bluuebunny/crossref_metadata_2025 huggingface dataset:
P805 Selnoflast, a potent NLRP3 inhibitor - results from a phase 1b experimental medicine study in patients with Ulcerative Colitis
Authors: Klughammer B , Piali L , Nica A C , Nagel S , Bailey L , Jochum C , Ignatenko S , Bläuer A , Danilin S , Gulati P , Hayward J , Scepanovic P , Retout S , Zhang J D , Bhosale S , Sue-Ling K , Chong C F , Christ A
Published: January 2023

Background

The Nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome is a driver of caspase 1-dependent release of IL-1β and IL-18 and has been identified as a potential drug target for ulcerative colitis (UC) (Tourkochristou et al. 2019). Selnoflast (RO7486967) is an orally active, potent, selective, and reversible small molecule NLRP3 inhibitor. To assess whether NLRP3 is a driver of inflammation and more specifically of IL-1β production and signaling in UC, we performed a Phase 1b study (BP43099) with selnoflast in patients with UC.

Methods

A randomized, placebo-controlled, double blind study assessed safety, tolerability, PK and PD of selnoflast in patients with active, moderate to severe UC. 19 patients were recruited: 6 were treated with placebo and 13 were treated with 450 mg selnoflast QD for 7 days. Stool and blood samples were taken at baseline, during and at the end of treatment. Sigmoidal tissue samples were taken at baseline and at the end of treatment. Adverse events were assessed throughout the study. https://www.isrctn.com/ISRCTN16847938

Results

Selnoflast was well tolerated in all patients, with mainly mild AEs. No serious or severe AEs were reported. Plasma PK was in line with PK data from previous studies in healthy subjects. In addition, selnoflast demonstrated a good distribution in sigmoidal tissue in all treated patients.

The gene signature of 8 genes (i.e. CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CCL2, IL-6, TNFAIP6) downstream of IL-1β, known to be responsive to IL-1β stimulation across different cell types and differentially expressed in colonic biopsies (UC vs healthy), was assessed and showed on average a slight decrease from baseline after treatment with selnoflast compared to placebo (log2 fold change mean (sd) = -1.14 (1.8) and +0.38 (3.26) respectively, t-test p-value = 0.206) in sigmoidal tissue biopsies. Single-cell RNA sequencing showed minimal differences between the two treatment arms.

Conclusion

Selnoflast was well tolerated and achieved the plasma and tissue exposure predicted to inhibit NLRP3. Expression of IL-1β gene signature in sigmoidal tissue biopsies, single-cell RNA sequencing and additional biomarker analyses showed no robust differences between the two treatment arms, suggesting that targeting the NLRP3 inflammasome with selnoflast may be of limited therapeutic benefit to reduce inflammation in UC.

Tourkochristou E, Aggeletopoulou I, Konstantakis C, Triantos C. Role of NLRP3 inflammasome in inflammatory bowel diseases. World J Gastroenterol. 2019
P824 Sexual Dysfunction among young patients with Crohn′s disease. A Spanish case control study.
Authors: Gutiérrez Casbas A , Madero Velázquez L , Herreros B , Zapater P , Rodríguez A , Muñoz R , Bernal L , Orts B , Belen O , Sempere L , Moreno-Pérez O , Francés R
Published: January 2023

Background

Sexuality is a complex entity and a major determinant of quality of life in patients diagnosed with inflammatory bowel disease (IBD). It has been estimated that sexual dysfunction (SD) affects 30% of women and 5% of men in the general population as well as 50% in women and 25% in men with IBD.

Objectives

To compare the rates of SD between young female and male patients with Crohn’s disease (CD) and healthy controls matched by age and sex and to search for predictors of SD in CD patients.

Methods

Observational, case-control, prospective study including CD patients with CD, 18-40 years of age. Age and sex-matched (2:1) healthy controls (HC) were selected.

Demographic characteristics of all subjects and clinical features of CD were collected. The variables explored were SD in women (Index of Female Sexual Function (IFSF), SD in men (International Index of Erectile Function [IIFE-15]) and presence of anxiety-depression (Hospital Anxiety/Depression Scale [HADS]).

Results

A total of 163 subjects were included: 83 men (58 CD, median 28 years (RIQ 24-36) and 25 male HC, median 31 years (RIQ 26-37) and 80 women (50 female CD, median 26 years (RIQ 21-36) and 30 HC, median 28 (RIQ 26-32). 24% of women with CD and 8% of men had clinical activity (HBI >4). Table 1 summarizes main clinical characteristics of overall study population. Demographic characteristics of men with CD and HC were not significantly different. Sedentary lifestyle was more common among women with CD vs HC (46% vs 3.3%, p<0.001), as well as educational level (universitary studies 44% CD vs 83%, HC,p= 0.003) and employment status (unemployment CD 26% vs CS 3%, p=0.01) were significantly different between groups.

SD in men, measured by IIFE, was more common in CD patients than among HC, 14/58 (24%) vs 1/25 (4%), p=0.031. CD male patients scored significantly lower than HC regarding overall sexual satisfaction 8 (6-9) vs 9 (8-10), p=0,02. Erectile dysfunction occurred only in CD (7/46, 15%), p= 0.08. Female SD was, likewise more frequent in women with CD vs female HC, (18/50 (38%) CD vs 3/30 (12%) HC,p=0.017), and female CD patients scored significantly lower with regard sexual desire (5 vs 7, p=0.008), arousal (9.0 vs 11, p=0.06) and lubrication (10 vs 13, p=0.04) than female HC. Logistic regression analysis showed that only anxiety was associated with SD in women, finding no associated risk factors with SD in CD male patients.

Conclusion

CD patients present a disease activity-independent higher risk of SD compared to the general population. Domain affected in male patients is impairment of satisfaction whereas lubrication, sexual desire and arousal, being associated with anxiety, are affected in female CD patients.
P904 Genetic Variants in IBD Chilean Patients are related to clinical outcomes
Authors: Pérez T , Bustamante M L , Travisany D , Magne F , Hernandez-Rocha C , Alvarez-Lobos M , Orellana M , Ascui G , Azocar L , Espino A , Aguilar N , Baez P , Zazueta A , Estela R , Silva V , Escobar S , De la Vega A , Arriagada E , Miquel J F , Alvares D
Published: January 2023

Background

IBD has emerged as a worldwide disease with an increased incidence in newly industrialized countries such as Chile. This population has been underrepresented in genome-wide association studies (GWAS) because IBD genetics studies have focused mainly on North America and European populations. In addition, specific IBD risk alleles have been related to different races and ethnicities. Aim: To investigate the association of IBD risk variants reported in previous GWAS studies with clinical outcomes in our Chilean patients.

Methods

192 Chilean individuals with IBD (145 UC and 47 CD) were genotyped using Illumina GSA Arrays. From IBD GWAS (Jostin et al. and Liu et al.), we selected gene variants with pGWAS value < 5x10-8 and looked for them in our Chilean IBD group. Then, we built a Chilean dataset (clinical-genotype information). Using this dataset, we performed a Spearman correlation matrix to correlate clinical outcomes with IBD variants. Further, we built regression models to predict the clinical outcomes using the variants obtained from the correlation matrix (p <0.05). Then, we selected the best models using significance testing (P values) or likelihood-based information criterion, such as the Akaike Information Criterion (AIC) and plotted the models using a Receiver Operating Characteristic Curve (ROC). Finally, to evaluate the association among variants in each model, we perform a Gene Ontology biological process enrichment analysis using PANTHER (Fisher, FDR).

Results

As shown in Figure 1 and Table 1, the best predictive regression models (more than 80%) for the clinical outcomes were surgery, Clinical/Endoscopy remission for more than five years, and Naïve anti-TNF. Association with genetic variants was observed significantly (p<0.05) in the enrichment analysis for the model Clinical/endoscopy remission (Table 2).

Conclusion

Conclusion. Candidates’ genes related to clinical outcomes in our Chilean IBD cohort were related to epithelial, innate, and adaptative immune responses and host-microbial interactions. Future research is needed to validate these findings.
N21 Patient education is (sometimes) better than cure
Authors: Müskens B ,   P. (Petra) Waayenberg MSc K.H.N. (Nanne) De Boer MD PhDA S. (Sigrid) Müller-Schotte OD PhD FAAOB
Published: January 2023

Background

About half of all patients with Inflammatory Bowel Disease (IBD) experience Extra Intestinal Manifestations (EIMs)1. One of these EIMs are non-inflammatory joint complaints. Preliminary research2 has shown that IBD patients treated by Amsterdam university medical centers (UMC) experience a lack in pre-symptomatic patient education regarding these complaints. The patients interviewed in this preliminary study were all unaware of the possible development of these joint complaints in addition to their IBD.

Methods

A practice-oriented study was set up. Both qualitative and quantitative research techniques were used. Literature research into innovations for patient education was performed. Questionnaires were distributed among IBD patients in Amsterdam UMC to identify wishes and needs regarding patient education about non-inflammatory joint complaints. To determine how this education is provided elsewhere, questionnaires were distributed among caregivers of IBD patients in other Dutch hospitals.

Results

According to literature research, verbal education, information leaflets, informational websites, group education and educational programs contribute to an increased knowledge of disease in IBD patients. Surveyed IBD patients from Amsterdam UMC wish to be informed about non-inflammatory joint complaints via verbal education or by information leaflets and/or internet. Of the surveyed caregivers in other Dutch hospitals, the majority do not have educational materials and/or methods about (non-inflammatory) joint complaints. Information is given verbally by most of them. The innovation is an information leaflet entitled 'Joint complaints in IBD'. This can be used to support verbal patient education and can be used as a reference work. The leaflet is also offered via internet.

Conclusion

Offering the information leaflet 'Joint complaints in IBD' is an appropriate innovation that meets the wishes of IBD patients in Amsterdam UMC with regard to patient education about non-inflammatory joint complaints. The leaflet is preferably used to support verbal patient education and is subsequently given to the IBD patient as a reference work or offered via the internet. Content optimization is recommended. Afterwards, a pilot implementation can be set up. After implementation, further research is recommended to investigate whether the innovation actually contributes to optimization of pre-symptomatic patient education about non-inflammatory joint complaints.
Sibling Cannibalism in Group-Living Larvae of the Solitary Wasp,Isodontia harmandi(Hymenoptera: Sphecidae): Effects of Prey Availability and Size Discrepancy
Authors: Imasaki Yui , Endo Tomoji
Published: January 2023

Sibling cannibalism has rarely been documented in the resource-based context of sibling rivalry. The solitary wasp Isodontia harmandi (Pérez) (Hymenoptera: Sphecidae) has an exceptional style of nursery ‘communal brood cells’, in which multiple larvae gregariously develop while relying on maternal prey provisioning. In this species there are several distinct features; e.g., cannibalism-driven brood reduction, single-sex broods, and mass provisioning. Rearing of the wasp larvae in artificial nest chambers provides the novel opportunity to study larval interactions under controlled conditions. To determine the factors that influence the occurrence of cannibalism and its timing, we conducted a rearing experiment using sib and non-sib pairs under two prey-availability treatments, and recorded the occurrence of cannibalism and the processes of larval growth and prey consumption over a 96-hr period. Cannibalism occurred more frequently in the low-prey treatment than in the high-prey treatment, and in female pairs than in male pairs. Cannibalism tended to occur earlier when the amount of prey remaining decreased rapidly. However, cannibalism did not occur only when all prey had been completely consumed, implying that it was not triggered directly by prey exhaustion. Cannibals were always larger than their victims, whose growth rates had often slowed before they were eaten. These results strongly imply that wasp larvae commit sibling cannibalism in the context of resource-based sibling rivalry, ensuring the double benefit of nutritional gains and reduced resource competition. We also investigated the possibility that wasp larvae monitor the size difference and/or body condition of brood-mates as an indicator of prey availability.
Long-term survival outcomes after lobe-specific nodal dissection in patients with early non-small-cell lung cancer
Authors: Kamigaichi Atsushi , Aokage Keiju , Ikeno Takashi , Wakabayashi Masashi , Miyoshi Tomohiro , Tane Kenta , Samejima Joji , Tsuboi Masahiro
Published: January 2023

OBJECTIVES

We investigated the long-term outcomes of lobe-specific nodal dissection (LSD) and systematic nodal dissection (SND) in patients with non-small-cell lung cancer (NSCLC).

METHODS

Patients with c-stage I and II NSCLC who underwent lobectomy with mediastinal nodal dissection were retrospectively analysed. After propensity score matching, we assessed the overall survival (OS), recurrence-free survival (RFS) and cumulative incidence of death (CID) from primary lung cancer and other diseases.

RESULTS

The median follow-up period was 8.4 years. Among 438 propensity score-matched pairs, OS and RFS were similar between the LSD and SND groups [hazard ratio (HR), 0.979; 95% confidence interval (CI), 0.799–1.199; and HR, 0.912; 95% CI, 0.762–1.092, respectively], but the LSD group showed a better prognosis after 5 years postoperatively. CID from primary lung cancer was similar between the 2 groups (HR, 1.239; 95% CI, 0.940–1.633). However, the CID from other diseases was lower in the LSD group than in the SND group (HR, 0.702; 95% CI, 0.525–0.938). According to c-stage, the LSD group tended towards worse OS and RFS, with higher CID from primary lung cancer than the SND group, in patients with c-stage II.

CONCLUSIONS

LSD provides acceptable long-term survival for patients with early-stage NSCLC. However, LSD may not be suitable for patients with c-stage II NSCLC due to the higher mortality risk from primary lung cancer.
Effects of thinning intensity and rotation length on albedo- and carbon stock-based radiative forcing in boreal Norway spruce stands
Authors: Kellomäki Seppo , Strandman Harri , Kirsikka-Aho Sara , Kirschbaum Miko U F , Peltola Heli
Published: January 2023

We investigated how thinning intensity and rotation length affect radiative forcing, and thus climate warming or cooling, through changes in albedo and carbon stocks in Norway spruce (Picea abies Kart. (L.)) stands. Forest ecosystem model simulations were conducted under the current climate on sub-mesic sites in central Finland (62oN). Even-aged management regime with a business-as-usual (baseline) thinning from below over an 80-year rotation length was used as the reference management regime with which others were compared. Other even-aged management regimes included baseline thinning with ±20 per cent changes in basal area thinning thresholds over rotation lengths of 80, 100 and 120 years. Additionally, we used as a comparison an uneven-aged management regime, with selective cuttings (from above) at ca. 15-year intervals, and no management regime, over the simulation periods of 80–120 years. Under even-aged management, a simultaneous decrease in thinning intensity and extension of rotation length from 80 to 120 years reduced total radiative forcing compared to the reference management regime. Thus, it had an overall net cooling effect. Under even-aged management with baseline thinning and/or higher thinning intensity with rotation lengths of 80–100 years, and under uneven-aged management, there was little net climatic effect. This was because the opposing effects of changes in albedo and ecosystem carbon stocks largely cancelled each other out. No management regime resulted in the highest net cooling effect but provided no harvest income for timber. Thus, proper incentives for forest owners would likely be required to promote such potential cooling effects in forest management.
Trans-dimensional Bayesian joint inversion of magnetotelluric and geomagnetic depth sounding responses to constrain mantle electrical discontinuities
Authors: Yao Hongbo , Ren Zhengyong , Tang Jingtian , Guo Rongwen , Yan Jiayong
Published: January 2023

Joint inversion of magnetotelluric (MT) and geomagnetic depth sounding (GDS) responses can constrain the crustal and mantle conductivity structures. Previous studies typically use either deterministic inversion algorithms that provide limited information on model uncertainties or using stochastic inversion algorithms with a predetermined number of layers that is generally not known a priori. Here, we present a new open-source Bayesian framework for the joint inversion of MT and GDS responses to probe 1D layered Earth’s conductivity structures. Within this framework, model uncertainties can be accurately estimated by generating numerous models that fit the observed data. A trans-dimensional Markov Chain Monte Carlo (MCMC) method is employed to self-parametrize the model parameters, where the number of layers is treated as an inversion parameter that is determined automatically by the data. This adaptability can overcome the under or over-parametrization problem and may be able to automatically detect the conductivity discontinuities in the Earth’s interior. To accelerate the computations, a large number of Markov chains with different initial states can be run simultaneously using the MPI parallel technique. Synthetic data sets are used to validate the feasibility of our method and illustrate how separate and joint inversions, as well as various priors affect the posterior model distributions. The trans-dimensional MCMC algorithm is then applied to jointly invert the MT and GDS responses estimated at the Tucson geomagnetic observatory, North America. Our results not only contain model uncertainty estimates but also indicate two distinct conductivity discontinuities at around 85 and 440 km, which are likely related to the lithosphere-asthenosphere boundary and the upper interface of the mantle transition zone, respectively.
Biosynthesis of the O antigen of pathogenicEscherichia coliO157:H7. Characterization of α1,4-Fuc-transferase WbdO
Authors: Melamed Jacob , Brockhausen Inka
Published: January 2023

The O157:H7 strain of Escherichia coli is responsible for frequent outbreaks of hemorrhagic colitis worldwide. Its lipopolysaccharide is a virulence factor and contains an O antigen having repeating units with the tetrasaccharide structure [2-D-PerNAcα1-3-L-Fucα1-4-D-Glcβ1-3-D-GalNAcα1-]n. Genes encoding glycosyltransferases WbdN, WbdO, and WbdP are responsible for the biosynthesis of this repeating unit. We have previously characterized the second enzyme in the pathway, WbdN, which transfers Glc in β1-3 linkage to GalNAcα-O-PO3-PO3-(CH2)11-O-Ph (GalNAc-PP-PhU). In this work, Fuc-transferase WbdO from E. coli O157:H7 expressed in BL21 bacteria was characterized using the product of WbdN as the acceptor substrate. We showed that WbdO is specific for GDP-β-L-Fuc as the donor substrate. Compounds that contained terminal Glc or Glcβ1-3GalNAc structures but lacked the diphosphate group did not serve as acceptor substrates. The structure of the WbdO product was identified by mass spectrometry and Nuclear magnetic resonance (NMR) as L-Fucα1-4-D-Glcβ1-3-D-GalNAc PP-PhU. WbdO is an unusual bivalent metal ion-dependent Fuc-transferase classified as an inverting GT2 family enzyme that has 2 conserved sequences near the N-terminus. The Asp37 residue within the 36VDGGSTD42 sequence was found to be essential for catalysis. Mutation of Asp68 to Ala within the conserved 67YDAMNK72 sequence resulted in a 3-fold increase in activity. These studies show that WbdOO157 is a highly specific Fuc-transferase with little homology to other characterized Fuc-transferases.
What accounts for the different regional responses to COVID-19 in China? Exploring the role of institutional environment, governance capacity and legitimacy
Authors: Mao Yexin
Published: January 2023

The coronavirus disease 2019 (COVID-19) pandemic has brought enormous challenges for public health crisis management in China. Crisis responses vary greatly among provinces. Many studies focus on the role of the central government in crisis management. However, how regional governments respond to such pandemic crises is underexplored. The existing literature lacks extensive comparative studies explaining why different regions respond differently to the crisis and how different regional institutional environments affect crisis management. By proposing an analytical framework based on governance capacity and legitimacy theory, this article seeks to address these questions. This study mainly focuses on provincial governments because they play a crucial role in coordinating various organizations and different levels of government in response to the crisis. By comparing the different COVID-19 responses of Hubei and Zhejiang provinces, this study finds that different regional institutional environments based on the triangular linkage of government, business and society influence regional crisis management by shaping different governance capacities (coordination, analytical, regulation and delivery capacity) and legitimacy (input, throughput and output legitimacy). Regional governments with strong governance capacity can promote crisis management through cross-organizational collaboration, scientific analysis and timely decision-making and effective policy implementation. Promoting citizen participation and information disclosure in the policy process and enhancing citizens’ support can improve governance legitimacy, thereby facilitating crisis management. Governance capacity and legitimacy also affect each other. These findings contribute to the literature on public health crisis management. They also shed light on how regional governments in China and other countries with regional variation can effectively tackle public health crises under different institutional environments.
The utilization of systematic review evidence in formulating India’s National Health Programme guidelines between 2007 and 2021
Authors: Rajwar Eti , Pundir Prachi , Parsekar Shradha S , D S Anupama , D’Souza Sonia R B , Nayak Baby S , Noronha Judith Angelitta , D’Souza Preethy , Oliver Sandy
Published: January 2023

Evidence-informed policymaking integrates the best available evidence on programme outcomes to guide decisions at all stages of the policy process and its importance becomes more pronounced in resource-constrained settings. In this paper, we have reviewed the use of systematic review evidence in framing National Health Programme (NHP) guidelines in India. We searched official websites of the different NHPs, linked to the main website of the Ministry of Health and Family Welfare (MoHFW), in December 2020 and January 2021. NHP guideline documents with systematic review evidence were identified and information on the use of this evidence was extracted. We classified the identified systematic review evidence according to its use in the guideline documents and analysed the data to provide information on the different factors and patterns linked to the use of systematic review evidence in these documents. Systematic reviews were mostly visible in guideline documents addressing maternal and newborn health, communicable diseases and immunization. These systematic reviews were cited in the guidelines to justify the need for action, to justify recommendations for action and opportunities for local adaptation, and to highlight implementation challenges and justify implementation strategies. Guideline documents addressing implementation cited systematic reviews about the problems and policy options more often than citing systematic reviews about implementation. Systematic reviews were linked directly to support statements in few guideline documents, and sometimes the reviews were not appropriately cited. Most of the systematic reviews providing information on the nature and scale of the policy problem included Indian data. It was seen that since 2014, India has been increasingly using systematic review evidence for public health policymaking, particularly for some of its high-priority NHPs. This complements the increasing investment in research synthesis centres and procedures to support evidence-informed decision making, demonstrating the continued evolution of India’s evidence policy system.
Accelerated epigenetic aging and DNA methylation alterations in Berardinelli–Seip congenital lipodystrophy
Authors: Qannan Abeer , Bejaoui Yosra , Izadi Mahmoud , Yousri Noha A , Razzaq Aleem , Christiansen Colette , Martin George M , Bell Jordana T , Horvath Steve , Oshima Junko , Megarbane Andre , Ericsson Johan , Pourkarimi Ehsan , El Hajj Nady
Published: January 2023

Berardinelli–Seip congenital lipodystrophy type 2 (CGL2) is a very rare human genetic disorder with potential significance to the understanding of the pathobiology of aging. CGL2 patients display characteristic progeroid features and suffer from type 2 diabetes, insulin resistance and fatty liver. In this study, we profiled genome-wide DNA methylation levels in CGL2 patients with BSCL2 mutations to study epigenetic age acceleration and DNA methylation alterations. This analysis revealed significant age acceleration in blood DNA of CGL2 patients using both first- and second-generation epigenetic clocks. We also observed a shortened lifespan of Caenorhabditis elegans following knockdown of the BSCL2 homolog seip-1 on a daf-16/forkhead box, class O mutant background. DNA methylation analysis revealed significant differentially methylated sites enriched for lyase activity, kinase regulator activity, protein kinase regulator activity and kinase activator activity. We could also observe significant hypomethylation in the promoter of the dual specificity phosphatase 22 gene when comparing CGL2 patients versus controls. We conclude that in line with the observed progeroid features, CGL2 patients exhibit significant epigenetic age acceleration and DNA methylation alterations that might affect pathways/genes of potential relevance to the disease.
Normal range CAG repeat size variations in the HTT gene are associated with an adverse lipoprotein profile partially mediated by body mass index
Authors: Faquih Tariq O , Aziz N Ahmad , Gardiner Sarah L , Li-Gao Ruifang , de Mutsert Renée , Milaneschi Yuri , Trompet Stella , Jukema J Wouter , Rosendaal Frits R , van Hylckama Vlieg Astrid , van Dijk Ko Willems , Mook-Kanamori Dennis O
Published: January 2023

Tandem cytosine-adenine-guanine (CAG) repeat sizes of 36 or more in the huntingtin gene (HTT) cause Huntington's disease (HD). Apart from neuropsychiatric complications, the disease is also accompanied by metabolic dysregulation and weight loss, which contribute to a progressive functional decline. Recent studies also reported an association between repeats below the pathogenic threshold (<36) for HD and body mass index (BMI), suggesting that HTT repeat sizes in the non-pathogenic range are associated with metabolic dysregulation. In this study, we hypothesized that HTT repeat sizes < 36 are associated with metabolite levels, possibly mediated through reduced BMI. We pooled data from three European cohorts (n = 10 228) with genotyped HTT CAG repeat size and metabolomic measurements. All 145 metabolites were measured on the same targeted platform in all studies. Multilevel mixed-effects analysis using the CAG repeat size in HTT identified 67 repeat size metabolite associations. Overall, the metabolomic profile associated with larger CAG repeat sizes in HTT were unfavorable—similar to those of higher risk of coronary artery disease and type 2 diabetes—and included elevated levels of amino acids, fatty acids, low-density lipoprotein (LDL)-, very low-density lipoprotein- and intermediate density lipoprotein (IDL)-related metabolites while with decreased levels of very large high-density lipoprotein (HDL)-related metabolites. Furthermore, the associations of 50 metabolites, in particular, specific very large HDL-related metabolites, were mediated by lower BMI. However, no mediation effect was found for 17 metabolites related to LDL and IDL. In conclusion, our findings indicate that large non-pathogenic CAG repeat sizes in HTT are associated with an unfavorable metabolomic profile despite their association with a lower BMI.
Efficacy, Effectiveness, and Safety of Ustekinumab for the Treatment of Ulcerative Colitis: A Systematic Review
Authors: Gisbert Javier P , Parody-Rúa Elizabeth , Chaparro María
Published: January 2023

Objective

This study aimed to evaluate ustekinumab efficacy, effectiveness, and safety as a treatment for ulcerative colitis in adult patients.

Methods

A systematic review of the efficacy, effectiveness, and safety of ustekinumab in ulcerative colitis was carried out. The search was conducted via PubMed, Embase, and the Cochrane library. Two reviewers independently assessed the quality of studies and extracted study data.

Results

Of the 892 studies identified, 17 were included: 1 randomized controlled trial (RCT), 3 long-term extensions, and 13 observational studies. In the randomized clinical trial evaluating efficacy at week 8, clinical remission was achieved in 16% of patients, whereas clinical response was achieved in 51% and 62% of patients who received intravenous ustekinumab at a dose of 130 mg and 6 mg/kg, respectively. At 3 years’ follow-up, symptomatic remission was achieved in 68% of patients. On the other hand, the effectiveness of ustekinumab was evaluated in 13 observational studies. In these studies, clinical remission at induction was achieved in 24% to 61% of cases, whereas clinical response at induction was achieved in 47% to 77% of cases. Moreover, clinical remission was achieved in 33% to 79% of cases at 52 weeks of follow-up. The adverse events ranged from 2.6% to 77% of all the studies that reported safety data. Adverse events leading to discontinuation ranged from 2.6% to 8.1%, and serious adverse events were uncommon and ranged from 3.7% to 6.0%.

Conclusions

Ustekinumab has demonstrated efficacy (in RCTs), effectiveness (in real clinical practice), and safety for the treatment of ulcerative colitis.
Dupuytren’s contracture-associated SNPs increase SFRP4 expression in non-immune cells including fibroblasts to enhance inflammation development
Authors: Kida Hiroaki , Jiang Jing-Jing , Matsui Yuichiro , Takahashi Ikuko , Hasebe Rie , Kawamura Daisuke , Endo Takeshi , Shibayama Hiroki , Kondo Makoto , Nishio Yasuhiko , Nishida Kinya , Matsuno Yoshihiro , Oikawa Tsukasa , Kubota Shimpei I , Hojyo Shintaro , Iwasaki Norimasa , Hashimoto Shigeru , Tanaka Yuki , Murakami Masaaki
Published: January 2023

Dupuytren’s contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two single nucleotide polymorphisms (SNPs) associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and βTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC.
A historic religious sanctuary may have preserved ancestral genetics of Japanese sika deer (Cervus nippon)
Authors: Takagi Toshihito , Murakami Ryoko , Takano Ayako , Torii Harumi , Kaneko Shingo , Tamate Hidetoshi B
Published: January 2023

Deer have been a major resource for human populations for thousands of years. Anthropogenic activities, such as hunting, have influenced the genetic structure and distribution of deer populations. In Japan, wild Japanese sika deer (Cervus nippon) have been hunted since ancient times but have also been historically protected as sacred animals in several sanctuaries. Sika deer have been protected for over a thousand years in the religious sanctuary around the Kasuga Taisha Shrine on the Kii Peninsula, located in the center of Japan. Here, we used short sequence repeats (SSR) and mitochondrial DNA (mtDNA) to investigate the genetic diversity, population structure, and demography of Japanese sika deer inhabiting the Kii Peninsula, Japan, and discuss possible anthropogenic influences. Using SSR, three distinct genetic groups were distinguished on the Kii Peninsula: an Eastern genetic group, a Western genetic group, and an isolated genetic group with individuals in the religious sanctuary of Kasuga Taisha Shrine in Nara city. The isolated genetic sanctuary group had only the mtDNA haplotype S4. The SSR genotype data suggested a newer divergence time of the genetic groups of the religious sanctuary than would have occurred as a result of Late Quaternary climate change. This time scale coincided with the establishment of the sanctuary with Kasuga Taisha Shrine. Thus, the religious protection conserved genetic variation over a thousand years.
A toolbox of different approaches to analyze and present PRO-CTCAE data in oncology studies
Authors: Regnault Antoine , Loubert Angély , Gorsh Boris , Davis Randy , Cardellino Anna , Creel Kristin , Quéré Stéphane , Sapra Sandhya , Nelsen Linda , Eliason Laurie
Published: January 2023

Background

The patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is used to assess symptomatic adverse events in oncology trials. Currently, no standard for PRO-CTCAE analysis exists.

Methods

Key methods of descriptive analysis and longitudinal modeling using PRO-CTCAE data from an oncology clinical trial, DRiving Excellence in Approaches to Multiple Myeloma-2 (DREAMM-2), a phase II trial of belantamab mafodotin in multiple myeloma (NCT03525678), were explored. Descriptive methods included maximum postbaseline ratings, mean change over time, ratings above a predefined cutoff, line graphs, and stacked bar charts to illustrate patient-reported adverse events at one timepoint or dynamics over time. Analysis methods involving modeling over time included toxicity over time (ToxT) (repeated measurement model, time-to-event, area under the curve analyses), generalized estimating equations (GEE), and ordinal log-linear models (OLLMs).

Results

Visualizations of PRO-CTCAE data highlighted different aspects of the data. Selection of the appropriate visualization will depend on the audience and message to be conveyed. Consistent results were obtained by all modeling approaches; no difference was found between dose groups of the DREAMM-2 study in any PRO-CTCAE item by the ToxT approach or the more sophisticated GEE and OLLM methods. Interpretation of GEE results was the most challenging. OLLM supported the interval nature of the PRO-CTCAE response scale in the DREAMM-2 study. All modeling approaches account for multiple testing (driven by the number of items).

Conclusions

Descriptive analyses and longitudinal modeling approaches are complementary approaches to presenting PRO-CTCAE data. In modeling, the ToxT approach may be a good compromise compared with more sophisticated analyses.
Detection of colon cancer recurrences during follow-up care by general practitioners vs surgeons
Authors: Vos Julien A M , Sert Edanur , Busschers Wim B , Duineveld Laura A M , Wieldraaijer Thijs , Wind Jan , Donkervoort Sandra C , Govaert Marc J P M , Beverdam Frédérique H , Smits Anke B , Bemelman Willem A , Heuff Gijsbert , van Weert Henk C P M , van Asselt Kristel M ,   I CARE study Group, van Geloven A A W , van de Ven A W H
Published: January 2023

Background

In the I CARE study, colon cancer patients were randomly assigned to receive follow-up care from either a general practitioner (GP) or a surgeon. Here, we address a secondary outcome, namely, detection of recurrences and effect on time to detection of transferring care from surgeon to GP.

Methods

Pattern, stage, and treatment of recurrences were described after 3 years. Time to event was defined as date of surgery, until date of recurrence or last follow-up, with death as competing event. Effects on time to recurrence and death were estimated as hazard ratios (HRs) using Cox regression. Restricted mean survival times were estimated.

Results

Of 303 patients, 141 were randomly assigned to the GP and 162 to the surgeon. Patients were male (67%) with a mean age of 68.0 (8.4) years. During follow-up, 46 recurrences were detected; 18 (13%) in the GP vs 28 (17%) in the surgeon group. Most recurrences were detected via abnormal follow-up tests (74%) and treated with curative intent (59%). Hazard ratio for recurrence was 0.75 (95% confidence interval [CI] = 0.41 to 1.36) in GP vs surgeon group. Patients in the GP group remained in the disease-free state slightly longer (2.76 vs 2.71 years). Of the patients, 38 died during follow-up; 15 (11%) in the GP vs 23 (14%) in the surgeon group. Of these, 21 (55%) deaths were related to colon cancer. There were no differences in overall deaths between the groups (HR = 0.76, 95% CI = 0.39 to 1.46).

Conclusion

Follow-up provided by GPs vs surgeons leads to similar detection of recurrences. Also, no differences in mortality were found.
Comparison between external and internal doses to the thyroid after the Fukushima Daiichi Nuclear Power Plant accident
Authors: Ishikawa Tetsuo , Ohba Takashi , Hasegawa Arifumi , Akahane Keiichi , Yasumura Seiji , Kamiya Kenji , Suzuki Gen
Published: January 2023

To analyze the association between radiation dose and thyroid cancer after the 2011 Fukushima Daiichi Nuclear Power Plant (FDNPP) accident, external doses have often been used because of the difficulty to estimate internal thyroid doses individually due to the lack of human data. However, no evaluation has been made as to whether external dose is a good surrogate marker for internal thyroid dose individually. This study aimed at analyzing the relationship between external doses and internal thyroid doses estimated by recently developed methodology. For four municipalities affected by the accident, 200 individuals aged under 20 at the time of the accident per municipality were randomly selected, and their external and internal thyroid doses and their ratios were estimated individually. In a separate analysis, median and arithmetic mean values for external thyroid doses estimated for persons of 16 municipalities that included the above four were compared with those for previously estimated internal thyroid doses. The ratios of the median of internal thyroid dose to that of external thyroid dose in these 16 municipalities ranged from 0.56 to 13.8 for 15-year-old children and 0.91 to 21.1 for 1-year-old children. No consistent relationship between external and internal thyroid doses was found in all 16 municipalities. Thus, thyroid doses from both external and internal exposures should be used to analyze the association between radiation dose and thyroid cancer detection rates for persons who lived in Fukushima Prefecture at the time of the FDNPP accident. (240).
Bayesian fusion: scalable unification of distributed statistical analyses
Authors: Dai Hongsheng , Pollock Murray , Roberts Gareth O
Published: January 2023

There has been considerable interest in addressing the problem of unifying distributed analyses into a single coherent inference, which arises in big-data settings, when working under privacy constraints, and in Bayesian model choice. Most existing approaches relied upon approximations of the distributed analyses, which have significant shortcomings—the quality of the inference can degrade rapidly with the number of analyses being unified, and can be substantially biased when unifying analyses that do not concur. In contrast, recent Monte Carlo fusion approach is exact and based on rejection sampling. In this paper, we introduce a practical Bayesian fusion approach by embedding the Monte Carlo fusion framework within a sequential Monte Carlo algorithm. We demonstrate theoretically and empirically that Bayesian fusion is more robust than existing methods.
Cholera vaccine and mass gatherings: protecting the crowds
Authors: Farahat Ramadan A , Khan Sheharyar H , Benson Frew , Heymann David L , Memish Ziad A
Published: January 2023

With the ongoing outbreaks of cholera in many countries globally, the risk to MG events cannot be overlooked. Cholera vaccine should be a tool used to vaccinate high-risk populations in countries where cholera epidemics continue, but the shortage of vaccines precludes its use emphasizing the need for increasing vaccine supplies.
Catching profound optical flares in blazars
Authors: Bhatta Gopal , Zola Staszek , Drozdz M , Reichart Daniel , Haislip Joshua , Kouprianov Vladimir , Matsumoto Katsura , Sonbas Eda , Caton D , Pajdosz-Śmierciak Urszula , Simon A , Provencal J , Góra Dariusz , Stachowski Grzegorz
Published: January 2023

Flaring episodes in blazars represent one of the most violent processes observed in extra-galactic objects. Studies of such events shed light on the energetics of the physical processes occurring in the innermost regions of blazars, which cannot otherwise be resolved by any current instruments. In this work, we present some of the largest and most rapid flares captured in the optical band in the blazars 3C 279, OJ 49, S4 0954+658, TXS 1156+295, and PG 1553+113. The source flux was observed to increase by nearly ten times within a time-scale of a few weeks. We applied several methods of time series analysis and symmetry analysis. Moreover, we also performed searches for periodicity in the light curves of 3C 279, OJ 49 and PG 1553+113 using the Lomb–Scargle method and found plausible indications of quasi-periodic oscillations (QPOs). In particular, the 33- and 22-day periods found in 3C 279, i.e. a 3:2 ratio, are intriguing. These violent events might originate from magnetohydrodynamical instabilities near the base of the jets, triggered by processes modulated by the magnetic field of the accretion disc. We present a qualitative treatment as the possible explanation for the observed large amplitude flux changes in both the source-intrinsic and source-extrinsic scenarios.
A naive Bayes classifier for identifying Class II YSOs
Authors: Wilson Andrew J , Lakeland Ben S , Wilson Tom J , Naylor Tim
Published: January 2023

A naive Bayes classifier for identifying Class II YSOs has been constructed and applied to a region of the Northern Galactic Plane containing 8 million sources with good quality Gaia EDR3 parallaxes. The classifier uses the five features: Gaia G-band variability, WISE mid-infrared excess, UKIDSS and 2MASS near-infrared excess, IGAPS Hα excess, and overluminosity with respect to the main sequence. A list of candidate Class II YSOs is obtained by choosing a posterior threshold appropriate to the task at hand, balancing the competing demands of completeness and purity. At a threshold posterior greater than 0.5, our classifier identifies 6504 candidate Class II YSOs. At this threshold, we find a false positive rate around 0.02 per cent and a true positive rate of approximately 87 per cent for identifying Class II YSOs. The ROC curve rises rapidly to almost one with an area under the curve around 0.998 or better, indicating the classifier is efficient at identifying candidate Class II YSOs. Our map of these candidates shows what are potentially three previously undiscovered clusters or associations. When comparing our results to published catalogues from other young star classifiers, we find between one quarter and three quarters of high probability candidates are unique to each classifier, telling us no single classifier is finding all young stars.
Gravito-turbulence in local disc simulations with an adaptive moving mesh
Authors: Zier Oliver , Springel Volker
Published: January 2023

Self-gravity plays an important role in the evolution of rotationally supported systems such as protoplanetary discs, accretion discs around black holes, or galactic discs, as it can both feed turbulence and lead to gravitational fragmentation. While such systems can be studied in the shearing box approximation with high local resolution, the large density contrasts that are possible in the case of fragmentation still limit the utility of Eulerian codes with constant spatial resolution. In this paper, we present a novel self-gravity solver for the shearing box based on the TreePM method of the moving-mesh code arepo. The spatial gravitational resolution is adaptive, which is important to make full use of the quasi-Lagrangian hydrodynamical resolution of the code. We apply our new implementation to two- and three-dimensional, self-gravitating discs combined with a simple β-cooling prescription. For weak cooling we find a steady, gravito-turbulent state, while for strong cooling the formation of fragments is inevitable. To reach convergence for the critical cooling efficiency above which fragmentation occurs, we require a smoothing of the gravitational force in the two-dimensional case that mimics the stratification of the three-dimensional simulations. The critical cooling efficiency we find, β ≈ 3, as well as the box-averaged quantities characterizing the gravito-turbulent state, agrees well with various previous results in the literature. Interestingly, we observe stochastic fragmentation for β > 3, which slightly decreases the cooling efficiency required to observe fragmentation over the lifetime of a protoplanetary disc. The numerical method outlined here appears well suited to study the problem of galactic discs as well as the magnetized, self-gravitating discs.
galstreams: A library of Milky Way stellar stream footprints and tracks
Authors: Mateu Cecilia
Published: January 2023

Nearly a hundred stellar streams have been found to date around the Milky Way and the number keeps growing at an ever faster pace. Here we present the galstreams library, a compendium of angular position, distance, proper motion, and radial velocity track data for nearly a hundred (95) Galactic stellar streams. The information published in the literature has been collated and homogenized in a consistent format and used to provide a set of features uniformly computed throughout the library: e.g. stream length, end points, mean pole, stream’s coordinate frame, polygon footprint, and pole and angular momentum tracks. We also use the information compiled to analyse the distribution of several observables across the library and to assess where the main deficiencies are found in the characterization of individual stellar streams, as a resource for future follow-up efforts. The library is intended to facilitate keeping track of new discoveries and to encourage the use of automated methods to characterize and study the ensemble of known stellar streams by serving as a starting point. The galstreams library is publicly available as a python package and served at the galstreams GitHub repository.