no remarkable influence on adverse events (OR, 0.87; 95% CI, 0.36–2.09; P = 0.75) or serious adverse events (OR, 2.20; 95% CI, 0.55–8.70; P = 0.26).

Conclusions

Adjuvant temozolomide in combination with radiotherapy may improve the treatment efficacy for glioblastoma.
Expression of zebrafish Brn1.2 (Pou3f2) and two Brn-3a (Pou4f1) POU genes in brain and sensory structures
Authors: Kitambi Satish , Chandrasekar Gayathri
Published: May 2021

POU genes are characterized by a conserved POU DNA-binding domain, and are divided into six subclasses. Class III and IV POU genes are predominantly expressed in the developing nervous system. POU class III genes are critical for several neuronal cell differentiation and class IV POU genes serve important functions in the differentiation and survival of sensory neurons. In this study, we attempted to identify POU genes in the zebrafish and pufferfish genomes by using existing bioinformatics tools. We analysed the expression of zebrafish brn1.2 and brn3a genes (brn3a1 and brn3a2)) using whole-mount in situ hybridisation. Similarly to the mammalian orthologue, zebrafish brn1.2 was widely expressed in the forebrain, midbrain and hindbrain. During the late stages of embryogenesis, brn1.2 expressing cells were located in the preoptic area and in the auditory vesicles. Expression of both zebrafish brn3a genes was detected in trigeminal ganglia, cranial sensory ganglia, sensory neurons along the dorsal spinal cord, in the anterior and posterior lateral line placodes (ALL and PLL), retinal ganglion cell layer, optic tectum and in small cell clusters in the forebrain and hindbrain. Similar to mammalian Brn3a, zebrafish brn3a genes were detected in the retina and sensory structures. However, different domains of expression were also observed, namely in spinal sensory neurons, and lateral line system.
The gilded path: capital, habitus and illusio in the fund management field
Authors: Millar John
Published: May 2021

Purpose

The fund management sector plays an important role in society. The sector exists in close proximity to the accounting profession and the concerns of the paper reflect themes discussed by accounting scholars, particularly financialization, inequality and life within elite professional service organizations.

Design/methodology/approach

This is an interpretive study of the fund management field based in the UK. It is based on 32 semi-structured interviews with individuals with personal experience of the field, combined with reflections from the researcher's own experience as a practitioner within the field.

Findings

The paper describes the backgrounds and motivations of individuals entering the field, the recruitment processes through which they are admitted, and the different strategies used to gain admission to the field. It explores the habitus of successful professionals in the field and the effects of this habitus.

Social implications

An important social implication of the paper is the problematization of the fund management industry's dislocation from broader society.

Originality/value

By identifying the different strategies employed by applicants from different backgrounds, it highlights the role of reflexive agency and the complicity between agent and field. Recognizing that professional fund management is organized as a game, it suggests that individuals are so committed to the game they know they are playing that they fail to realize that they are also drawn into a different game, namely the absorbing game of being a fund manager.
IPD-inspired framework for measuring stakeholder integration in public-private partnerships
Authors: Malaeb Zeina , Hamzeh Farook R.
Published: May 2021

Purpose

In a public-private partnership (PPP), the private sector is represented by a company termed the special purpose vehicle (SPV), which combines different stakeholders including designers, contractors and service providers under one umbrella. Correct SPV team selection is critical to ensure PPP success as the SPV must act as an integrated entity. In fact, unless the SPV takes an active role in developing trust and promoting integration principles, segmentation of interests, highly adversarial atmospheres, loss of value and economic inefficiency will prevail. Absence of awareness of such principles among stakeholders and the scarcity of literature investigating SPV stakeholder integration create great risks that jeopardize project success. Accordingly, to mitigate the aforementioned risks and provide stakeholders with both the knowledge and the tools to instigate and maintain integration, this paper aims to develop and test a framework to measure SPV stakeholder integration, inspired by the correlation between integrated project delivery (IPD) and SPV operations.

Design/methodology/approach

Following a design science research approach, a structured review is conducted to develop the SPV integration metrics and framework. The framework is then validated through face validation by a panel of industry and academic experts to assess its applicability in measuring SPV integration. Finally, the framework is tested on a well-recognized international PPP project to measure the SPV integration level, and the outcomes are discussed and analyzed.

Findings

The framework was able to assess the integration level of the studied SPV highlighting several areas of low-integration settings and providing guidance for achieving better integration.

Originality/value

This research is the first that develops a model to investigate the SPV’s integration level, from a holistic IPD perspective, to enable successful relationship management and enhance collaboration success. This study inspires practical recommendations for PPP practitioners to reduce the risks of segregated SPVs and their contribution to PPP failure.
Can efficient transport moderate real sector productivity?
Authors: Arshed Noman , Sardar Muhammad Shahzad , Iqbal Mubasher
Published: May 2021

Purpose

This study aims to test the role of infrastructure for economic growth. For this purpose, panel data of the world is selected from 1998 to 2018 and the study has used slope moderator to test the productivity of real economic activity with economic growth.

Design/methodology/approach

In this context, the feasible generalized least square method is adopted to estimate the results. Four types of infrastructure indicators i.e. quality of air, port, rail and road are used along with disaggregated GDP.

Findings

According to the results of this study, the role of industrial and agricultural value addition without infrastructure is negative. For industrial value addition, the cross product with all infrastructure types positively impacts economic growth. All the infrastructures, along with services value addition, except seaport, are contributing to economic growth positively. Along with agriculture value addition, only road infrastructure is contributing to economic growth positively. This study has also used two control variables i.e. quality of education and institutions. These variables are also found to be positive and significant with economic growth.

Originality/value

This study explores the moderating role of quality of infrastructure sector on real sector productivity, which is leading to economic growth.