bluuebunny/crossref_metadata_2025 huggingface dataset:
The type of DNA damage response after Decitabine treatment depends on the level of DNMT activity
Authors: Aumer Tina , Bergmayr Linda , Kartika Stephanie , Zeng Theodor , Ge Qingyi , Giorgio Grazia , Däther Maike , Hess Alexander J. , Michalakis Stylianos , Traube Franziska R.
Published: September 2023

Decitabine and Azacytidine are considered as epigenetic drugs that induce DNA- methyltransferase (DNMT)-DNA crosslinks, resulting in DNA-hypomethylation and -damage. Although they are applied against myeloid cancers, important aspects of their mode of action remain unknown, which highly limits their clinical potential. Using a combinatorial approach, we reveal that the efficacy profile of both compounds primarily depends on the level of induced DNA-damage. Under low DNMT-activity, only Decitabine has a substantial impact. Conversely, when DNMT-activity is high, toxicity and cellular response to both compounds are dramatically increased, but do not primarily depend on DNA-hypomethylation or RNA-associated processes, contradicting an RNA-dependent effect of Azacytidine. By applying spatial proteomics, we show that Decitabine induces a strictly DNMT-dependent multifaceted DNA- damage response based on chromatin-recruitment of various repair-associated proteins. The choice of DNA-repair pathway herby depends on the severity of Decitabine-induced DNA- lesions. While mismatch (MMR) and base-excision DNA repair (BER) as well as RAD50- dependent DNA double-strand break repair are always activated in response to Decitabine, Fanconi anemia-dependent DNA-repair combined with homologous recombination is only activated when DNMT-activity is moderate. In contrast, high DNMT-activity and therefore immense replication stress, induce DNA repair by non-homologous and alternative end-joining.
Patchy and widespread distribution of bacterial translation arrest peptides associated with the protein localization machinery
Authors: Fujiwara Keigo , Tsuji Naoko , Yoshida Mayu , Takada Hiraku , Chiba Shinobu
Published: September 2023

Regulatory arrest peptides exert cellular functions via mechanisms involving regulated translational arrest. Monitoring substrates, a class of arrest peptides, feedback-regulate the expression of the Sec or YidC protein localization machinery. Previously, only a limited number of monitoring substrates were identified. In this study, we performed a bacterial domain-wide search, followed byin vivoandin vitroanalyses, leading to a comprehensive identification of many novel Sec/YidC-related arrest peptides that showed patchy, but widespread, phylogenetic distribution throughout the bacterial domain. Identification of five novel arrest-inducing sequences suggests that bacteria have evolved various arrest-inducing mechanisms. We also identified many arrest peptides that share an R-A-P-P like sequence, suggesting that this sequence could serve as a common evolutionary seed that could overcome the species-specific structures of ribosomes, to evolve arrest peptides. Our comprehensive phylogenetic study revealed that arrest peptide is a prevalent mechanism for the gene regulation of the protein localization machinery.
Small RNAs from Mitochondrial Genome Recombination Sites are Incorporated intoT. gondiiMitoribosomes
Authors: Tetzlaff Sabrina , Hillebrand Arne , Drakoulis Nikiforos , Gluhic Zala , Maschmann Sascha , Lyko Peter , Wicke Susann , Schmitz-Linneweber Christian
Published: September 2023

The mitochondrial genomes of apicomplexans comprise merely three protein-coding genes, alongside a set of thirty to forty genes encoding small RNAs (sRNAs), many of which exhibit homologies to rRNA fromE. coli. The expression status and integration of these short RNAs into ribosomes remains unclear and direct evidence for active ribosomes within apicomplexan mitochondria is still lacking. In this study, we conducted small RNA sequencing on the apicomplexanToxoplasma gondiito investigate the occurrence and function of mitochondrial sRNAs. To enhance the analysis of sRNA sequencing outcomes, we also re-sequenced theT. gondiimitochondrial genome using an improved organelle enrichment protocol and Nanopore sequencing. It has been established previously that theT. gondiigenome comprises 21 sequence blocks that undergo recombination among themselves but that their order is not entirely random. The enhanced coverage of the mitochondrial genome allowed us to characterize block combinations at increased resolution. Employing this refined genome for sRNA mapping, we find that many small RNAs originated from the junction sites between protein-coding blocks and rRNA sequence blocks. Surprisingly, such block border sRNAs were incorporated into polysomes together with canonical rRNA fragments and mRNAs. In conclusion, apicomplexan ribosomes are active within polysomes and are indeed assembled through the integration of sRNAs, including previously undetected sRNAs with merged mRNA-rRNA sequences. Our findings lead to the hypothesis thatT. gondii’sblock-based genome organization enables the dual utilization of mitochondrial sequences as both messenger RNAs and ribosomal RNAs, potentially establishing a link between the regulation of rRNA and mRNA expression.
Parkin is not required to sustain OXPHOS function in adult mammalian tissues
Authors: Filograna Roberta , Gerlach Jule , Choi Hae-Na , Rigoni Giovanni , Barbaro Michela , Oscarson Mikael , Lee Seungmin , Tiklova Katarina , Ringnér Markus , Koolmeister Camilla , Wibom Rolf , Riggare Sara , Nennesmo Inger , Perlmann Thomas , Wredenberg Anna , Wedell Anna , Motori Elisa , Svenningsson Per , Larsson Nils-Göran
Published: September 2023

Loss-of-function variants in thePRKNgene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson’s disease (PD). Extensivein vitroandin vivostudies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditionalParkinknockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development ofParkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygousPRKNpathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.
HCN channels sense temperature and determine heart rate responses to heat
Authors: Wu Yuejin , Wang Qinchuan , Granger Jonathan , Gaido Oscar Reyes , Aguilar Eric Nunez , Ludwig Andreas , Moroni Anna , Bianchet Mario A. , Anderson Mark E.
Published: September 2023

Heart rate increases with heat, [1–3] constituting a fundamental physiological relationship in vertebrates. Each normal heartbeat is initiated by an action potential generated in a sinoatrial nodal pacemaker cell. Pacemaker cells are enriched with hyperpolarization activated cyclic nucleotide-gated ion channels (HCN) that deliver cell membrane depolarizing inward current that triggers action potentials. HCN channel current increases due to cAMP binding, a mechanism coupling adrenergic tone to physiological ‘fight or flight’ heart rate acceleration. However, the mechanism(s) for heart rate response to thermal energy is unknown. We used thermodynamical and homology computational modeling, site-directed mutagenesis and mouse models to identify a concise motif on the S4-S5 linker of the cardiac pacemaker HCN4 channels (M407/Y409) that determines HCN4 current (If) and cardiac pacemaker cell responses to heat. This motif is required for heat sensing in cardiac pacemaker cells and in isolated hearts. In contrast, the cyclic nucleotide binding domain is not required for heat induced HCN4 current increases. However, a loss of function M407/Y409 motif mutation prevented normal heat and cAMP responses, suggesting that heat sensing machinery is essential for operating the cAMP allosteric pathway and is central to HCN4 modulation. The M407/Y409 motif is conserved across all HCN family members suggesting that HCN channels participate broadly in coupling heat to changes in cell membrane excitability.
Determinants of Load capacity factor in BRICS countries: A panel data analysis
Authors: Yang Minjing , Magazzino Cosimo , Awosusi Abraham Ayobamiji , Abdulloev Navzodbek
Published: September 2023

Several developing markets, such as Brazil, Russia, India, China, and South Africa (BRICS), are facing challenges in attaining the targets set with regard to the Sustainable Development Goals (SDGs). While previous studies have extensively examined the Environmental Kuznets Curve in BRICS nations, focusing on other proxy of environmental degradation like CO2 emissions and ecological footprint, little attention has been given to the Load Capacity Curve (LCC) hypothesis specifically in relation to emerging economies. Consequently, there exists a gap in the literature regarding the validation of the LCC hypothesis for these economies. To bridge this gap, our research intends to assess the validity of the LCC hypothesis in the context of the BRICS countries. Specifically, we investigate the impact of biomass energy and social globalization on the load capacity factor (a proxy for ecological quality) in the BRICS countries from 1990 to 2018, while considering the roles of economic growth and natural resources. Additionally, we explore the development of an SDG framework tailored for the BRICS nations, which can serve as a blueprint for other emerging economies. To analyze the data, we employ the Method of Moments‐Quantile‐Regression (MMQR) approach along with long‐run estimators. The findings of the MMQR analysis reveal that natural resources, social globalization, and gross domestic product have adverse effects on ecological quality, while biomass energy exhibits a positive influence on ecological quality. Furthermore, our research validates the LCC hypothesis for the BRICS economies. We also observe evidence of causality between the load capacity factor and its determinants. Based on our investigation, we recommend a transition in energy policies from hydrocarbon energy to sustainable energy options by implementing innovative approaches to biomass technology that can enhance conversion efficiency. Implementing these policy changes will not only enhance ecological quality but also align the SDG targets.
Letter: non‐steroidal anti‐inflammatory drugs reduce the risk of post‐colonoscopy colorectal cancer—authors' reply
Authors: Cheung Ka Shing , Leung Wai K.
Published: September 2023

LINKED CONTENT

This article is linked to Cheung et al and TanTai et al papers. To view these articles, visit https://doi.org/10.1111/apt.15693 and https://doi.org/10.1111/apt.16105
The risk of later surgery at the anastomotic site following right hemicolectomy for Crohn's disease in a national cohort of 12 230 patients
Authors: King Dominic , Coupland Benjamin , Dosanjh Amandeep , Cole Andrew , Adderley Nicola J. , Reulen Raoul C. , Patel Prashant , Trudgill Nigel J.
Published: September 2023

Background

Crohn's disease (CD) has a high‐risk of bowel resection and later surgery for recurrent disease. Recent guidelines recommend colonoscopy 6‐12 months following surgery to reduce further surgical intervention through medical therapy intensification.

Aims

To investigate the risk of further surgery at the anastomosis following right hemicolectomy for CD.

Methods

Hospital Episode Statistics were used to identify patients with CD and a right hemicolectomy between 2007 and 2016. Adherence to post‐resection colonoscopy guidance timing and risk of further surgery at the anastomosis were examined. Cox proportional hazards models assessed risk factors for further surgery.

Results

12 230 patients were identified: 45% male; median age 36 (IQR 26‐49) years. Median follow‐up was 5.9 (IQR 3.6‐8.6) years: totalling 74 960 person‐years. Median time to further surgery was 2.9 (IQR 1.2‐5.3) years. By 5 years 9% and by 10 years 16.9% of those with sufficient follow‐up had at least one further surgery involving the anastomotic site. Older, less deprived patients and those whose index surgery took place on an elective admission had a reduced risk of further surgery. The annual number of right hemicolectomies increased over the study from 1063 to 1317, driven by the increasing prevalence of CD. Overall, 78% of patients did not have a colonoscopy, as recommended, within 6‐12 months following index resection.

Conclusions

Further surgery involving the anastomotic site remains common following index right hemicolectomy for CD. Post‐surgical colonoscopy was only undertaken in 22% of patients within suggested timeframes. Increased colonoscopy may lead to a reduced need for surgery if early optimisation of medical therapy is undertaken for recurrence.
Letter: TIPSS improves muscle mass indices in patients with cirrhosis and severe portal hypertension
Authors: Debnath Prasanta , Rathi Pravin
Published: September 2023

LINKED CONTENT

This article is linked to Artru et al papers. To view these articles, visit https://doi.org/10.1111/apt.16080 and https://doi.org/10.1111/apt.16154
Letter: TIPSS is a promising therapy for sarcopenia in cirrhosis
Authors: Hey Penelope , Sinclair Marie , Testro Adam , Gow Paul
Published: September 2023

LINKED CONTENT

This article is linked to Artru et al and Kumar & Dixit papers. To view these articles, visit https://doi.org/10.1111/apt.16080, https://doi.org/10.1111/apt.16129 and https://doi.org/10.1111/apt.16152
Letter: TIPSS and reversal of sarcopenia
Authors: Kumar Karan , Dixit Indresh
Published: September 2023

LINKED CONTENT

This article is linked to Artru et al and Hey et al papers. To view these articles, visit https://doi.org/10.1111/apt.16080, https://doi.org/10.1111/apt.16128 and https://doi.org/10.1111/apt.16152
Targeted versus universal tuberculosis chemoprophylaxis in 1968 patients with inflammatory bowel disease receiving anti‐TNF therapy in a tuberculosis endemic region
Authors: Ye Lingna , Chapman Thomas P. , Wen Zhenzhen , Lin Lang , Qiu Yun , Liu Zhanju , Ran Zhihua , Qian Jiaming , Wu Kaichun , Gao Xiang , Hu Pinjin , Chen Minhu , Travis Simon P. L. , Cao Qian ,   The Chinese IBD Elite Union
Published: September 2023

Background

Anti‐tumour necrosis factor (anti‐TNF) therapy increases the risk of tuberculosis (TB). Given limitations of screening techniques, it remains uncertain if patients receiving anti‐TNF in TB endemic regions should be screened for latent infection with chemoprophylaxis restricted to those with proven infection, or if all patients should receive chemoprophylaxis.

Aims

To compare the incidence of active TB with infliximab (IFX) following targeted and universal TB chemoprophylaxis, and to determine the rates of adverse events (AE) related to TB chemoprophylaxis

Methods

A multi‐centre retrospective cohort study was performed at 18 hospitals in China of 1968 adult patients with IBD receiving IFX from 2009 to 2017. TB screening prior to IFX was performed with chest X‐ray and/or computed tomography [CT] and immune reactivity testing (interferon‐γ release assay and/or tuberculin skin test). Patients were followed‐up for a minimum of 3 months after IFX discontinuation, or until last hospital visit if IFX therapy was ongoing. Targeted strategy was defined as TB chemoprophylaxis only for patients with a positive latent TB screen, with universal strategy defined as TB chemoprophylaxis for all patients.

Results

Mean follow‐up was 1.07 ± 0.87 years with a total follow‐up of 2102 patient‐years. There were 1433 patients in the targeted and 483 patients in the universal TB chemoprophylaxis groups, with no significant difference in the incidence rates of active TB between groups (673.3 per 100 000 population per year vs 891.5 per 100 000 population per year, P = 0.60). In the targeted group, 55/1433 patients received TB chemoprophylaxis compared with 483/483 in the universal group, with significantly fewer AEs related to TB chemoprophylaxis in the targeted compared to the universal group (0.35% (5/1433) vs 6.8% (33/483), P < 0.05).

Conclusions

In this study of patients receiving IFX in a TB endemic area, universal chemoprophylaxis was not associated with a reduced risk of active TB when compared to a targeted chemoprophylaxis strategy, and AEs were more common. This supports the use of targeted TB chemoprophylaxis when anti‐TNF therapy is initiated in TB endemic regions.
Letter: no‐biopsy pathway for diagnosing adult coeliac disease
Authors: Paul Siba Prosad , Lau Wing‐Yu Siobhan , Khan Zubair Hanif , Heaton Paul Anthony
Published: September 2023

LINKED CONTENT

This article is linked to Fuchs et al and Kurppa et al papers. To view these articles, visit https://doi.org/10.1111/apt.15109 and https://doi.org/10.1111/apt.16195
Validating the positivity thresholds of drug‐tolerant anti‐infliximab and anti‐adalimumab antibody assays
Authors: Nice Rachel , Chanchlani Neil , Green Harry , Bewshea Claire , Ahmad Tariq , Goodhand James R. , McDonald Timothy J. , Perry Mandy H. , Kennedy Nicholas A.
Published: September 2023

Background

When used proactively, drug‐tolerant anti‐tumour necrosis factor (TNF) antibody assays provide early opportunity to suppress immunogenicity.

Aim

To validate positivity thresholds of IDKmonitor drug‐tolerant anti‐infliximab and ‐adalimumab antibody assays.

Methods

We applied positivity thresholds, defined by testing sera from 498 anti‐TNF naive healthy adults, from the Exeter Ten Thousand study to data from our therapeutic drug monitoring (TDM) service and Personalised Anti‐TNF Therapy in Crohn's disease (PANTS) cohort to explore associations with drug level and treatment outcomes.

Results

The 80% one‐sided lower confidence interval of the 99th centile concentration for anti‐infliximab and –adalimumab antibodies were lower than the manufacturers threshold of 10 arbitrary units (AU)/mL; 9 and 6 AU/mL, respectively. Using these new thresholds in the TDM cohort, more adalimumab‐ than infliximab‐ (11.2% [814/7272] vs 3.1% [390/12 683] P < 0.0001) treated patients were reclassified as antibody‐positive. Adalimumab drug concentrations in this reclassified group (median 8.1, interquartile range [IQR] 5.5‐11.0 mg/L) were lower than those below the new threshold (<5AU/mL) (median 9.9, IQR 7.1‐13.0 mg/L; P < 0.0001), but higher than at the manufacturer's threshold (10‐29 AU/mL) (median 5.9 mg/L, IQR 3.5‐8.7; P < 0.0001). No difference in infliximab drug concentration was observed using the new or manufacturer's positivity threshold (P = 0.11). In the PANTS cohort, patients with anti‐adalimumab antibody concentrations at or above the new threshold were more likely to be in primary non‐response (25/68 [37%] vs. 64/332 [19%], P = 0.0035), and non‐remission at week 54 (51/62 [82%] vs. 168/279 [60%], P = 0.0011), than patients with anti‐drug antibody concentrations in the group below the new threshold (0‐5 AU/mL); this was not seen for anti‐infliximab antibodies.

Conclusion

Laboratories should derive antibody positivity thresholds for assays they use. For adalimumab, low‐concentration anti‐drug antibodies were associated with lower drug levels and treatment failure.
Editorial: acid suppression with potassium‐competitive acid blockers dismissing genotype concerns
Authors: Scarpignato Carmelo , Hunt Richard H.
Published: September 2023

LINKED CONTENT

This article is linked to Hwang et al and Hwang & Lee papers. To view these articles, visit https://doi.org/10.1111/apt.16131 and https://doi.org/10.1111/apt.16158
Editorial: pharmacodynamics of potassium‐competitive acid blockers: comparing apples with apples—and with oranges
Authors: Howden Colin W.
Published: September 2023

LINKED CONTENT

This article is linked to Sunwoo et al papers. To view these articles, visit https://doi.org/10.1111/apt.16121 and https://doi.org/10.1111/apt.16165
The significance of histological activity measurements in immune checkpoint inhibitor colitis
Authors: Pai Rish K. , Pai Reetesh K. , Brown Ian , Choi Won‐Tak , Schaeffer David F. , Farnell David , Kumarasinghe M. Priyanthi , Gunawardena Dilini , Kim Baek Hui , Friedman Mark , Ghayouri Masoumeh , Lauwers Gregory Y.
Published: September 2023

Background

Colitis is a significant complication of immune checkpoint inhibitors (ICI). Currently, clinical and endoscopic severity are used to guide therapy.

Aims

To investigate associations between clinical, endoscopic, and histological features with outcomes

Methods

We identified 149 patients from seven institutions with biopsy‐proven ICI colitis. Biopsies were evaluated for histological features including the Geboes score, and the Robarts histopathological index (RHI) was calculated. Clinical, endoscopic, and histological data were tested for associations with biological use and adverse colitis outcomes (biological‐refractory colitis, colectomy or death from colitis).

Results

Three mutually exclusive histological patterns were identified: acute colitis, chronic active colitis and microscopic colitis. Microscopic colitis was associated with older age (68.5 vs 61 years for acute colitis pattern, P = 0.02) and longer time to colitis (5.5 vs 3 months for the other patterns, P = 0.05). Biological use was associated with earlier time to colitis (2 vs 3 months, P = 0.04) and higher RHI (18 vs 12, P = 0.007). On multivariate analysis, RHI ≥14 was associated with biological use with an odds ratio of 4.5 (95% CI 1.4‐13.8; P = 0.01). Adverse colitis outcomes were associated with shorter time to colitis (2 vs 3 months, P = 0.008) and higher RHI (24 vs 14, P = 0.001). On multivariate analysis, RHI ≥24 was associated with adverse colitis outcomes with an odds ratio 9.5 (95% CI 2.1‐42.3 P = 0.003).

Conclusion

Histological activity as measured by RHI is the only factor independently associated with biological use and adverse colitis outcomes. Prospective studies are needed to validate these findings to determine if histological activity should be incorporated into therapeutic algorithms.
Systematic review with meta‐analysis: the appropriateness of colonoscopy increases the probability of relevant findings and cancer while reducing unnecessary exams
Authors: Frazzoni Leonardo , La Marca Marina , Radaelli Franco , Spada Cristiano , Laterza Liboria , Zagari Rocco Maurizio , Bazzoli Franco , Hassan Cesare , Frazzoni Marzio , Dinis‐Ribeiro Mario , Fuccio Lorenzo
Published: September 2023

Background

Colonoscopy is frequently performed in industrialised countries. Inappropriate colonoscopies might lead to unnecessary exams, increasing risks and costs.

Aim

To estimate the impact of colonoscopy appropriateness in terms of gain in additional diagnoses and sparing of unnecessary exams.

Methods

Systematic review including studies reporting the prevalence of relevant findings, colorectal cancer (CRC) and inflammatory bowel disease (IBD) according to colonoscopy appropriateness as defined by the American Society for Gastrointestinal Endoscopy and European Panel on Appropriateness of Gastrointestinal Endoscopy.

Results

Twenty‐one studies with 19,822 patients were included. Colonoscopy was appropriate in 15,162 (71%, CI 64%‐78%). Appropriateness significantly increased the probability of relevant findings (34% vs. 18%; RR 1.81, CI 1.53‐2.14), CRC (7% vs. 2%; RR 3.62, CI 2.44‐5.37) and IBD (6% vs. 4%; RR 1.86, CI 1.09‐3.19). Appropriateness had sensitivity 88% (CI 85%‐91%), 97% (CI 93%‐98%) and 89% (CI 80%‐94%), and specificity 24% (CI 20%‐29%), 22% (CI 18%‐26%) and 24% (CI 20%‐28%) for relevant findings, CRC and IBD, respectively. On average, performing colonoscopy with appropriate indication would find 15 (CI 10‐21) more relevant findings, five (CI 3‐9) more CRCs and three (CI 1‐9) more diagnoses of IBD per 100 patients, and save 24 (CI 20‐29), 22 (CI 18‐26) and 24 (CI 20‐28) examinations per 100 patients for relevant findings, CRC and IBD, respectively.

Conclusions

Appropriateness affects the diagnostic yield of colonoscopy for CRC, IBD and relevant findings. Appropriateness criteria are useful, although integrated with clinical evaluation of the patient.
Fatigue in inflammatory bowel disease and its impact on daily activities
Authors: Schreiner Philipp , Rossel Jean‐Benoît , Biedermann Luc , Valko Philipp O. , Baumann Christian R. , Greuter Thomas , Scharl Michael , Vavricka Stephan R. , Pittet Valérie , Juillerat Pascal , Rogler Gerhard , von Känel Roland , Misselwitz Benjamin ,   the Swiss IBD Cohort Study Group
Published: September 2023

Background

Fatigue is a common symptom of chronic inflammation, including inflammatory bowel disease (IBD), resulting in significant impairment in quality of life.

Aims

To identify the prevalence of fatigue in a large IBD cohort compared to the general population, address risk factors, and evaluate its impact on daily life.

Methods

We evaluated 1208 IBD patients from the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS) and 414 healthy controls. Significant fatigue was defined as a visual analogue scale (VAS‐F, range 0‐10) score ≥ 4. Secondary endpoints were severity of fatigue and its impact on daily activities with the Fatigue Severity Scale (FSS), with a score ≥ 4 indicative of fatigue. Demographic, IBD‐related and psychiatric symptoms were assessed with a multivariate analysis of variance (MANOVA) model optimised for prediction of VAS‐F (primary outcome) and FSS scores.

Results

Overall, 672 IBD patients (55.6%) reported significant fatigue compared to 145 (35%) controls (OR 2.71; 95% CI 2.08‐3.54; P < 0.001). In IBD, fatigue also significantly affected daily activities (FSS ≥ 4; 405 (33.5%) IBD patients vs 81 (19.6%) controls, P < 0.001). In the MANOVA model, fatigue levels were associated with female gender (coefficient 0.839; 0.556 ‐ 1.123; P < 0.001), younger age at diagnosis (−0.031 per year; −0.042– −0.019; P < 0.001), shorter disease duration (−0.036 per year; −0.050– −0.022; P < 0.001), nocturnal diarrhoea (0.718; 0.295‐1.141; P = 0.001), low educational level (P = 0.034) and symptoms of depression and anxiety.

Conclusions

Fatigue is both more frequent and more severe in patients with IBD than in the general population.
Letter: accuracy of magnetic resonance index of activity score to predict response to biologics in Crohn’s disease
Authors: Debnath Prasanta , Rathi Pravin
Published: September 2023

LINKED CONTENT

This article is linked to Rimola et al papers. To view these articles, visit https://doi.org/10.1111/apt.16069 and https://doi.org/10.1111/apt.16163
Systematic review: the global incidence of faecal microbiota transplantation‐related adverse events from 2000 to 2020
Authors: Marcella Cicilia , Cui Bota , Kelly Colleen R. , Ianiro Gianluca , Cammarota Giovanni , Zhang Faming
Published: September 2023

Background

Faecal microbiota transplantation (FMT) is an effective treatment in C. difficile infection (CDI) and is currently being investigated in other diseases. There is concern around the safety of FMT and that side effects or complications may be under‐reported in the medical literature.

Aim

To evaluate the safety of FMT by summarising the overall reported Adverse Events (AEs) over a 20‐year period

Methods

We searched EMBASE, MEDLINE, and Cochrane Library databases, and CNKI and Wanfang Data from January 2000 to April 2020. All original studies reporting FMT‐related AEs were considered for inclusion. FMT‐related AEs were further classified as delivery‐related or microbiota‐related.

Results

Based on the inclusion criteria, 129 studies, which included 4241 patients (5688 FMT courses), were finally eligible. The most common indication for FMT was CDI. Overall, FMT‐related AEs were observed in 19% of FMT procedures. The most frequently reported FMT‐related AEs were diarrhoea (10%) and abdominal discomfort/pain/cramping (7%). FMT‐related serious adverse events (SAEs), including infections and deaths, have been reported in 1.4% of patients who underwent FMT (0.99% microbiota‐related SAEs). Four of five FMT‐related deaths were reported in patients receiving FMT via the upper gastrointestinal route. Importantly, all reported FMT‐related SAEs were in patients with mucosal barrier injury.

Conclusion

Most FMT‐related AEs were mild or moderate and self‐limiting. Although FMT appears to be highly safe, its methodology should be improved to reduce both delivery‐related AEs and, microbiota‐related AEs.
Editorial: can quantitative fibrosis assessment be used to enhance prediction of outcomes in patients with alcohol‐related liver disease? Authors’ reply
Authors: Israelsen Mads , Guerrero Misas Marta , Tsochatzis Emmanuel A.
Published: September 2023

LINKED CONTENT

This article is linked to Israelsen et al and Moodley & Dhanda papers. To view these articles, visit https://doi.org/10.1111/apt.16111 and https://doi.org/10.1111/apt.16134
Propensity score matching analysis: incidence and risk factors for “stardust” gastric mucosa, a novel gastric finding potentially induced by vonoprazan
Authors: Yoshizaki Tetsuya , Morisawa Toshiyuki , Fujinami Maho , Matsuda Tatsuya , Katayama Norio , Inoue Kazuki , Matsumoto Masanori , Ikeoka Seitaro , Takagi Megumi , Sako Tomoya , Momose Kenji , Noda Mari , Eguchi Takaaki , Okada Akihiko
Published: September 2023

Background

Vonoprazan, a potassium‐competitive acid blocker, is used for acid‐related diseases. Occasionally, small white protrusions called “stardust” gastric mucosa have been detected in the stomachs of some patients taking vonoprazan.

Aims

To determine the incidence of, and risk factors for, stardust gastric mucosa potentially induced by vonoprazan

Methods

In this study, we enrolled 19 503 patients who underwent endoscopy at our hospital between 2016 and 2019. Using propensity score matching, we retrospectively compared patients who received and did not receive vonoprazan. The two groups were matched for age, sex, history of proton pump inhibitor use, and atrophic gastritis.

Results

After 1:1 propensity score matching, each group comprised 2516 patients. Stardust gastric mucosa was detected significantly more often in the stomachs of patients receiving vonoprazan than those who had not received vonoprazan (4.9% vs 0.2%, P < 0.001). Its location was 70.7% in the upper third of the stomach, 29.3% in the middle third and none in the lower third. Histologically, this lesion had a mucus pool within a dilated duct surrounded by flattened glandular epithelium. The cumulative incidence rate of stardust gastric mucosa at 1, 2 and 3 years was 4.6%, 16.5% and 26.2%, respectively. The factors independently associated with the presence of stardust gastric mucosa were >205 days of vonoprazan oral intake (odds ratio [OR]: 6.99, 95% confidence interval [CI]: 4.60‐10.88) and female sex (OR: 1.75, 95% CI: 1.20‐2.58).

Conclusions

Stardust gastric mucosa appeared more frequently in the stomachs of patients taking vonoprazan.
TIPSS and reversal of sarcopenia, and TIPSS is a promising therapy for sarcopenia in cirrhosis—Authors’ reply
Authors: Artru Florent , Labreuche Julien , Louvet Alexandre
Published: September 2023

LINKED CONTENT

This article is linked to Artru et al, Hey et al and Kumar & Dixit papers. To view these articles, visithttps://doi.org/10.1111/apt.16080,https://doi.org/10.1111/apt.16128andhttps://doi.org/10.1111/apt.16129
Letter: TIPSS improves muscle mass indices in patients with cirrhosis and severe portal hypertension – authors' reply
Authors: Artru Florent , Labreuche Julien , Louvet Alexandre
Published: September 2023

LINKED CONTENT

This article is linked to Artru et al and Debnath & Rathi papers. To view these articles, visithttps://doi.org/10.1111/apt.16080andhttps://doi.org/10.1111/apt.16127
Non‐selective beta‐blocker use in cirrhotic patients is associated with a reduced likelihood of hospitalisation for infection
Authors: Sasso Roula , Rockey Don C.
Published: September 2023

Background

Non‐selective beta‐blockers (NSBBs) reduce enteric bacterial translocation rates and the frequency of spontaneous bacterial peritonitis (SBP) in animal models.

Aim

To evaluate the effect of NSBBs on infection‐related admissions.

Methods

We performed a case‐control study of cirrhotic patients' first in‐patient admission between 1 January 2011 and 31 December 2016. We examined NSBB use and the development of infection. We performed a propensity score‐matched analysis in those with NSBB use vs no use and calculated odds ratios on this matched cohort to determine the odds of outcomes based on NSBB use.

Results

We identified 2165 cirrhotic patients who met our inclusion criteria. Most patients were Caucasian (69%), male (62%). Admission Model for End stage Liver Disease (MELD) score, Charlson comorbidity index and Child‐Pugh score were 12 ± 1, 4 ± 2, and 8 ± 2, respectively. Ascites was the most common complication of portal hypertension (44%); 23% of patients used NSBBs at home. Infections occurred in 33% of admissions. In the propensity score‐matched cohort, the use of NSBBs at home was associated with lower overall, and specific, infections. The effect was similar in patients taking NSBBs for either primary or secondary oesophageal variceal prophylaxis and for those on NSBBs for other indications. Patients not on NSBBs had higher odds of infection (OR = 2.5), SBP (OR = 4.0), and bacteraemia (OR = 6.0).

Conclusion

Home use of NSBBs by patients with cirrhosis was associated with fewer infection‐related admissions. The data suggest that NSBBs in this group of patients reduce the risk of infection.
The diagnostic and prognostic significance of liver histology in alcoholic hepatitis
Authors: Forrest Ewan , Petts Gemma , Austin Andrew , Lloyd Kirsty , Wright Mark , Vergis Nikhil , Atkinson Stephen , Masson Steven , Patch David , Quaglia Alberto , Thursz Mark , Goldin Robert
Published: September 2023

Background

Liver biopsy may be of diagnostic and prognostic value but its role in alcoholic hepatitis (AH) has been controversial.

Aim

To assess the utility of liver biopsy in the assessment of clinically severe AH

Methods

The histological features of alcoholic steatohepatitis (ASH) were recorded and scored in patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial who underwent liver biopsy. These features were then assessed relative to outcome and established clinical prognostic scores.

Results

The STOPAH trial recruited 1068 patients; biopsies were obtained in 182 (17%). One hundred and sixty‐one biopsies were adequate for histological assessment and 140 (87%) were diagnostic for ASH. Only three biopsies (2%) did not have histological features of alcohol‐related liver injury. In biopsies performed prior to randomisation, ASH was identified in 92.5% of patients meeting clinical trial definitions of severe AH. In biopsies with ASH, taken before or within 48 hours of randomisation, survival differences between Alcoholic Hepatitis Histological Score (AHHS) groups were not significant: comparison of mild / moderate (91%: 21 of 23 patients) with severe (78%: 29 of 37 patients) groups: P = 0.18. The AHHS was not superior to clinical scores of prognosis: area under the curve for 28‐day mortality was 0.728, compared with 0.799 for the Glasgow alcoholic hepatitis score and 0.728 for the MELD score.

Conclusion

Liver histology taken before treatment rarely changes the diagnosis in patients meeting strict criteria for a clinical diagnosis of AH. The AHHS is similar to clinical scores in determining prognosis.

Clinical trial registration

EudraCT reference number: 2009‐013897‐42.

ISRCTN reference number: 88782125.

MREC number: 09/MRE09/59.

UKCRIN ID: 9143.
Editorial: acid suppression with potassium‐competitive acid blockers—dismissing genotype concerns. Authors' reply
Authors: Hwang Jun Gi , Lee SeungHwan
Published: September 2023

LINKED CONTENT

This article is linked to Hwang et al and Scarpignato & Hunt papers. To view these articles, visit https://doi.org/10.1111/apt.16131 and https://doi.org/10.1111/apt.16139
Review article: exposure to microbes and risk of coeliac disease
Authors: Størdal Ketil , Kahrs Christian , Tapia German , Agardh Daniel , Kurppa Kalle , Stene Lars C.
Published: September 2023

Background

Coeliac disease is an immune‐mediated intestinal disease characterised by lifelong intolerance to dietary gluten in genetically predisposed individuals. Microbial factors including infections or bacterial microbiota have long been suspected to be involved in the aetiology, but the scientific literature on the topic is scattered and heterogeneous.

Aims

To review human observational studies on microbes and coeliac disease

Methods

We identified 135 publications judged relevant. Most studies were cross‐sectional, and prone to reverse causation and other biases. Only a few were prospective. Cohort studies and longitudinal studies that have sampled biological specimens before disease onset are emphasised in the review.

Results

Infections during early childhood were associated with an increased risk of subsequent coeliac disease in nine studies , whereas maternal infections during pregnancy did not show a clear association. For the most frequently studied microbial factors, some evidence for an association was found, includingHelicobacter pylori(four out of 16 studies), adenovirus (two out of nine studies) and enterovirus (two out of six studies). Rotavirus infections have been associated with disease development, and rotavirus vaccination may reduce the risk. Among the many studies of gut microbiota, most were cross‐sectional and, therefore, potentially influenced by reverse causation. Only two smaller prospective case‐control studies with sampling before disease onset were identified; they reported inconsistent findings regarding the faecal microbiome.

Conclusions

Several microbes are potentially linked to coeliac disease. As microbial factors are amenable to interventions, larger prospective studies are still warranted.
Letter: elevated HBV DNA predicts poor survival in hepatocellular carcinoma after hepatic resection—authors' reply
Authors: Tseng Tai‐Chung , Kao Jia‐Horng
Published: September 2023

LINKED CONTENT

This article is linked to Kao et al and Liu et al papers. To view these articles, visit https://doi.org/10.1111/apt.16097 and https://doi.org/10.1111/apt.16132
Letter: accuracy of magnetic resonance index of activity score to predict response to biologics in Crohn's disease—authors' reply
Authors: Rimola Jordi , Panés Julian , Ordás Ingrid
Published: September 2023

LINKED CONTENT

This article is linked to Rimola et al and Debnath & Rathi papers. To view these articles, visithttps://doi.org/10.1111/apt.16069andhttps://doi.org/10.1111/apt.16146
Letter: rates and determinants of significant liver inflammation in chronic hepatitis B virus‐infected patients with low ALT levels in the absence of significant fibrosis
Authors: Huang Rui , Liu Jiacheng , Wang Jian , Wu Chao
Published: September 2023

LINKED CONTENT

This article is linked to Sonneveld et al papers. To view these articles, visit https://doi.org/10.1111/apt.16067 and https://doi.org/10.1111/apt.16183
Editorial: pharmacodynamics of potassium‐competitive acid blockers: comparing apples with apples – and with oranges. Authors’ reply
Authors: Sunwoo Jung , Nam Ji Yeon , Kim Bongtae , Song Geun Seog , Lee SeungHwan
Published: September 2023

LINKED CONTENT

This article is linked to Sunwoo et al and Howden papers. To view these articles, visithttps://doi.org/10.1111/apt.16121andhttps://doi.org/10.1111/apt.16140
Randomised clinical trial: high‐dose oral thiamine versus placebo for chronic fatigue in patients with quiescent inflammatory bowel disease
Authors: Bager Palle , Hvas Christian Lodberg , Rud Charlotte Lock , Dahlerup Jens Frederik
Published: September 2023

Background

Fatigue is a burdensome symptom for patients with inflammatory bowel disease (IBD). Few pharmacological interventions have documented effect on fatigue in patients with IBD. A pilot study indicated a 20‐day effect  with high‐dose thiamine.

Aims

To investigate the effect and safety of high‐dose oral thiamine (600‐1800 mg/d) based on gender and weight on chronic fatigue in patients with quiescent IBD.

Methods

This was a randomised, double‐blinded, placebo‐controlled crossover trial. Patients had quiescent IBD, severe chronic fatigue and no other explanation for fatigue. Patients were allocated 1:1 to either 1) high‐dose oral thiamine for 4 weeks, 4 weeks of washout, 4 weeks of oral placebo or 2) oral placebo for 4 weeks, 4 weeks of washout, 4 weeks of high‐dose oral thiamine. Fatigue was measured using the Inflammatory Bowel Disease‐Fatigue Questionnaire. The primary outcome was improvement (≥3 points) of fatigue after 4 weeks on thiamine.

Results

Forty patients were enrolled between November 2018 and October 2019. Crossover analysis showed a mean reduction of 4.5 points (95% CI 2.6‐6.2) in fatigue after thiamine compared with a mean increase of 0.75 point (95% CI −1.3‐2.8; P = 0.0003) after placebo. Furthermore, 55% of group 1 and 75% of group 2 showed an improvement ≥ 3 points while on thiamine compared with 25% of group 1 and 35% of group 2 while on placebo. Only mild side effects were detected.

Conclusion

We showed a significant beneficial effect of high‐dose oral thiamine on chronic fatigue in IBD. The treatment was well tolerated.

Trial registration: NCT03634735.
Serum triiodothyronine‐to‐thyroxine (T3/T4) ratio predicts therapeutic outcome to biological therapies in elderly IBD patients
Authors: Bertani Lorenzo , Tricò Domenico , Pugliese Daniela , Privitera Giuseppe , Linsalata Giuseppe , Zanzi Federico , Gloria Mumolo Maria , Barberio Brigida , Monzani Fabio , Marchi Santino , Guidi Luisa , Blandizzi Corrado , Armuzzi Alessandro , Costa Francesco
Published: September 2023

Introduction

Rates of elderly patients with inflammatory bowel diseases (IBDs) are increasing, and biomarkers are needed to optimise their therapies. Serum triiodothyronine‐to‐thyroxine (T3/T4) ratio has been correlated with geriatric patient frailty.

Aim

To assess the suitability of T3/T4 ratio as a response marker to biologics in elderly patients with IBD.

Methods

Patients with IBD over 60 years old were enrolled, when starting biological therapy. Therapeutic outcome was assessed after 54 weeks of treatment as mucosal healing (Mayo endoscopic score < 2 for ulcerative colitis; ulcer disappearance for Crohn's disease) and clinical remission (Partial Mayo Score < 2 for ulcerative colitis; Harvey‐Bradshaw Index < 5 for Crohn's disease). T3/T4 ratio was evaluated at baseline, and its association with therapeutic outcomes was tested by multivariable logistic regression and receiver operating characteristic (ROC).

Results

We enrolled 80 patients; 44 achieved clinical remission and 36 mucosal healing. Baseline T3/T4 ratio was higher in patients with mucosal healing, as compared with those without mucosal healing (P < 0.0001), regardless of the disease type or biological drug (OR 6.4 [2.9‐14.3] for each T3/T4 unit increase, P < 0.0001). A cut point of 3.3 was identified as the optimal threshold of baseline T3/T4 ratio for predicting mucosal healing, providing 78% sensitivity and 89% specificity (area under the ROC curve 0.88 [0.79‐0.94]; positive and negative likelihood ratios 6.8 [2.9‐15.9] and 0.3 [0.1‐0.5] respectively).

Conclusions

T3/T4 ratio seems a reliable tool for predicting therapeutic outcome of biological therapy in elderly patients with IBD. If validated, the assessment of this parameter before starting biological treatment might be suggested.
Editorial: biomarkers in HBV and prediction of treatment response
Authors: Ridruejo Ezequiel
Published: September 2023

LINKED CONTENT

This article is linked to Lim et al papers. To view these articles, visit https://doi.org/10.1111/apt.16149 and https://doi.org/10.1111/apt.16226
Similarly low risk of hepatocellular carcinoma after either spontaneous or nucleos(t)ide analogue‐induced hepatitis B surface antigen loss
Authors: Yip Terry Cheuk‐Fung , Wong Vincent Wai‐Sun , Tse Yee‐Kit , Liang Lilian Yan , Hui Vicki Wing‐Ki , Zhang Xinrong , Li Guan‐Lin , Lui Grace Chung‐Yan , Chan Henry Lik‐Yuen , Wong Grace Lai‐Hung
Published: September 2023

Background

It is unknown whether patients with chronic hepatitis B (CHB) who achieved hepatitis B surface antigen (HBsAg) seroclearance spontaneously or following anti‐viral therapy have similar clinical outcomes.

Aim

To compare the risk of hepatocellular carcinoma (HCC) in patients with CHB who either cleared HBsAg spontaneously or following anti‐viral therapy

Methods

Adult CHB‐monoinfected patients who cleared HBsAg between January 2000 and March 2019 were identified from a territory‐wide database in Hong Kong. Patients with liver transplantation and/or HCC before HBsAg loss were excluded. Patients’ demographics, comorbidities, anti‐viral treatment, laboratory parameters and HCC development were analysed.

Results

Of 7,124 identified patients with CHB who cleared HBsAg, mean age was 58.1 ± 13.8 years; 4,340 (60.9%) were male; 451 (6.3%) had cirrhosis; 5,917 (83.1%) and 1,207 (16.9%) had spontaneous and nucleos(t)ide analogue (NA)‐induced HBsAg seroclearance, respectively. Most patients had normal liver function at HBsAg loss. Patients with NA‐induced HBsAg seroclearance were younger, and more likely to be male and cirrhotic than patients with spontaneous HBsAg loss. At a median (interquartile range) follow‐up of 4.3 (2.2‐7.6) years, 97 (1.6%) and 16 (1.3%) patients with spontaneous and NA‐induced HBsAg loss developed HCC, respectively. Patients who achieved NA‐induced HBsAg loss had comparable HCC risk as those with spontaneous HBsAg loss (adjusted subdistribution hazard ratio 0.75, 95% CI 0.43‐1.32, P = 0.323). The results remained robust in propensity score weighting and matching analyses.

Conclusion

The HCC risk was similarly low after either spontaneous or NA‐induced HBsAg seroclearance in a territory‐wide cohort of patients with CHB who had cleared HBsAg.