bluuebunny/crossref_metadata_2025 huggingface dataset:
P489 Rescue treatment with original versus biosimilar infliximab in biologic-naïve patients with moderate-severe Ulcerative Colitis and corticosteroid failure
Authors: Muñoz-Villafranca C , Ogueta M Á , Ramírez de la Piscina P , Álvarez-Herrero B , Loizate A , Gómez-Zabala J M , De La Maza-Ortiz S , Aresti U , Gorostiza I , Arreba P , Irigoyen M , Ortiz de Zárate J
Published: May 2021

Background

Infliximab is effective as rescue therapy in moderate-severe Ulcerative Colitis (UC). Subsequently, a biosimilar of infliximab has been approved for the same indications, as its effectiveness is considered similar to the original infliximab. Our aim was to analyse the colectomy rate and the efficacy of original infliximab (Remicade®) versus biosimilar infliximab (Inflectra®) in patients with moderate-severe UC who failed to respond to intravenous corticosteroids.

Methods

We performed a retrospective and observational study in two hospitals in the Basque Country. All patients hospitalised between 2010–2020 with moderate-severe UC, without response to intravenous corticosteroids and rescue treatment with infliximab were consecutively included. Two cohorts were established: the first one from 2010 to 2015 in patients treated with Remicade®, and the second one from 2015 to 2020 in patients with Inflectra®. We assessed all patients that had received at least one dose of infliximab. Patients were followed for a period of one year until loss of response or colectomy. Early colectomy is the surgery performed until week 12, and late colectomy between week 12 and one year. At the moment of hospitalisation all patients were clinically and endoscopically evaluated by Mayo Score. The clinical response was assessed in week 14 and 52.

Results

A total of 85 patients were evaluated, 53 (64.4%) in Remicade® group and 32 (37.6%) in Inflectra® group. 21.17% (18/85) of the patients had a colectomy in one year. 77.7% of the colectomies took place in the first 12 weeks (14/18, 7 patient in each group). Rates of early (13.8% vs 21.9%, p=0.297) and late colectomy (17% vs 28.1%, p=0.223) showed a numerical but non-statistically significant difference in favour of Remicade®.

Transfusion (OR=4.20, IC 95% [1.38–12.77], p=0.011) and the presence of cytomegalovirus in the colonic mucosa (OR=4.07, IC 95% [1.31–12.63], p=0.015) were univariate predictors of colectomy. A statistically significant difference was found in clinical remission at week 14 (49.1% vs 25%, p=0.040) but not at week 52 (73.7% vs 50%, p=0.074) in patients with Remicade® versus Inflectra®. Neither clinical activity nor mucosa activity showed relationship with risk of colectomy.

Conclusion

1. The rescue therapy with infliximab in patients with moderate-severe Ulcerative Colitis who failed to respond to intravenous corticosteroids could show a favourable trend for Remicade® against Inflectra®. However, further research is needed to confirm it.

2. The need of transfusion and the presence of cytomegalovirus in the colonic mucosa could be predictive factors of colectomy.
P564 Validation of the IBD-Disk instrument in a Portuguese cohort
Authors: Silva Mendes S , Ferreira P , Antunes P , Gonçalves M , Leal T , Gonçalves B , Rebelo A , Arroja B , Caetano A C , Gonçalves R , Soares J B
Published: May 2021

Background

Inflammatory bowel disease (IBD) affects several dimensions of health-related quality of life. The IBD-Disk scale was designed to provide immediate illustration of disability reported by patients with IBD, previously validated in two cohort studies. The aim of this study is to validate the IBD-Disk in a Portuguese cohort in a clinical setting according to the COnsensus-based Standards for the selection of the health Measurement INstruments (COSMIN) recommendations.

Methods

After translation to Portuguese, a group of IBD patients was invited to fill-in the IBD-Disk at baseline (T0), after 2 weeks (T1), and after 3 months (T2), from July 2020 to February 2021. At T0 and T2 the patients also completed the IBD-Disability Index. We evaluated reliability (internal consistency, test-retest, and inter-rater reliability and measurement error), construct validity, responsiveness, and interpretability.

Results

At baseline, 154 patients (107 - Crohn′s disease; 46 - ulcerative colitis) completed the IBD-Disk. After 2 weeks and 3 months, 64 and 114 patients repeated the questionnaire, respectively. Factor analysis confirmed the unidimensionality of the scale and reduced the final version to 10 items. Internal consistency was excellent with a Cronbach’s α of 0.916. The intraclass correlation coefficient was 0.95 for test-retest (baseline and 2 weeks). To evaluate construct validity, the IBD-Disk was compared with the IBD-Disability Index with a significative positive correlation (r=0.850; p<0.001). IBD-Disk scores ranged from 0 to 93 with a mean of 38.18±25.39. Female gender (β =0,3; p<0,001) and professional inactivity (β=0.28, p=0.014) were associated with higher IBD-Disk scores. Neither floor nor ceiling effects were observed.

Conclusion

The Portuguese version of IBD-Disk is a reliable, valid, and responsive tool to assess disability in Portuguese IBD patients. This study confirms the utility of this instrument in the evaluation of IBD patients in diverse populations.
P577 Withdrawal of thiopurines in patients with Ulcerative Colitis in remission
Authors: Amor Costa C , Suárez Ferrer C , Poza Cordón J , Rueda García J L , Sánchez Azofra M , Martín Arranz E , González Diaz I , Amiama Roig C , García Ramirez L , Martín Arranz M D
Published: May 2021

Background

Thiopurines (TP) are widely used in monotherapy in patients with ulcerative colitis (UC), mainly for the maintenance of remission in case of corticodependence or corticoresistance after cyclosporine use. However, these are drugs with significant side effects, especially in the long term.

The optimal duration of treatment with TP remains unknown, so it is important to determine the risk factors for relapse in order to identify the group of patients in which treatment can be withdrawn.

Methods

A retrospective study was performed. Patients with UC in remission, in maintenance treatment with TP, who had discontinued the drug due to either maintained remission or the onset of adverse effects were included.

Results

26 patients were included, 1 with proctitis, 9 with left colitis and 16 with pancolitis. 24 (92.31%) were treated with azathioprine and 2 (7.69%) with mercaptopurine. The mean treatment time with TP was 68.09 months (standard deviation 56.65). 11 patients (42.31%) discontinued TP due to adverse effects and the remaining patients (57.69%) discontinued it by medical decision because they were in prolonged remission. After withdrawal of TP, 92.34% of patients continued treatment with mesalazine and the remaining 7.69% without concomitant treatment.

During follow-up, 10 patients (38.4%) relapsed and 16 patients (61.53%) had no relapse until the end of follow-up. The mean time from TP withdrawal to the onset of relapse was 69.15 months (standard deviation 52.53). Of the 10 patients who presented a flare, 5 (50%) were controlled by optimizing the dose of mesalazine, 4 (40%) required the addition of oral corticosteroids and 1 (10%) required biologics.

No significant differences were found when comparing the time to relapse if the reason for discontinuation of TP was having had an adverse effect (65.05 months) or maintained remission (79.79 months) (p=0.42). No statistically significant differences were found in time to relapse when comparing time on TP treatment, presence of concomitant treatment with mesalazine or active smoking.

Conclusion

One third of patients relapsed after TP withdrawal. Discontinuation of TP in patients with UC in remission should be individualized according to the patient’s risk factors, the indication and the duration of treatment.
P604 Evaluation of management heterogeneity and complications of Crohn’s disease in Catalonia. A population quality care study
Authors: Brunet E , Melcarne L , Llovet L , Vela E , Cleries M , Pontes C , Garcia-Iglesias P , Albert V , Calvet X
Published: May 2021

Background

Heterogeneity in the treatment of a disease is a marker of suboptimal quality of care. Recent studies suggest that there is a marked heterogeneity in the management of inflammatory bowel disease.

The aim of this study is to evaluate the heterogeneity in the treatment used and the outcomes (rate of hospitalization and surgery) for Crohn’s disease (CD) in the different health areas of Catalonia.

Methods

All patients with CD included in the Catalan Health Surveillance System (CHSS) including data on more than 7 million individuals from 2011 to 2017 were identified using with the ICD-9-CM codes. The different Catalonian health areas were grouped into 19 groups according to the reference hospital (figure 1). Exposures to different treatments were retrieved from the electronic dispensation records.

Data on hospitalizations and surgeries were also extracted from the CHSS according to ICD-9-CM codes. Treatment used rates (systemic corticosteroids, non-biological and biological immunosuppressant) and outcome rates (hospitalization and surgery) were calculated.

Results

The use of systemic corticosteroids presented a decreasing trend over the study period, with an average rate of use of the total number of patients in the different territories between 10% and 16% (figure 2). The use of non-biological immunosuppressant treatment has remained stable, with an average rate of use ranging from 20% to 40% (figure 3). On the other hand, the use of biological immunosuppressant treatment increased, with an average rate of use in the different territories ranging from 10 to 22% (figure 4).

Hospitalizations for any reason showed an increasing trend between 2011–2017 with an average rate between 19% and 30% per year depending on the area. Contrarily, hospitalizations for CD presented a decreasing trend, with an average rate between 5% and 10% per year.

Surgical treatment (both resections and ostomies) remained stable over time. Rates per year were between 1% and 2%.

Conclusion

In this population study we appreciated an important heterogeneity in the use of non-biological and biological immunosuppressant treatments, identifying use rates of almost the double in some of the areas. There is also a remarkable variability in the rate of hospitalizations for CD between certain areas of Catalan territory.
P634 Trajectories of oral budesonide use in Crohn’s disease cohort of Tuscan patients
Authors: Bertani L , Ferraro S , Bartolini C , Convertino I , Giometto S , Cappello E , Valdiserra G , Tillati S , Blandizzi C , Lucenteforte E , Gini R , Tuccori M , Costa F
Published: May 2021

Background

Crohn’s disease (CD) is an immune-mediated inflammatory chronic disorder of the gastrointestinal tract. The therapeutic approach includes firstly oral budesonide (OB), followed by immunomodulatory drugs and biologics. The aim of the present study was to identify and characterize adherence trajectories of OB in CD patients and related patterns.

Methods

In this retrospective cohort study, data was retrieved from administrative healthcare databases in Tuscany, an Italian region. Patients were included if they had a first record of a diagnosis of ICD-9 or disease exemption or a first record of dispensation of OB as CD patient, in the period from 6/1/2011 to 6/30/2016 (index date, ID). Patients < 18 years old at ID or with history of data before ID < 5 years or follow-up of data after ID < 3 years were excluded. Patients with autoimmune hepatitis, cancer and no dispensation of OB were excluded from CD cohort. We considered as covariates sex, age, and number of concomitant drugs during the month before ID. We estimated adherence to OB monthly through the Medication Possession Ratio and computed trajectory of adherence treatment with a procedure consists into 3 steps: 1) computation of 24 statistical measures; 2) factor analysis; 3) cluster analysis. We described the adherence in the clusters.

Results

3333 patients were included CD cohort, among them 1262 were excluded for no dispensation of OB. 2071 were patients included the computation of trajectory of OB use. Trajectories’ curves showed three difference clusters of adherences to OB, which identify two main subgroups of OB users: 925, 603 and 543 were the patients in each cluster. Cluster 1 is represented by a curve of adherence that rapidly decreased to 20–30% of adherence within 5 months. Instead, cluster 2 and 3 described patterns of a short therapy timing, with discontinuation within about 4 months, likely referring to an acute treatment of CD, typical treatment approach used in mild to moderate CD. Statistically significance differences were evidenced between covariates across the clusters.

Conclusion

Trajectories’ curves showed three difference clusters of adherences, which identify two main subgroups of OB users. Further analyses need to characterize the identified clusters in order to evaluate possible inappropriate use of drug (cluster 1) and potential switch to other therapies (cluster 2 and 3). Finally, these results could clarify drug use in patients with CD and provide new insights in order to improve management of patients by clinicians.
P658 Is vitamin D deficiency related to fat malabsorption or inflammation in Inflammatory Bowel Disease? Preliminary results from the Fat-D study
Authors: Müller C , Aksan S , Farrag K , Schröder O , Aksan A , Stein J M
Published: May 2021

Background

Vitamin D deficiency is highly prevalent in patients with inflammatory bowel disease (IBD). The question of whether vitamin D status is a contributory factor or a consequence of IBD, or maybe both, remains unanswered, and is confounded by the complexity of inflammation, IBD and vitamin D. Fat malabsorption has been proposed as a possible reason for deficiencies of vitamin D in IBD. The aim of this study was to further understanding of vitamin D deficiency in IBD by investigating possible causal relationships of fat malabsorption and inflammation on vitamin D levels in this complex context.

Methods

In a comparative, cross-sectional study in IBD patients, 25(OH)D was analysed by LCMS/MS. Serum β-carotene levels were used as a biomarker for fat malabsorption. Vitamin K1, another fat-soluble vitamin, was used to affirm a possible causative relation between β-carotene and vitamin D in case of fat malabsorption. β-carotene and vitamin K were measured in serum by HPLC. Inflammation was characterised by serum hsCRP<5mg/L.

Results

51 IBD patients (30f;20CD/18UC;45.3±16.3y; 21 with inflammatory activity) were enrolled. In patients with vs. without inflammation, serum 25(OH)D levels were significantly lower (26.5±14.6ng/mL vs. 36.8±12.6ng/mL, p<0.05), while serum vitamin K1 (1.4±0.5µg/L vs. 1.2±0.4µg/L) and β-carotene (28.5±0.6.0µg/dL vs. 35.9±5.4µg/dL) levels were similar (p>0.05). 36/51 of the patients had low serum β-carotene levels, indicating steatorrhoea. Neither 25(OH)D (32.1.5±13.8ng/mL vs. 33.6±15.8ng/mL) nor vitamin K1 (1.3±0.5µg/L vs. 1.2±0.4µg/L) levels differed according to the presence vs. absence of steatorrhoea (p>0.05). Similarly, no correlation was found for 25(OH)D (r=0.024, p=0.875) or serum vitamin K1 (r=0.111, p=0.462) with β-carotene levels. On the other hand, 25(OH)D levels were significantly inversely correlated with hsCRP (r=-0.338, p=0.015), whereas vitamin K1(r=0.050, p=0.731) and β-carotene (r=-0.118, p=0.438) did not show a similar relation.

Conclusion

Vitamin D levels were confirmed to be related to inflammation in IBD. A lack of correlation with fat malabsorption, as indicated by β-carotene levels, or with steatorrhoea, was found for vitamin D and confirmed by measuring and comparing serum levels of an additional fat-soluble vitamin, K1. We conclude that low vitamin D levels in patients with IBD are related to inflammation rather than fat malabsorption.
P672 A tertiary multicenter cohort of patients with chronic intestinal pseudo-obstruction and Crohn’s disease: a rare association with a high prevalence of monogenic disorders
Authors: De castelbajac F , Charbit-Henrion F , Goulet O , Cerf-Bensussan N , Treton X , Stefanescu C , Cazals-Hatem D , Billiauws L , Bouhnik Y , Joly F , Uzzan M
Published: May 2021

Background

Chronic intestinal pseudo-obstruction (CIPO) is a rare condition that is not commonly associated with Crohn’s disease (CD).

We performed a cohort study aiming at identifying clinical, immunological and genetic features as well as response to conventional CD treatments of patients co-affected with CIPO and CD.

Methods

We conducted an observational retrospective cohort study in two tertiary CIPO and IBD centers.

Patients with parenteral nutrition-dependent CIPO and features of CD including large intestinal or perianal ulcers, strictures, abscesses and fistula with pathology findings compatible with CD, were included.

We used flow-cytometry and targeted-next generation sequencing to identify immune defects and monogenic causes in 129 predefined genes responsible for monogenic enteropathies

Results

Eight unrelated patients were studied. 5 had a myogenic phenotype and 3 had a neurogenic form with histological exam for all patients. CD involved small bowel in all cases whereas one patient had ileocolonic involvement. Two patients had perianal complex fistula. Seven patients had a stricturing form and 1 had an inflammatory-only behavior. No patient had a penetrating form. All patients were diagnosed with CIPO prior to CD. Median age at CIPO diagnosis was 11.5 years old (IQR 0,31.5) while it was 22.5 (IQR 19,29) at CD diagnosis. At CD diagnosis, mean fecal calprotectin level was 551 ug/g (range 390 - 1200) and citrulline averaged 23.6 umol/l (range 15–35 umol/l).

Histopathological analyses of intestinal specimens revealed ulcerations for half of the patients, increase in intraepithelial lymphocytes in 3, granuloma and cryptitis in 1 patient.

Abnormalities in peripheral lymphocytes’ subsets were found in 2 patients. 5 patients were ultimately diagnosed with monogenic forms of enteropathy: 2 in ACTG2, with an autosomal dominant inheritance, 1 with a STAT1gain of function, (GOF) and two with recessive inheritance: TYMP. All patients received steroids with clinical response in 2. 6 patients received antiTNF, with only one sustained remission. Two patients received vedolizumab and 2 were treated with ustekinumab. Except for antiTNF in 1 patient, common CD treatments did not lead to any improvement. Of note, antiJAK therapy in a patient with STAT1GOF failed to induce remission.

Conclusion

Herein is described the first cohort of extensively genetically and immunologically explored patients co-affected with CIPO and CD. Immune defects were common and monogenic forms were found with a high prevalence. Rates of response to biologic treatment were very low. Identification of monogenic cause through immunological and genetic explorations is warranted in patient with CIPO-CD association as it could lead to targeted therapy and genetic counseling.
P675 Flavonoid-degrading bacteria have central positions in correlation network analysis in patients with Inflammatory Bowel Disease
Authors: Pisani A , Rausch P , Ellul S , Bang C , Tabone T , Marantidis Cordina C , Zahra G , Ellul P , Franke A
Published: May 2021

Background

Correlation networks are employed to assess the interactions between different bacteria. The aim of this study was to assess which bacterial species had central positions in a network analysis in faecal samples of patients with IBD who are in remission.

Methods

The fecal microbiota of 98 Maltese patients with IBD who were in remission and a control group (97 controls) were analyzed by 16S rRNA sequencing.

To generate co-abundance networks the SparCC algorithm as implemented in mothur was employed (50 samplings, 100 iterations, 10,000 permutations) based on Amplicon sequence variants (ASV) abundances (shared among 10% samples) at a P-value cutoff of PFDR≤0.05 and a correlation strength above the median of non-zero correlations.

Results

Correlation network analysis identified two flavonoid-degrading bacteria to be more important than expected by chance. Flavonifractor plautii (previously known as Clostridium Orbiscindens and Eubacterium plautii) which associated to IBD more than to controls and Eggertella lenta, which associated to patients with Ulcerative colitis (UC), had a high network importance on several levels, with a very central position (betweenness) and many associations to other community members (node degree), which are themselves important mediators (PageRank®) (Figure 1) Other bacteria occupying highly central positions in the community network included Oscillibacter uncl., Alistipes shahii and members of the order Clostridiales. These associated to controls and are known butyrate producers, usually associated with a beneficial effect on gut homeostasis. Eigenvalue centrality identified a strongly correlated group of Enterobacteriaceae.

Figure 1: The barplots show the top 50 bacteria within the network based on their centrality measures (Betweenness, Degree, Eigenvalue centrality, PageRank).

Highlighted in red are network members with a higher importance than expected by chance, based on a Z-test against 10’000 randomized networks (P ≤ 0.05). Highlighted as well are the associations of the respective ASVs to various factors, as detected by indicator species analysis (p≤0.05).

Conclusion

Flavonoids have been described to have anti-inflammatory properties and flavonoid-degrading bacteria have been associated with the prevention of malignancy, cardiovascular disease, diabetes type 2 and cognitive decline. In mice studies, oral administration of Flavinofractor plautii was noted to suppress Th2 immune responses. Thus, one may postulate that their presence may be important in the maintenance of IBD, although in a state of remission. Future studies should provide more evidence on their role and whether the colonization of flavonoid degrading bacteria can induce remission or conversely increase chronicity or severity of IBD.
P678 Definition of a microbial signature as a predictor of post-surgical recurrence in patients with Crohn’s disease
Authors: Oliver L , Amoedo J , Julià D , Camps B , Ramió-Pujol S , Malagón M , Torres P , Domènech E , Guardiola J , Serra-Pagès M , Garcia-Gil J , Aldeguer X
Published: May 2021

Background

Although there are several effective drugs for the treatment of Crohn’s disease (CD), almost 80% of patients will end up needing a surgical resection throughout their lives. This procedure is not always curative, as the disease often reappears in the intestine. Endoscopic recurrence occurs in 65%-90% of patients after one year from surgery. The aetiology of the recurrence is unknown; however, several studies have shown how the resident microbiota is modified after surgery.

The aim of this study is to evaluate samples from patients with CD before and after an intestinal resection to determine if at baseline there are differences in the abundance of different microbial markers, which could be capable of predicting endoscopic recurrences.

Methods

In this observational study, a stool sample was obtained from 20 patients with CD before undergoing surgery, recruited at Hospital Universitari Dr. Josep Trueta, Hospital Universitari of Bellvitge, and the Hospital Universitari Germans Trias i Pujol.

From each sample, DNA was purified and the relative abundance of the following microbial markers was quantified using qPCR: F. prausnitzii (Fpra) and its phylogroups (PHG-I and PHG-II), E. coli (Eco ), A. muciniphila (Akk), Ruminococcus sp. (Rum), Bacteroidetes (Bac), M. smithii (Msm), and total bacterial load (Eub).

Results

Individually, none of the biomarkers demonstrated the ability to differentiate patients who will develop post-surgical recurrence from those who will not. In contrast, the combination of 4 microbial markers (Eco, PHGI, Bac, and Eub) showed a high capacity of discrimination between the 2 groups. The algorithm that incorporates these three markers shows a sensitivity and specificity of 100% and 90.91%, respectively, and a positive and negative predictive value of 90.00% and 100%, respectively.

Conclusion

A microbial signature to determine patients who will have post-surgical recurrence has been identified. This tool can be very useful in daily clinical practice allowing to schedule a personalized therapy, enabling preventive treatment only in that subgroup of patients who really require it. A broader prospective study will be needed to validate these results.
Comparison of Sex Pheromone and Kairomone-Enhanced Pheromone Lures for Monitoring Oriental Fruit Moth (Lepidoptera: Tortricidae) in Mating Disruption and Non-Disruption Tree Fruit Orchards
Authors: Walgenbach James F , Schoof Steven C , Bosch Dolors , Escudero-Colomar Lucia-Adriana , Lingren Bill , Krawczyk Grzegorz
Published: May 2021

Oriental fruit moth, Grapholita molesta (Busck), populations were monitored using standard sex pheromone lures (OFM L2) and kairomone-enhanced lures to aid the interpretation of trap captures with enhanced relative to conventional lures. Initially, comparison of 10 different lures showed that a10X load of OFM pheromone, codlemone, terpinyl acetate, and acetic acid were key components of the most attractive lures (TRE11034 and 1123). Subsequent trapping studies in mating disruption and non-disrupted orchards in the United States and Spain compared trap captures with TRE1123 and OFM L2 lures. Compared to the OFM L2 lure, the TRE1123 lure captured more moths in mating disruption and non-disrupted orchards, caught female moths, improved the precision of mean population estimates, and led to greater resolution of generational flights. Suppression of trap captures in mating disruption versus non-disrupted orchards was similar with both lures. There were significant linear correlations between weekly trap captures with the two lures in the majority of mating disruption and non-disrupted orchards across locations and years. Furthermore, regression of the slopes of trap capture regressions (i.e., attractiveness of enhanced lures relative to sex pheromone lures alone) versus moth density (as measured by mean cumulative moth capture with TRE1123 and OFM L2 lures) exhibited a significant positive relationship in non-disrupted orchards, indicating enhanced lures were relatively more attractive under high population densities. This relationship was not significant in mating disruption orchards, likely due to the density independent, non-competitive mechanism of mating disruption for oriental fruit moth when using high-dose reservoir dispensers.
What causes hot markets for equity IPOs? An analysis of initial public offerings in the Netherlands, 1876–2015
Authors: de Jong Abe , Legierse Wilco
Published: May 2021

This paper explains fluctuations in the number of initial public offerings (IPOs) between 1876 and 2015 in the Netherlands. We test an econometric model and find that the number of IPOs is strongly related to the economic growth and the size of the stock exchange. We also find that IPOs are timed to coincide with favorable market conditions. Our model explains almost 50 percent of the fluctuations and most of the hot markets. To further understand IPO waves, we conduct a descriptive analysis, which yields two additional causes for hot markets, i.e., high capital needs and investors’ expectations for specific industries.
Quality of child healthcare in European countries: common measures across international databases and national agencies
Authors: Rocco Ilaria , Tamburis Oscar , Pecoraro Fabrizio , Luzi Daniela , Corso Barbara , Minicuci Nadia
Published: May 2021

Background

The evaluation of child healthcare is not yet widely explored, especially from a cross-country comparison perspective. The routine adoption of measures by national assessment agencies is under-investigated. Though the guiding principles developed at international level call for a child-centric multi-dimensional evaluation of child care, its feasibility is hampered by the availability of robust and harmonized data.

Methods

To explore the data availability, international databases (IDBs) were scrutinized and measures dealing with child health-related issues were collated. In parallel, an ad hoc questionnaire was administrated to 30 Country Agents (CAs) to gather measures routinely adopted at local level. To facilitate the comparison of measures, a three-level conceptual map was developed.

Results

The IDBs yielded at 207 measures that pertained mainly to non-health determinants of health, whereas the 352 measures obtained from CAs focused on process and outcome. A set of 33 common measures that related to immunization, morbidity and mortality were identified.

Conclusions

A limited set of measures used both in IDBs and at national level identify common areas of concerns that certainly capture crucial issues with child prevention and health outcomes. However, they are far from satisfying a child-centric multi-dimensional approach to the evaluation of child well-being and well-becoming. There is room for improvement at both international and national levels. IDBs should include and harmonize measures that concern the provision of child-centric services and encompass physical, social and mental development. At the national level, efforts towards the inclusion of measures that concern non-health determinants of health should be pursued.
Were immigrants on the frontline during the lockdown? Evidence from France
Authors: Gosselin Anne , Melchior Maria , Desprat Diane , Devetter François-Xavier , Pannetier Julie , Valat Emmanuel , Memmi Sarah
Published: May 2021

In France, immigrants’ excess of mortality was higher than natives’ during the Spring 2020 lockdown. Were immigrants in frontline jobs and more exposed to Covid-19? Based on a nationally representative survey, we model the probability to work in a frontline job according to migratory status, taking sociodemographic and occupational characteristics into account. Compared to natives (Metropolitan France), being an African immigrant was associated to higher probability to work in a frontline job [adjusted odds ratio (aOR) = 1.82 (1.23–2.71)], as well as being born in French Overseas Departments [aOR = 1.64 (1.23–2.18)], reflecting racial division of work and higher Sars-Cov-2 exposure of immigrant and minority populations.
Genome-wide analysis in Drosophila reveals diet-by-gene interactions and uncovers diet-responsive genes
Authors: Francis Deanne , Ghazanfar Shila , Havula Essi , Krycer James R , Strbenac Dario , Senior Alistair , Minard Annabel Y , Geddes Thomas , Nelson Marin E , Weiss Fiona , Stöckli Jacqueline , Yang Jean Y H , James David E
Published: May 2021

Genetic and environmental factors play a major role in metabolic health. However, they do not act in isolation, as a change in an environmental factor such as diet may exert different effects based on an individual’s genotype. Here, we sought to understand how such gene–diet interactions influenced nutrient storage and utilization, a major determinant of metabolic disease. We subjected 178 inbred strains from the Drosophila genetic reference panel (DGRP) to diets varying in sugar, fat, and protein. We assessed starvation resistance, a holistic phenotype of nutrient storage and utilization that can be robustly measured. Diet influenced the starvation resistance of most strains, but the effect varied markedly between strains such that some displayed better survival on a high carbohydrate diet (HCD) compared to a high-fat diet while others had opposing responses, illustrating a considerable gene × diet interaction. This demonstrates that genetics plays a major role in diet responses. Furthermore, heritability analysis revealed that the greatest genetic variability arose from diets either high in sugar or high in protein. To uncover the genetic variants that contribute to the heterogeneity in starvation resistance, we mapped 566 diet-responsive SNPs in 293 genes, 174 of which have human orthologs. Using whole-body knockdown, we identified two genes that were required for glucose tolerance, storage, and utilization. Strikingly, flies in which the expression of one of these genes, CG4607 a putative homolog of a mammalian glucose transporter, was reduced at the whole-body level, displayed lethality on a HCD. This study provides evidence that there is a strong interplay between diet and genetics in governing survival in response to starvation, a surrogate measure of nutrient storage efficiency and obesity. It is likely that a similar principle applies to higher organisms thus supporting the case for nutrigenomics as an important health strategy.
Genomic prediction and QTL mapping of root system architecture and above-ground agronomic traits in rice (Oryza sativa L.) with a multitrait index and Bayesian networks
Authors: Sharma Santosh , Pinson Shannon R M , Gealy David R , Edwards Jeremy D
Published: May 2021

Root system architecture (RSA) is a crucial factor in resource acquisition and plant productivity. Roots are difficult to phenotype in the field, thus new tools for predicting phenotype from genotype are particularly valuable for plant breeders aiming to improve RSA. This study identifies quantitative trait loci (QTLs) for RSA and agronomic traits in a rice (Oryza sativa) recombinant inbred line (RIL) population derived from parents with contrasting RSA traits (PI312777 × Katy). The lines were phenotyped for agronomic traits in the field, and separately grown as seedlings on agar plates which were imaged to extract RSA trait measurements. QTLs were discovered from conventional linkage analysis and from a machine learning approach using a Bayesian network (BN) consisting of genome-wide SNP data and phenotypic data. The genomic prediction abilities (GPAs) of multi-QTL models and the BN analysis were compared with the several standard genomic prediction (GP) methods. We found GPAs were improved using multitrait (BN) compared to single trait GP in traits with low to moderate heritability. Two groups of individuals were selected based on GPs and a modified rank sum index (GSRI) indicating their divergence across multiple RSA traits. Selections made on GPs did result in differences between the group means for numerous RSA. The ranking accuracy across RSA traits among the individual selected RILs ranged from 0.14 for root volume to 0.59 for lateral root tips. We conclude that the multitrait GP model using BN can in some cases improve the GPA of RSA and agronomic traits, and the GSRI approach is useful to simultaneously select for a desired set of RSA traits in a segregating population.
The Assembled and Annotated Genome of the Fairy-Ring Fungus Marasmius oreades
Authors: Hiltunen Markus , Ament-Velásquez Sandra Lorena , Johannesson Hanna
Published: May 2021

Marasmius oreades is a basidiomycete fungus that grows in so called “fairy rings,” which are circular, underground mycelia common in lawns across temperate areas of the world. Fairy rings can be thought of as natural, long-term evolutionary experiments. As each ring has a common origin and expands radially outwards over many years, different sectors will independently accumulate mutations during growth. The genotype can be followed to the next generation, as mushrooms producing the sexual spores are formed seasonally at the edge of the ring. Here, we present new genomic data from 95 single-spore isolates of the species, which we used to construct a genetic linkage map and an updated version of the genome assembly. The 44-Mb assembly was anchored to 11 linkage groups, producing chromosome-length scaffolds. Gene annotation revealed 13,891 genes, 55% of which contained a pfam domain. The repetitive fraction of the genome was 22%, and dominated by retrotransposons and DNA elements of the KDZ and Plavaka groups. The level of assembly contiguity we present is so far rare in mushroom-forming fungi, and we expect studies of genomics, transposons, phylogenetics, and evolution to be facilitated by the data we present here of the iconic fairy-ring mushroom.
Closer Appendage Spacing Augments Metachronal Swimming Speed by Promoting Tip Vortex Interactions
Authors: Ford Mitchell P , Santhanakrishnan Arvind
Published: May 2021

Numerous species of aquatic invertebrates, including crustaceans, swim by oscillating multiple closely spaced appendages. The coordinated, out-of-phase motion of these appendages, known as “metachronal paddling,” has been well-established to improve swimming performance relative to synchronous paddling. Invertebrates employing this propulsion strategy cover a wide range of body sizes and shapes, but the ratio of appendage spacing (G) to the appendage length (L) has been reported to lie in a comparatively narrow range of 0.2 < G/L ≤ 0.65. The functional role of G/L on metachronal swimming performance is unknown. We hypothesized that for a given Reynolds number and stroke amplitude, hydrodynamic interactions promoted by metachronal stroke kinematics with small G/L can increase forward swimming speed. We used a dynamically scaled self-propelling robot to comparatively examine swimming performance and wake development of metachronal and synchronous paddling under varying G/L, phase lag, and stroke amplitude. G/L was varied from 0.4 to 1.5, with the expectation that when G/L is large, there should be no performance difference between metachronal and synchronous paddling due to a lack of interaction between vortices that form on the appendages. Metachronal stroking at nonzero phase lag with G/L in the biological range produced faster swimming speeds than synchronous stroking. As G/L increased and as stroke amplitude decreased, the influence of phase lag on the swimming speed of the robot was reduced. For smaller G/L, vortex interactions between adjacent appendages generated a horizontally oriented wake and increased momentum fluxes relative to larger G/L, which contributed to increasing swimming speed. We find that while metachronal motion augments swimming performance for closely spaced appendages (G/L <1), moderately spaced appendages (1.0 ≤ G/L ≤ 1.5) can benefit from the metachronal motion only when the stroke amplitude is large.
Deterrence in the Cyber Realm: Public versus Private Cyber Capacity
Authors: Kostyuk Nadiya
Published: May 2021

Can cyber deterrence work? Existing scholarly works argue that deterrence by punishment using cyberattacks is ineffective because the difficulty of attributing the origin of cyberattacks makes the threat of future attacks less credible. However, these works have told us relatively little about the deterrence ability of public cyberinstitutions (PCIs), defined as publicly observable proactive efforts aimed at signaling a country’s level of cyber offensive and defensive capability. This research shows that middle powers (that have scarce cyber arsenals) can use PCIs to deter cyber attacks that cause significant damage to their economy and prosperity; however, this deterrent capability is rather limited. Using an incomplete-information model, we demonstrate that PCIs only deter adversaries that are susceptible to the costs created by these institutions. Despite this limited deterrence ability, middle powers tend to over-invest resources in these cyberinstitutions: Weak cyber states tend to over-invest to convince strong cyber adversaries that they are strong, whereas strong cyber states over-invest so that adversaries do not believe that they are weak states pretending to be strong. By doing so, states reduce their overall cybercapacity. We establish the empirical plausibility of these results using election interference campaigns as examples of strategic attacks. Our focus on the strategic use of PCIs as a deterrent represents a departure from existing literature—which has focused only on cyberoperations—and has important policy implications.
Multi-Site Evaluation of Immunoassays for Antipsychotic Drug Measurement in Clinical Samples
Authors: Clarke William A , Salyer Bruce , Hussey Casey , Gardiner JoAnn , Johnson-Davis Kamisha , Milone Michael C
Published: May 2021

Background

Atypical antipsychotic drugs are frequently used in the treatment of serious mental illness (SMI), specifically schizophrenia and bipolar disorder. Adherence to these prescribed drug regimens is a challenge to successful treatment with these drugs. For some of the more common drugs in this class, novel turbidimetric immunoassays have been developed for therapeutic drug monitoring (TDM) to aid in the management of patients prescribed these drugs.

Methods

Immunoassays for aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, and risperidone were set up at 2 centers: Johns Hopkins Hospital (JHH) on the Roche Cobas® c501, and the Hospital of the University of Pennsylvania (HUP) on the Beckman AU480. Assay imprecision, limit of quantification (LOQ), functional sensitivity, linearity, and recovery were assessed. Remnant clinical samples were obtained from a reference laboratory (ARUP), and immunoassay results were compared with those obtained by LC–MS/MS.

Results

Imprecision at both sites for all analytes and concentrations tested was <10%. The manufacturer’s LOQ was confirmed for each assay, and the functional sensitivity for each assay was found to be lower than the LOQ. All assays were found to be linear over the measuring range, with recoveries ranging from 91% to 123%. For method comparison, Deming regression slopes were found to be between 0.84 to 1.28.

Conclusion

The immunoassays evaluated here are suitable for quantifying drug concentrations to be used in TDM for all 6 drugs. Commercialization of these assays will enable increased access for TDM in psychiatric patient management.
Separation and Determination of Diflunisal and its Impurity by Two Chromatographic Methods: TLC–Densitometry and HPLC
Authors: Farid Nehal F , Naguib Ibrahim A , Moatamed Radwa S , El Ghobashy Mohamed R
Published: May 2021

Background

Diflunisal (DIF) has analgesic and anti-inflammatory activity. It is a pharmacopeial drug found in the British Pharmacopoeia (BP), and its major pharmacopeial impurity is biphenyl-4-ol (BPL).

Objective

DIF has not previously been determined together with BPL. The presence of BPL could significantly affect the dose of DIF in its dosage forms; hence it is crucial to determine DIF and BPL in each other’s presence.

Methods

TLC is the first proposed method, where DIF and BPL were separated on silica gel TLC F254 plates. The eluent was toluene–acetone–acetic acid solution (3.5:6.5:1, v/v). Reversed-phase (RP) HPLC is the second suggested method, where a mixture of DIF and BPL was separated on a C18 (5 µm ps, 250 mm and 4.6 id) column using phosphate buffer pH 4 (0.05 M)–acetonitrile (40:60, v/v). Detection was carried out at 254 nm in both methods.

Results

For the TLC method, concentration ranges of 0.5–3 and 0.3–1.7 µg/band were used, with mean percentage recoveries of 100.22% (SD 0.893) and 100.52% (SD 0.952) for DIF and BPL, respectively. The RP-HPLC method was carried out over a concentration range of 5–30 and 2–9 μg/mL, with mean percentage recoveries of 100.10% (SD 1.259) and 98.88% (SD 0.822) for DIF and BPL, respectively.

Conclusion

The TLC and RP-HPLC methods were successfully applied for the determination of DIF and BPL, quantitatively, whether in bulk powder or in pharmaceutical formulations.

Highlights

Two chromatographic methods were developed and validated according to International Council on Harmonization guidelines for the assay of DIF and its pharmacopeial impurity.
Determination of Drugs of Abuse in Hair by LC–MS-MS: Application to Suicide Attempts Investigation
Authors: Cardoso Marilia S , Lanaro Rafael , Dolores Raul C , Morais Damila R , Arantes Ana Carolina Furiozo , Oliveira Karina Diniz , Costa Jose Luiz
Published: May 2021

Considering that the use of psychoactive substances (PSs) is a risk factor to either higher intensity or frequency of suicidal behavior, hair analysis was conducted to investigate the most consumed PSs (opiates, amphetamine stimulants, marijuana, cocaine and heroin) in patients who attempted suicide and received urgent care at emergency service. Hair samples were extracted using methanol and sonicated under heating and then analyzed using liquid chromatography-tandem mass spectrometry. During validation, the method complied with international recommended criteria, with limits of detection between 0.0025 and 0.05 ng/mg and linearity between 0.1 and 4 ng/mg for methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), morphine, amphetamine, 6-acetylmorphine, 3,4-methylenedioxyamphetamine (MDA), fenproporex, diethylpropion and codeine; between 0.025 and 1 ng/mg for tetrahydrocannabinol (THC), benzoylecgonine and cocaethylene and between 0.25 and 10 ng/mg for cocaine and mazindol. A total of 109 hair samples were analyzed and segmented in 404 parts. Among all analyzed samples, 30.3% were positive for at least one PS (n = 33), such as cocaine (90.9%), codeine (12.1%), morphine (3.0%), MDMA (3.0%) and THC (3.0%). In segmental analysis of cocaine positive samples (n = 30), 76.7% of the samples indicated recent exposure to cocaine (<1 month). This same behavior was observed when analyzing codeine (n = 4) and morphine (n = 1). THC positive samples indicated exposure dated ∼4 months prior. In conclusion, the method was validated following international recommendations for the 12 most consumed PSs in Brazil, as well as two of the most common found metabolites.
Two Variants of KIT Causing White Patterning in Stock-Type Horses
Authors: Patterson Rosa Laura , Martin Katie , Vierra Micaela , Foster Gabriel , Lundquist Erica , Brooks Samantha A , Lafayette Christa
Published: May 2021

Over 30 polymorphisms in the KIT Proto-Oncogene Receptor Tyrosine Kinase (KIT) gene have been implicated in white spotting patterns ranging from small areas to full dermal depigmentation in the horse. We performed a candidate-gene exon sequencing approach on KIT and MITF, 2 known causatives of white spotting patterns, within 2 families of horses of unknown white spotting. Family 1 (Fam1, N = 5) consisted of a Quarter Horse stallion and 4 offspring with white spotting pattern ranging from legs, lower ventral, and head regions with jagged borders, to almost complete white. The second family (Fam2, N = 7) consisted of 6 half-sibling American Paint Horse/Quarter Horse and their dam, demonstrating unpigmented limbs with belly spots and an extensive white patterning on the face. This approach resulted in 2 variants significantly associated with familial phenotypes, where Fam1 variant is an indel leading to a frameshift mutation, and Fam2 a non-synonymous SNP. We validated the variants within an unrelated population of horses (Fam2 variant, P = 0.00271944) as well as for protein functional impact with ExPASy, Protter, Phyre2, SMART, PROVEAN, SIFT, and I-TASSER, confirming the reported associations. Fam1 associated variant, deemed W31, alters the protein sequence, leading to an early stop codon truncating the normal amino acid sequence from 972 to just 115 amino acids. Fam2 associated variant, deemed W32, may have a subtle impact on receptor function or could be in linkage with a non-coding or regulatory change creating the mild spotting pattern observed in this family.