bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational study of the effect of pump mounting to foundation compliance on pump natural frequencies
Authors: Yashchenko A , Verbovyi A , Rudenko A
Published: January 2021

This article deals with the development of more accurate models of high-performance pump machines, which are mounted onto the foundation by means of compliant supports. These models demonstrate dependence between support foundation compliance and dynamics of pump elements such as rotor, pump casing and casing of pump bearings. After application of these approaches, the method of vibrational calculation with variable values of support compliance taken into account is provided. This task has been performed by using the multifunctional program complex ANSYS Workbench. In particular, the investigation employs the Modal Analysis subprogram, which implements the finite element method at the tasks of vibration analysis of constructions. The degree of effect of pump baseplate compliance on the rotor dynamics behaviour has been determined. Data charts of dependencies of rotor, pump casing and bearing housings natural frequencies on pump mounting to foundation compliance have been obtained.
Analysis of elastic supports and rotor flexibility for dynamics of a cantilever impeller
Authors: Tkachuk M M , Grabovskiy A , Tkachuk M A , Zarubina A , Lipeyko A
Published: January 2021

Turbochargers of modern internal combustion engines experience severe service conditions. In particular the compressor impeller is driven at extremely high angular velocity (30,000 rpm and more). Furthermore the increased requirements for the air intake dictate ever larger dimensions of the rotor disk up to 250 mm. These two factors lead to a pressing problem of stiffness, strength and dynamic stability of the newly designed units. This problem is analyzed with the help of a newly created parametric model of cantilever impeller rotor dynamics. This model accounts for the flexibility of the drive shaft and the impeller disk, quasistatic inertial and aerodynamic loads. The rotordynamics analysis is performed with a specific focus on the support behavior. The effect of initial gap and resilient characteristics of bearings and bushings is taken into account. As a result various components of displacements can be evaluated for different values of the disk diameter and angular velocity. It is critical for the design that neither radial nor axial displacement should not exceed given bounds. Furthermore, critical speeds of the studied rotor system have been determined for the various configurations of the disk and shaft dimensions. The proposed solution is to lower the first one or two eigenfrequencies of the system below the operating domain, so that the rotor becomes stable to any external excitations. Altogether, the developed mechanical analysis tool has proved itself as a useful tool for the engineering practice that allows to eliminate fatal flaws at early design stages.
Increasing fretting resistance of flexible element pack for rotary machine flexible coupling Part 2. The influence of coupled shafts misalignment on flexible coupling flexible elements stress-strain state
Authors: Tarelnyk V , Dumanchuk M , Martsynkovskyy Vas , Mikulina M , Smolyarov G , Semernya O
Published: January 2021

It has been performed the analysis of stress-strain state of flexible element pack for flexible coupling. Plots of internal force factors arising in the flexible elements (plates) of the pack due to the transmitted torque and misalignments caused by the assembly errors when coupling the shafts have been constructed. The analytical dependences of the deflections and rotations of the sections have been obtained. The pressure between the plates, the friction forces in the pack and the loss of power because of strain and friction have been determined.
Increasing fretting resistance of flexible element pack for rotary machine flexible coupling Part 3. The influence of dynamic loads on flexible coupling flexible element stress-strain state
Authors: Tarelnyk V , Dumanchuk M , Martsynkovskyy Vas , Dovzhyk M , Nahornyi M , Vasilenko O , Bondarev S
Published: January 2021

It has been carried out the analysis of stress-strain state of flexible element pack for flexible coupling as a result of the combined action of the forces from the torque transmitted by the coupling and the forces caused by misalignment of the coupled shafts. Plots of bending moments from external load and reactive forces arising in the flexible elements of the pack have been constructed. There have been obtained the analytical dependences of the deflections and rotations of the sections on the complex load. The effects of various force factors on the stress-strain state of a flexible element have been compared. Directions of increasing the fretting resistance of the flexible elements are proposed.
Diagnosing air quality changes in the UK during the COVID-19 lockdown using TROPOMI and GEOS-Chem
Authors: Potts Daniel A , Marais Eloise A , Boesch Hartmut , Pope Richard J , Lee James , Drysdale Will , Chipperfield Martyn P , Kerridge Brian , Siddans Richard , Moore David P , Remedios John
Published: January 2021

The dramatic and sudden reduction in anthropogenic activity due to lockdown measures in the UK in response to the COVID-19 outbreak has resulted in a concerted effort to estimate local and regional changes in air quality, though changes in underlying emissions remain uncertain. Here we combine satellite observations of tropospheric NO2 from TROPOspheric Monitoring Instrument and the Goddard Earth Observing System (GEOS)-Chem 3D chemical transport model to estimate that NO
x
emissions declined nationwide by ∼20% during the lockdown (23 March to 31 May 2020). Regionally, these range from 22% to 23% in the western portion of the country to 29% in the southeast and Manchester, and >40% in London. We apply a uniform 20% lockdown period emission reduction to GEOS-Chem anthropogenic emissions over the UK to determine that decline in lockdown emissions led to a national decline in PM2.5 of 1.1 μg m−3, ranging from 0.6 μg m−3 in Scotland to 2 μg m−3 in the southwest. The decline in emissions in cities (>40%) is greater than the national average and causes an increase in ozone of ∼2 ppbv in London and Manchester. The change in ozone and PM2.5 concentrations due to emission reductions alone is about half the total change from 2019 to 2020. This emphasizes the need to account for emissions and other factors, in particular meteorology, in future air pollution abatement strategies and regulatory action.
Finding more than one path through a simple maze with a quantum walk
Authors: Hillery Mark
Published: January 2021

We study quantum walks through chains consisting of two and three star graphs. The first star has a distinguished vertex labelled START and the last has one labelled END. There are multiple paths between these two vertices, and the object is to find these paths. We show that a quantum walk can do this with a quantum speedup.
Hierarchical coarse-grained approach to the duration-dependent spreading dynamics on complex networks
Authors: Chen Jin-Fu , Du Yi-Mu , Dong Hui , Sun C P
Published: January 2021

Various coarse-grained models have been proposed to study the spreading dynamics on complex networks. A microscopic theory is needed to connect the spreading dynamics with individual behaviors. In this letter, we unify the description of different spreading dynamics by decomposing the microscopic dynamics into two basic processes, the aging process and the contact process. A hierarchical duration coarse-grained (DCG) approach is proposed to study the duration-dependent processes. Applied to the epidemic spreading, such formalism is feasible to reproduce different epidemic models, e.g., the SIS and the SIR models, and to associate the macroscopic spreading parameters with the microscopic mechanism. The DCG approach enables us to study the steady state of the duration-dependent SIS model. The current hierarchical formalism can also be used to describe the spreading of information and public opinions, or to model a reliability theory on networks.
A Method for Estimating 24-Hour Urinary Sodium Excretion by Casual Urine Specimen in Chinese Hypertensive Patients
Authors: Sun Yan , Wang Hongyi , Liang Hao , Yuan Yifang , Shu Chang , Zhang Yanwei , Zhu Yihua , Yu Mingxin , Hu Songnian , Sun Ningling
Published: January 2021

Background

High salt intake is a known risk factor of hypertension, which in turn increases the risk of stroke and cardiovascular diseases. The aim of this study was to develop and evaluate a method for predicting 24-hour urinary sodium excretion (UNa24h) using casual urine specimens in Chinese hypertensive patients.

Methods

A total of 966 patients with hypertension were included from 8 provinces across China. A UNa24h prediction model (Sun_C method) was developed for males and females using linear regression based on age, weight, sodium concentration in the spot urine (UNaspot), and creatinine concentration in the spot urine (UCrspot). The data were split into the training (70%) and testing (30%) sets to, respectively, develop and evaluate the Sun_C method.

Results

Compared with the Kawasaki, INTERSALT, and Tanaka methods, Sun_C method achieved a low and consistent mean bias (1.1 mmol/d) within the range from 106 to 212 mmol/d of UNa24h (equivalent to NaCl intake of 6–12 g/d). In addition, the Sun_C method showed no significant difference between the measured and estimated UNa24h in a paired t-test (P = 0.689). At individual level, Sun_C method had 79.8% of individuals at the cutoff under ±30% level.

Conclusions

Sun_C method may prove a reasonable method to estimate the daily dietary sodium intakes (particularly in the range of 6–12 g/d of NaCl) in Chinese hypertensive patients using spot urine measurements. As the amount of data increases in the future, the performance of our formulae will be further improved.
Medication Management Performance in Parkinson’s Disease: Examination of Process Errors
Authors: Sumida Catherine A , Lopez Francesca V , Van Etten Emily J , Whiteley Nicole , Moore Raeanne C , Litvan Irene , Lessig Stephanie , Gilbert Paul E , Schmitter-Edgecombe Maureen , Filoteo J Vincent , Schiehser Dawn M
Published: January 2021

Objective

Individuals with Parkinson’s disease (PD) are at risk for increased medication mismanagement, which can lead to worse clinical outcomes. However, the nature of the errors (i.e., undertaking or overtaking medications) contributing to mismanagement and their relationship to cognition in PD is unknown. Therefore, this study sought to examine errors committed on the Medication Management Ability Assessment (MMAA) between PD participants with normal cognition (PD-NC) or mild cognitive impairment (PD-MCI) relative to healthy adults (HA).

Method

HA (n = 74), PD-NC (n = 102), and PD-MCI (n = 45) participants were administered the MMAA to assess undertaking, overtaking, and overall errors as well as overall performance (total score). Additionally, participants were administered a comprehensive neuropsychological battery from which cognitive composites of Attention, Learning, Memory, Language, Visuospatial, and Executive Functioning were derived.

Results

Separate negative binomial regression analyses indicated the PD-MCI group performed significantly worse overall on the MMAA (total score) and committed more undertaking and overall errors relative to HA and PD-NC. In the PD-MCI group, poorer MMAA performance was associated with worse delayed memory performance, whereas cognitive performance was not related to MMAA in HA or PC-NC.

Conclusion

Compared to PD and healthy adults with normal cognition, PD-MCI patients exhibited greater difficulty with medication management, particularly with undertaking medications. Poorer medication management in PD-MCI was associated with worse delayed recall. Thus, PD-MCI patients experiencing memory problems may require additional assistance with their medications. Findings have clinical relevance suggesting that objective measures of medication errors may assist clinicians in identifying PD patients needing adherence strategies.
Induction of tocopherol biosynthesis through heat shock treatment in Arabidopsis
Authors: Kusajima Miyuki , Fujita Moeka , Nishiuchi Takumi , Nakashita Hideo , Asami Tadao
Published: January 2021

Plants have developed various self-defense systems to survive many types of unfavorable conditions. Heat shock (HS) treatment, an abiotic stress, activates salicylic acid (SA) biosynthesis to enhance resistance to biotic stresses in some plant species. Since SA is produced from the shikimate pathway, other related metabolic pathways were expected to be upregulated by HS treatment. We speculated that tocopherol biosynthesis utilizing chorismic acid would be activated by HS treatment. In Arabidopsis, expression analysis of tocopherol biosynthetic genes, HPPD, VTE2, VTE3, VTE1, and VTE4, in combination with measurement of metabolites, indicated that HS treatment enhanced the biosynthesis and accumulation of tocopherols. Analyses using an SA biosynthesis-deficient mutant indicated that the upregulation of tocopherol biosynthesis was independent of the SA-mediated signaling pathway.
Pathways from Relative Deprivation to Individual Violence: The Effect of Subjective Perception and Emotional Resentment in South Korea
Authors: Park Seong-Min , Hong Young-Oh , Kennedy Logan P , Clouse Stacey L
Published: January 2021

Criminological studies assert that individuals’ psychological cognition and emotional resentment mediate the effect of economic deprivation on individual violence; however, a limited number of studies have empirically addressed these subjective mediations. Furthermore, the effect of relative deprivation in Asian counties is seldom investigated. To fill this gap, we construct theoretical path models and examine the argument of relative deprivation in South Korea. A total of 2,040 individuals are surveyed face to face through stratified random sampling. The results show that the objective status of economic inequality does not directly affect individual violence. We conclude that the subjective perception of deprivation and emotional response are essential mediators for the effect of economic deprivation on individual violence.
Christian Humility and the Goods of Perinatal Hospice
Authors: Cobb Aaron D
Published: January 2021

Perinatal palliative and hospice care (hereafter, perinatal hospice) is a novel approach to addressing a family’s varied needs following an adverse in utero diagnosis. Christian defenses of perinatal hospice tend to focus on its role as an ethical alternative to abortion. Although these analyses are important, they do not provide adequate grounds to characterize the wide range of goods realized through this compassionate form of care. This essay draws on an analysis of the Christian virtue of humility to highlight the ways a Christian virtue-based defense of perinatal hospice can account for these goods. I argue that humility can play an important facilitating role in helping Christian physicians to meet the needs of families in profoundly difficult circumstances.
Conduction Velocity Along the Local Axons of Parvalbumin Interneurons Correlates With the Degree of Axonal Myelination
Authors: Micheva Kristina D , Kiraly Marianna , Perez Marc M , Madison Daniel V
Published: January 2021

Parvalbumin-containing (PV+) basket cells in mammalian neocortex are fast-spiking interneurons that regulate the activity of local neuronal circuits in multiple ways. Even though PV+ basket cells are locally projecting interneurons, their axons are myelinated. Can this myelination contribute in any significant way to the speed of action potential propagation along such short axons? We used dual whole cell recordings of synaptically connected PV+ interneurons and their postsynaptic target in acutely prepared neocortical slices from adult mice to measure the amplitude and latency of single presynaptic action potential-evoked inhibitory postsynaptic currents. These same neurons were then imaged with immunofluorescent array tomography, the synapses between them identified and a precise map of the connections was generated, with the exact axonal length and extent of myelin coverage. Our results support that myelination of PV+ basket cells significantly increases conduction velocity, and does so to a degree that can be physiologically relevant.
Leveraging Vaccines to Reduce Antibiotic Use and Prevent Antimicrobial Resistance: A World Health Organization Action Framework
Authors: Vekemans Johan , Hasso-Agopsowicz Mateusz , Kang Gagandeep , Hausdorff William P , Fiore Anthony , Tayler Elizabeth , Klemm Elizabeth J , Laxminarayan Ramanan , Srikantiah Padmini , Friede Martin , Lipsitch Marc
Published: January 2021

This Action Framework identifies priority actions to prevent antimicrobial-resistant (AMR) through expanding the use of licensed vaccines, developing new vaccines that contribute to the prevention and control of AMR, and expanding knowledge about the impact of vaccines on AMR.
Effectiveness of Conjugate and Polysaccharide Pneumococcal Vaccines for Prevention of Severe Pneumococcal Disease Among Inflammatory Bowel Disease Patients
Authors: Love Bryan L , Finney Christopher J , Gaidos Jill K J
Published: January 2021

Background

Streptococcus pneumoniae is an important pathogen responsible for severe pneumococcal diseases, including pneumonia, bacteraemia/sepsis, and meningitis. Inflammatory bowel disease [IBD] patients have an increased risk for infections due to an altered immune system and treatment with immunosuppressive medications. The aim of this study was to assess the prevalence of severe pneumococcal disease [SPD] and evaluate the impact of pneumococcal vaccination on the risk of SPD in Veterans with IBD.

Methods

Subjects with IBD and SPD were identified from the VA Health Administration database using ICD9/10 codes. Pneumococcal vaccination and use of immunosuppressant medications were collected. Risk of SPD was evaluated using an adjusted Cox proportional hazards model controlling for demographics, medications, vaccination, and comorbidities.

Results

A total of 1798 cases of SPD were identified [283 pneumonia, 1513 bacteraemia, and two meningitis]. SPD patients were older [60.9 years vs 59.4 years; p <0.001], had more comorbidities [Charlson Comorbidity Index of 2.11 vs 0.96; p <0.001], and had increased mortality [4.6% vs 1.5%, p <0.001]. The risk of SPD was increased in Crohn’s disease (hazard ratio [HR] 1.15; 95% confidence interval [CI] 1.05–1.27) and with more comorbidities [HR 1.45; 95% CI 1.42–1.48]. Use of immunosuppressive medications increased the risk of SPD. Receipt of PCV13 either alone or in combination with PPSV23 predicted a 5-fold decreased risk of SPD compared with no vaccination.

Conclusions

Risk factors for severe pneumococcal disease include having Crohn’s disease, more comorbidities, and exposure to combination immunosuppression. Vaccination with PCV13 alone or in combination with PPSV23 and revaccination with PPSV23, was protective against SPD. All IBD patients should be evaluated for pneumococcal vaccination, particularly those receiving or expected to receive immunosuppressive therapies.
Preoperative evaluation for lung resection in patients with bronchiectasis: should we rely on standard lung function evaluation?
Authors: Mariani Alessandro Wasum , Vallilo Camilla Carlini , de Albuquerque André Luís Pereira , Salge João Marcos , Augusto Marcia Cristina , Suesada Milena Mako , Pêgo-Fernandes Paulo Manuel , Terra Ricardo Mingarini
Published: January 2021

OBJECTIVES

The scant data about non-cystic fibrosis bronchiectasis, including tuberculosis sequelae and impairment of lung function, can bias the preoperative physiological assessment. Our goal was to evaluate the changes in lung function and exercise capacity following pulmonary resection in these patients; we also looked for outcome predictors.

METHODS

We performed a non-randomized prospective study evaluating lung function changes in patients with non-cystic fibrosis bronchiectasis treated with pulmonary resection. Patients performed lung function tests and cardiopulmonary exercise tests preoperatively and 3 and 9 months after the operation. Demographic data, comorbidities, surgical data and complications were collected.

RESULTS

Forty-four patients were evaluated for lung function. After resection, the patients had slightly lower values for spirometry: forced expiratory volume in 1 s preoperatively: 2.21 l ± 0.8; at 3 months: 1.9 l ± 0.8 and at 9 months: 2.0 l ± 0.8, but the relationship between the forced expiratory volume in 1 s and the forced vital capacity remained. The gas diffusion measured by diffusing capacity for carbon monoxide did not change: preoperative value: 23.2 ml/min/mmHg ± 7.4; at 3 months: 21.5 ml/min/mmHg ± 5.6; and at 9 months: 21.7 ml/min/mmHg ± 8.2. The performance of general exercise did not change; peak oxygen consumption preoperatively was 20.9 ml/kg/min ± 7.4; at 3 months: 19.3 ml/kg/min ± 6.4; and at 9 months: 20.2 ml/kg/min ± 8.0. Forty-six patients were included for analysis of complications. We had 13 complications with 2 deaths. To test the capacity of the predicted postoperative (PPO) values to forecast complications, we performed several multivariate and univariate analyses; none of them was a significant predictor of complications. When we analysed other variables, only bronchoalveolar lavage with positive culture was significant for postoperative complications (P = 0.0023). Patients who had a pneumonectomy had a longer stay in the intensive care unit (P = 0.0348).

CONCLUSIONS

The calculated PPO forced expiratory volume in 1 s had an excellent correlation with the measurements at 3 and 9 months; but the calculated PPO capacity for carbon monoxide and the PPO peak oxygen consumption slightly underestimated the 3- and 9-month values. However, none of them was a predictor for complications. Better tools to predict postoperative complications for patients with bronchiectasis who are candidates for lung resection are needed.

Clinical trial registration number

Clinicaltrials.gov: NCT01268475
Severe aortic wall degeneration after aortic wrapping
Authors: Ehrlich Tristan , Federspiel Jan M , Bohle Rainer M , Schäfers Hans-Joachim
Published: January 2021

We report a case in whom aortic wrapping had been performed for aortic dilatation. Ten years later, further progression of aortic root diameter was documented (root size of 66 mm). We performed complete replacement of the proximal aorta. Macroscopically and microscopically, there was extreme degeneration and thinning of the aorta under the graft.
Access to inflammatory bowel disease speciality care: the primary healthcare physician perspective
Authors: Burns Eileen E , Mathias Holly M , Heisler Courtney , Cui Yunsong , Kits Olga , Veldhuyzen van Zanten Sander , Jones Jennifer L
Published: January 2021

Background

There is little literature related to access to inflammatory bowel disease (IBD) care that incorporates the perspective of key system stakeholders, such as primary healthcare providers (PHCP), despite their clear and integral role in facilitating access.

Objective

This study aimed to identify barriers to referring patients to speciality IBD care as perceived by referring PHCP. In particular, we sought to understand PHCP satisfaction with the current IBD specialist referral system, as well as indicators of geographic variance to access.

Methods

A population-based survey was mailed out to currently practising PHCPs who have referred or who are currently referring patients to IBD speciality care in Nova Scotia (Canada). Descriptive statistics and multivariate analyses were performed. Qualitative comments were themed using framework analysis to identify key barriers.

Results

The majority of PHCP (57%) were dissatisfied with the current referral process due to long patient wait times and perceived system inefficiency. Key areas of geographic variance in access included access to speciality care in the community and patient wait times. PHCPs suggested ideas to improve access including increased gastroenterologist supply, particularly in rural areas, and the creation of a provincial centralized referral and triage process.

Conclusions

PHCPs play an important role in identifying and managing patients with IBD in partnership with gastroenterologists. This study identifies key PHCP perceived barriers that may prevent patients from accessing speciality IBD care. Understanding and addressing barriers to access from multiple stakeholder perspectives, including PHCPs, has the potential to support informed system redesign and overcome access inequities.
First-arrival traveltime inversion of seismic diving waves observed on undulant surface
Authors: Yang Huachen , Zhang Jianzhong , Ren Kai , Wang Changbo
Published: January 2021

A non-iterative first-arrival traveltime inversion method (NFTI) is proposed for building smooth velocity models using seismic diving waves observed on irregular surface. The new ray and traveltime equations of diving waves propagating in smooth media with undulant observation surface are deduced. According to the proposed ray and traveltime equations, an analytical formula for determining the location of the diving-wave turning points is then derived. Taking the influence of rough topography on first-arrival traveltimes into account, the new equations for calculating the velocities at turning points are established. Based on these equations, a method is proposed to construct subsurface velocity models from the observation surface downward to the bottom using the first-arrival traveltimes in common offset gathers. Tests on smooth velocity models with rugged topography verify the validity of the established equations, and the superiority of the proposed NFTI. The limitation of the proposed method is shown by an abruptly-varying velocity model example. Finally, the NFTI is applied to solve the static correction problem of the field seismic data acquired in a mountain area in the western China. The results confirm the effectivity of the proposed NFTI.
Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia
Authors: Ishida Yamato , Kobayashi Takuya , Chiba Shuhei , Katoh Yohei , Nakayama Kazuhisa
Published: January 2021

Primary cilia contain specific proteins to achieve their functions as cellular antennae. Ciliary protein trafficking is mediated by the intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes. Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35, IFT122, IFT139/TTC21B, IFT140 and IFT144/WDR19) often result in skeletal ciliopathies, including cranioectodermal dysplasia (CED). We here characterized the molecular and cellular defects of CED caused by compound heterozygous mutations in IFT144 [the missense variant IFT144(L710S) and the nonsense variant IFT144(R1103*)]. These two variants were distinct with regard to their interactions with other IFT-A subunits and with the IFT-B complex. When exogenously expressed in IFT144-knockout (KO) cells, IFT144(L710S) as well as IFT144(WT) rescued both moderately compromised ciliogenesis and the abnormal localization of ciliary proteins. As the homozygous IFT144(L710S) mutation was found to cause autosomal recessive retinitis pigmentosa, IFT144(L710S) is likely to be hypomorphic at the cellular level. In striking contrast, the exogenous expression of IFT144(R1103*) in IFT144-KO cells exacerbated the ciliogenesis defects. The expression of IFT144(R1103*) together with IFT144(WT) restored the abnormal phenotypes of IFT144-KO cells. However, the coexpression of IFT144(R1103*) with the hypomorphic IFT144(L710S) variant in IFT144-KO cells, which mimics the genotype of compound heterozygous CED patients, resulted in severe ciliogenesis defects. Taken together, these observations demonstrate that compound heterozygous mutations in IFT144 cause severe ciliary defects via a complicated mechanism, where one allele can cause severe ciliary defects when combined with a hypomorphic allele.
STOCHASTIC INTERINDIVIDUAL MICROBIOME VARIATION MAY GUIDE PROTECTIVE PERINATAL PROBIOTIC DEVELOPMENT AGAINST IBD
Authors: Krishna Mahesh , Engevik Melinda , Queliza Karen , Britto Savini , Shah Rajesh , Ruan Wenly , Wang Hangtao , Versalovic James , Kellermayer Richard
Published: January 2021

The purpose of our experiment was to explore how stochastic inter-individual variation in the mammalian gut microbiome may link to inflammatory bowel disease (IBD) susceptibility, and guide the development of a perinatal preventative probiotic.

Dextran sodium sulfate (DSS) was introduced to C57BL/6J mice to induce acute colitis as a model of IBD. Potentially protective bacteria were identified using a discovery-validation cohort approach towards stochastic DSS susceptibility. Lactobacilli (two different cocktails of L. reuteri and L. johnsonii strains) or control media were supplemented by mouth to dams prior to delivery and during lactation (i.e. perinatal probiotic). The pups were evaluated for DSS susceptibility at young adulthood.

Fecal Lactobacillus was increased in the DSS-resistant mice in both the discovery and validation cohorts. Maternal supplementation of female offspring with an L. reuteri cocktail (strains 6798-1, 6798-jm, and 6798-cm) induced progressive microbiome separation and protection against colitis by young adulthood.

Maternal supplementation of L. reuteri could confer protection against DSS colitis in young adult female mice. This work is the first to exploit stochastic mammalian microbiome variation to guide microbial therapeutic identification. Our findings underscore neonatal microbiome plasticity and set the stage for the potential development of perinatally deliverable protective probiotics against human IBD.
EFFECT OF OZANIMOD ON FECAL CALPROTECTIN AND FECAL LACTOFERRIN, BIOMARKERS OF INTESTINAL INFLAMMATION, IN THE PHASE 2 TOUCHSTONE STUDY OF PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS
Authors: Sandborn William , Feagan Brian , Wolf Douglas , D’Haens Geert , Vermeire Séverine , Hanauer Stephen , Ghosh Subrata , Southworth Harry , Harris Sarah
Published: January 2021

Introduction

Efficacy and safety of ozanimod, an oral sphingosine-1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, was previously demonstrated in the double-blind phase 2 TOUCHSTONE study (NCT01647516) in patients with moderate-to-severe ulcerative colitis. Here we report the effect of ozanimod on levels of fecal calprotectin (FCP) and fecal lactoferrin (FLF), two markers of intestinal inflammation.

Methods

Patients in TOUCHSTONE were randomized 1:1:1 to once daily oral ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg), ozanimod HCl 1.0 mg (equivalent to ozanimod 0.92 mg), or placebo for 8 weeks; responders at week 8 (based upon Mayo score) entered a maintenance phase through week 32. Stool collection occurred at baseline and weeks 8 and 32 to measure levels of FCP and FLF.

Results

A total of 197 patients were randomized and received treatment (n=65, placebo; n=65, ozanimod 0.5 mg; n=67, ozanimod 1 mg). Median baseline levels of FCP were 1272, 1477, and 1238 μg/g, respectively; baseline FCP levels were not associated with baseline Mayo score. Median baseline levels of FLF were 29.0, 30.6, and 29.9 μg/g, respectively; baseline FLF was related to week 8 Mayo score even after adjusting for baseline Mayo score. At week 8, FCP levels declined across treatment groups (median percent change from baseline, -53.4, -68.7, and -70.0 in placebo, ozanimod 0.5 mg and 1 mg groups, respectively); declines in FCP were maintained at week 32 (median percent change from baseline, -42.3, -72.6, and -80.6, respectively). At week 8, declines in FCP were greater in patients achieving clinical response (based on Mayo score) than in non-responders on ozanimod 1 mg. Declines in FCP at week 8 were also greater in patients achieving clinical remission than in those who did not, with greater declines with ozanimod 1 mg relative to 0.5 mg. FLF levels declined at weeks 8 and 32 across treatment groups, with greater changes in the ozanimod 1 mg group vs placebo (median percent change from baseline, week 8: -35.7, -61.0, and -84.7, respectively; week 32: -60.2, -62.5, -85.3, respectively, for placebo, ozanimod 0.5 mg, and ozanimod 1 mg). Reductions in FLF at week 8 were greater for treatment responders vs non-responders and for those achieving vs not achieving clinical remission in the ozanimod 1 mg group.

Conclusion

In TOUCHSTONE, treatment with ozanimod was associated with declines in FCP levels in treatment responders (for the 1 mg dose group) or those who achieved clinical remission (both doses). Ozanimod 1 mg was also associated with declines in FLF for treatment responders and those achieving remission.
ROLE OF MAGNETIC RESONANCE ENTEROGRAPHY IN THE DIAGNOSTICS OF ACTIVE CROHN’S DISEASE IN CHILDREN
Authors: Siejka Karolina , Kuczynska Maryla , Grzegorczyk Magdalena , Nowakowska Malgorzata , Piekarska Monika , Zbroja Monika , Cyranka Weronika , Brodzisz Agnieszka , Wozniak Magdalena Maria
Published: January 2021

Background

Crohn’s disease (CD) is an idiopathic inflammatory bowel disease of the gastrointestinal tract. It is more common in the developed and industrialized countries, particularly in the Western Europe and North America. Up to 20–30% of patients present first symptoms during childhood or adolescence. Traditionally it is diagnosed by clinical indicates, endoscopy and histological findings. Assessment of the disease activity and location along the gastrointestinal tract are of crucial importance for diagnosis and implementation of the proper treatment. Active inflammation can manifest as mural thickening, edema, ulcerations, abscesses or fistulas. Magnetic resonance enterography (MRE) is the most modern radiological method in depicting all of these manifestations of CD.

Objective

The aim of the study was to assess the value of MRE in evaluation of Crohn’s disease in pediatric patients.

Materials and Methods

18 children (8 boys, 10 girls) with confirmed diagnosis of Crohn’s disease, were included in the study. Each patient underwent MR enterography with intravenous administration of a contrast agent. All studies were performed using a 1.5T scanner according to a local study protocol.

Results

All MRE findings were associated with small bowel inflammation. All patients showed asymmetric ileal wall thickening and edema. Edematous ileocecal valve was visible in 8 patients. In 7 cases reactive lymphadenopathy was detected (lymph nodes ≥ 10 mm in short axis). In 4 patients small intestine fistulas were found, whereas abscess was observed in another 4 patients. In contrast-enhanced images, a vivid enhancement of the affected bowel section was revealed in all patients and in 10 children inflammatory infiltration of periintestinal fat was depicted.

Conclusion

MRE is a reliable tool in diagnosis, evaluation of the disease activity and assessment of potential complications of Crohn’s disease. Due to the lack of ionizing radiation MRE exhibits beneficial safety profile and can be offered to patients who repeatedly require follow-up examinations, especially in pediatric patients.
COLORECTAL ADENOCARCINOMA DEVELOPING IN A YOUNG FEMALE WITH OVERLAP SYNDROME AND VERY EARLY ONSET-INFLAMMATORY BOWEL DISEASE: A CASE REPORT
Authors: Kandavel Prashanthi , Shakhin Victoria , Chavannes Mallory , Gayer Christopher , Naon Hillel , Larry Wang , Yanni George
Published: January 2021

We present a 4-year-old female diagnosed with very-early onset inflammatory bowel disease (VEO-IBD), ulcerative colitis type, and overlap syndrome based on clinical presentation, blood and stool studies, diagnostic endoscopies and liver biopsy. Her clinical course was complicated by pervasive psychological stressors, non-compliance with medical therapy, and frequent provider changes. Initial treatment included Prednisone, 6-mercaptopurine and Ursodiol. Treatment was escalated to include multiple biological agents which were stopped prematurely due to non-adherence. She developed weight loss and growth stunting, necessitating exclusive enteral nutrition and then parenteral nutrition. Due to medically refractory disease, she underwent a total colectomy with end ileostomy at the age of 13. Pathology revealed stage III colorectal adenocarcinoma (CRC) with lymph node involvement and transmural inflammation diagnostic of Crohn’s disease (CD). Genetic testing of the resected colon noted a missense mutation of TP53. Our patient completed 6 cycles of extensive and targeted chemotherapy with no evidence of disease reccurrence. She recently underwent ileal pouch-anal anastomosis and creation of a diverting ileostomy.

CRC is exceedingly rare in pediatric IBD (PIBD) patients, with less than 30 reported cases in the available literature1. Most cases occurred in males and patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC), where the risk of developing CRC is four times greater2. The risk of CRC increases with disease duration, with most PIBD patients developing CRC at 25 years of age1. Interestingly, mutations in TP53, a tumour suppressor gene, have been found to occur more frequently in patients with IBD-CRC compared to those with sporadic-CRC or IBD without dysplasia3. Mutations in TP53 may not only increase a patients general susceptibility to CRC but may also accelerate its development by contributing to excessive inflammation4.

Our patient’s treatment refractory clinical course and transition in IBD diagnosis from UC to CD highlights the complexity of VEO-IBD management. While rare in pediatric patients, the development of CRC is a life-threatening risk and it should be considered in patients with prolonged and severely refractory IBD with concomitant autoimmune liver disease. Our patient’s young age at the time of CRC diagnosis emphasizes the need for vigilant yearly endoscopic screening and development of pediatric guidelines for dysplasia monitoring in this high risk population. Further research is needed to evaluate the role of genetic variant screening in CRC risk stratification.

References:

1. Aardoom MA, et al. Inflamm Bowel Dis. 2018;24(4):732–741.

2. Soetikno RM, et al. Gastrointest Endosc. 2002;56(1):48–54.

3. Yaeger R, et al. Gastroenterology. 2016;151(2):278–287.

4. Cooks T, et al. Cancer Cell. 2013;23(5):634–46.
OUTCOMES FOR PATIENTS WITH ACUTE MYOCARDIAL INFARCTION AND IBD: ULCERATIVE COLITIS VERSUS CROHN’S DISEASE- AN ANALYSIS OF THE NATIONAL INPATIENT SAMPLE 2015–2017
Authors: Dasu Neethi , Khalid Yaser , Joo Lucy , Blair Brian
Published: January 2021

Introduction

There is a scarcity of data on the influence of sex, race, insurance status on mortality, hospital length of stay (LOS), and total hospital charges for patients with ulcerative colitis (UC) and acute myocardial infarction (AMI) versus patients with Crohn’s disease and AMI. Previous studies have identified that patients with inflammatory bowel disease (IBD) have a lower incidence of AMI compared to the general population, but Ulcerative Colitis has not been compared to Crohn’s Disease for AMI. The aim of this study was to identify risk factors in a national population cohort (in the USA) admitted to hospital between 2015 and 2017.

Methods

All patients aged 18 years with AMI and UC and AMI and Crohn’s disease,who had been admitted to hospital between 2015 and 2017, were identified from the US Nationwide Inpatient Sample (NIS), a large publicly available all-payer inpatient care database in the USA. Multivariate regression analysis was used to estimate the odds ratios of in-hospital mortality, average length of hospital stay, and hospital charges, after adjusting for age, gender, race, primary insurance payer status, hospital type and size (number of beds), hospital region, hospital teaching status, and other demographic characteristics.

Results

Our study identified approximately 200,000 patients who had been discharged with either UC or Crohn’s disease from 2015 to 2017. Of these patients, 208 were admitted with UC and AMI versus 258 with Crohn’s disease and AMI. The analysis revealed that mortality was decreased (OR -1.19, p <0.237), length of stay (LOS) was increased (OR 2.08, p <0.038), and total hospital charges were increased (OR 3.54, p <0.0001) for patients with UC and AMI compared to patients with Crohn’s disease and AMI. Independent positive predictors of mortality were age, black race, and Medicaid insurance. Independent positive predictors of increased hospital LOS were age and Hispanic ethnicity. Independent positive predictors of increased total hospital charges were Hispanic ethnicity and Medicare insurance.

Conclusions

Patients with UC and AMI have increased LOS and total hospital charges compared to patients with Crohn’s disease and AMI. We identified key drivers for these outcomes. Previous studies showed that patients with IBD had a lower incidence of AMI compared to the general population, but newer studies demonstrate that patients with IBD may be at higher risk. This could possibly be related to the underlying shared pathophysiology of inflammation. In the future, more randomized clinical trials are required to compare patients with UC to patients with Crohn’s disease, especially the impact of therapeutic interventions on the incidence of AMI for this patient population.
RISK OF ANAL CANCER IN INFLAMMATORY BOWEL DISEASE PATIENTS IN THE US: A POPULATION-BASED STUDY 2008–2018
Authors: Suk Ryan , Sonawane Kalyani , Bauer Cici , Lairson David , Deshmukh Ashish
Published: January 2021

Background

Patients with inflammatory bowel disease (IBD) are at elevated risk of developing anal cancer. However, it remains unclear whether the increased risk manifests from immunosuppressant use or location of the disease (inflammation). We aimed to examine whether the risk of anal cancer in IBD patients is attributable to immunosuppression or the disease’s location by comparing IBD patients with rheumatoid arthritis (RA) and diverticulitis patients, respectively.

Methods

We conducted a retrospective cohort study using the US Optum® commercial claims database (2008–2018). We estimated the risk of anal cancer in the IBD cohort compared to the RA cohort (to examine risk attributable to immunosuppressant use) and the diverticulitis cohort (to examine risk attributable to similar disease location). Disease cohorts and index dates were identified using a combination of ICD diagnosis codes and prescription drug use. Patients 18 years and older and with a minimum of 12 months of continuous insurance enrollment were included. All three cohorts were mutually exclusive; we excluded persons with HIV/AIDS or organ transplant. We estimated hazard ratios (HRs) using Cox proportional regression, adjusting for age at diagnosis, comorbidity, risk factors for HPV infection (smoking, obesity, genital wart, substance abuse, alcoholism), and prescription drug use. Analyses were stratified by sex.

Results

The study included 70,314 patients with IBD, 164,991 with RA, and 129,558 with diverticulitis. In men, the adjusted hazard ratio (aHR) of developing anal cancer was 6.78 (95% CI, 3.40–13.55) comparing IBD to RA, and was 2.68 (95% CI, 0.99–7.30) comparing IBD to diverticulitis. Among women, the risk of developing anal cancer was significantly higher in IBD compared to RA (aHR 2.70; 95% CI, 1.36–5.35), but not different compared to diverticulitis (aHR 0.70; 95% CI, 0.20–2.44). The factors associated with a higher risk of anal cancer in both men and women were age at diagnosis, history of genital wart, corticosteroid use, and immunosuppressant use.

Conclusion

We found a significantly elevated risk of anal cancer in IBD patients than RA patients. However, anal cancer risk was not significantly different when comparing IBD patients to diverticulitis patients. These results indicate that the location of the disease is more strongly associated with anal cancer incidence than the treatment of autoimmune disease.
INFLAMMATORY CYTOKINES AND MICROBIAL LIGANDS AND METABOLITES INTERACT TO MODULATE DUOX2 EXPRESSION AND ACTIVITY
Authors: Hazime Hajar , Fritsch Julia , Santander Ana , Brito Nivis , Fernandez Irina , Pignac-Kobinger Judith , Conner Gregory , Abreu Maria , Burgueno Juan
Published: January 2021

Background

The pathogenesis of inflammatory bowel diseases (IBD) is characterized by a dysregulated crosstalk between the host and the microbiome that leads to the development of inflammation and dysbiosis. Dysbiosis in IBD involves an expansion of Proteobacteria and a reduction of Firmicutes, particularly of butyrate-producing species such as Faecalibacterium prausnitzii. The epithelial NADPH oxidase dual oxidase 2 (DUOX2), which prevents bacterial colonization of the mucosa through the production of hydrogen peroxide (H2O2), is the only gene consistently altered in IBD patients before the onset of disease. However, the involvement of DUOX2 in IBD is not well understood. We aimed to define how inflammation and the microbiota regulate DUOX2 activity.

Methods

C57BI/6J males raised in specific-pathogen free (SPF) and germ-free (GF) conditions underwent a model of dextran sulfate sodium (DSS)-induced colitis for 6 days. We obtained colon specimens for histopathology and isolation of colon epithelial cells (CEC). We stimulated colonoids from wild-type (WT), toll-like receptor 4-KO (Tlr4-KO), and Duox2-KO mice with IFNγ, heat-killed adherent invasive Escherichia coli (AIEC) strain LF82, and heat-killed F. prausnitzii strain A2-165 and determined expression of Duox2, Duoxa2, and production of H2O2. We also treated colonoids with butyrate, a microbial metabolite with anti-inflammatory properties. Extracellular H2O2 production was analyzed by means of the Amplex Red assay, whereas gene expression was determined by qPCR.

Results

SPF mice undergoing DSS-induced colitis developed overt inflammation that was accompanied by upregulation of Duox2 and Duoxa2, as well as increased production of H2O2 in freshly isolated CECs. DSS-treated GF mice developed a mild inflammation that also caused increased H2O2 production and Duoxa2 upregulation. WT colonoid stimulation with IFNγ and the Crohn’s disease-associated pathobiont AIEC induced Duox2 and Duoxa2 expression, whereas heat-killed F. prausnitzii did not. Similarly, both IFNγ and AIEC promoted epithelial production of H2O2 in WT colonoids but not Duox2-KO colonoids, indicating that epithelial release of H2O2 in response to these stimuli is mediated by DUOX2. Response to AIEC additionally required functional TLR4. Although heat-killed F. prausnitzii did not alter H2O2 production, its metabolite butyrate caused a significant blockade in the release of H2O2 in response to both IFNγ and AIEC.

Conclusions

Our results show that both inflammation and pathobionts induce the expression and activity of DUOX2, which begets more inflammation. We posit that specific depletion of pathobionts or restitution with butyrate-producing bacteria such as F. prausnitzii may be beneficial in IBD.