bluuebunny/crossref_metadata_2025 huggingface dataset:
Polysubstance use in inflammatory bowel disease
Authors: Bogale Kaleb , Vrana Kent , Konsavage Wesley Raup‐ , Walter Vonn , Stuart August , Dalessio Shannon , Koltun Walter , Bernasko Nana , Tinsley Andrew , Williams Emmanuelle , Clarke Kofi , Coates Matthew D.
Published: November 2021

Objectives

We aimed to evaluate the incidence, predisposing factors and impacts of polysubstance use (PSU) (ie, the concurrent use or abuse of two or more drugs or substances) in inflammatory bowel disease (IBD).

Methods

Data of patients enrolled between 1 January 2015 and 31 August 2019 from a single tertiary care referral center were retrospectively collected. Patients’ baseline and clinical characteristics and their antidepressant and/or anxiolytic medications were abstracted. Associations between PSU and patients’ characteristics were analyzed. Multivariate logistic regression models were fit, incorporating significant clinical factors.

Results

Altogether 315 patients with IBD (166 women, 149 men; 214 with Crohn's disease and 101 ulcerative colitis) were enrolled. Of them, 66 (21.0%) exhibited PSU (CD 21.5%, UC 19.8%); 37.5% had moderate to severe disease activity, 34.3% with extraintestinal manifestations (EIM), 41.6% with an anxious or depressed state and 69.8% had used healthcare resources in the prior 12 months. Moreover, 71.2% used two substances, while 27.3% used three substances. In the total cohort, EIM (odds ratio [OR] 1.97, 95% confidence interval [CI] 1.14‐3.34, P = 0.019) and antidepressant or anxiolytic use (OR 2.51, 95% CI 1.45‐4.39, P < 0.001) were positively associated with PSU on multivariate analysis. PSU was associated with increased rate of IBD‐associated imaging (57.6% vs 47.0%, P < 0.05).

Conclusions

PSU is common in IBD. EIM, antidepressant and/or anxiolytic use and imaging studies were independently associated with PSU. This study reinforces the importance of screening patients with IBD for substance use, particularly those with EIM and using antidepressants and/or anxiolytics.
Thrombotic risk assessment in patients with systemic lupus erythematosus: Validation of the adjusted‐Global Antiphospholipid Syndrome Score (aGAPSS) in Thai patients
Authors: Chanloung Wanitcha , Kasitanon Nuntana , Wichainun Ramjai , Louthrenoo Worawit
Published: October 2021

Background

The adjusted‐Global Antiphospholipid Syndrome Score (aGAPSS) has been validated and used to predict antiphospholipid antibodies (aPL) related to vascular thrombosis (VT).

Objective

To validate aGAPSS for predicted aPL‐related VT and pregnancy complications (PC) in Thai systemic lupus erythematosus (SLE) patients.

Methods

A cross‐sectional study was performed among Thai SLE patients with clinical manifestations; history of VT and PC, cardiovascular risk factors, and aPL profiles were collected. The aGAPSS was calculated from the sum of the risk factors (hyperlipidemia = 3.0, arterial hypertension = 1.0, anti‐cardiolipin antibody = 5.0, anti‐b2 glycoprotein I antibody = 4.0, and lupus anticoagulant = 4.0).

Results

Of 132 SLE patients, 12 (9.1%) had VT and 5 (4.1%) had PC. When comparing the aGAPSS (median; interquartile range [IQR]) of patients with events (VT and/or PC) (6.5; IQR 3.3‐9.0), VT (8.0; IQR 4.0‐9.0), arterial thrombosis (3.5; IQR 1.0‐5.8), and PC (9.0; IQR 8.0‐11.5), and the aGAPSS of patients without an event (3.0; IQR 0‐4.0), aGAPSS of patients with events was significantly higher, except in patients with arterial thrombosis. An aGAPSS of 4.5 or more was associated with risk of aPL‐related VT (sensitivity 71.4%, specificity 76.7%), and an aGAPSS of 6.0 or more was associated with risk of aPL‐PC (sensitivity 100%, specificity 84.0%).

Conclusion

The aGAPSS could predict the risk of aPL‐PC and aPL‐related VT in Thai SLE patients.
Emerging role of TWEAK‐Fn14 axis in lupus, a disease related to autoimmunity and fibrosis
Authors: Xu Yuan , Wei Hui‐Ting , Jing Hao‐Yue , Tan Xiao‐Yang , Zhou Xiao‐Tao , Ma Yue‐Rong
Published: October 2021

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder. Lupus nephritis (LN) is one of the severe clinical implications in SLE, and this was relates to fibrosis in the kidney. As an important marker in the tumor necrosis factor (TNF) superfamily, TNF‐like weak inducer of apoptosis (TWEAK) has been given much attention with respect to its role in regulating pro‐inflammatory immune response. Fibroblast growth factor‐inducible 14 (Fn14), the sole receptor for TWEAK, has been found expressed in different immune and non‐immune cells. TWEAK binds to Fn14, and then regulates inflammatory components production via downstream signaling pathways. To date, dysregulated expression of TWEAK, Fn14 has been reported in SLE, LN patients, and in vivo, in vitro studies have discussed the significant role of TWEAK‐Fn14 axis in SLE, LN pathogenesis, partly through mediating the fibrosis process. In this review, we will discuss the association of TWEAK‐Fn14 axis in lupus. Understanding the relationship will better realize the potential for making TWEAK‐Fn14 as a marker for the diseases, and will help to give many clues for targeting them in treatment of lupus in the future.
Effects of mediastinal lymph node dissection in colorectal cancer‐related pulmonary metastasectomy
Authors: Yang Young Ho , Park Seong Yong , Kim Ha Eun , Park Byung Jo , Lee Chang Young , Lee Jin Gu , Kim Dae Joon , Paik Hyo Chae
Published: October 2021

Background

The benefits of mediastinal lymph node dissection (MLND) in colorectal cancer‐related pulmonary metastasectomy (PM) have been poorly reported. This study aimed to determine whether MLND affects survival in patients undergoing PM and to identify the prognostic factors for survival.

Methods

We retrospectively reviewed 275 patients who had undergone colorectal cancer‐related PM from January 2010 to December 2016. MLND was defined as the resection of at least six mediastinal lymph node stations according to the International Association for the Study of Lung Cancer criteria (N1, ≥3 stations; N2, ≥3 stations). The propensity score matching method was used to reduce bias.

Results

Thirty‐three (12%) patients underwent MLND, and 13 (4.7%) patients had mediastinal lymph node involvement. This study showed no difference in 5‐year overall survival (no MLND, 52.7% vs. MLND, 53.5%; p = 0.81). On multivariable analysis, negative prognostic factors for overall survival were preoperative carcinoembryonic antigen (CEA) level (p < 0.001), a higher number of metastatic nodules (p < 0.001), metastatic nodule size ≥2 cm (p < 0.001), and lymph node involvement (p = 0.006).

Conclusions

Mediastinal lymph node involvement, preoperative CEA level, higher metastatic nodule number, and nodule size negatively affected survival whereas MLND in PM was not associated with survival.
The SEC Filing Review Process: A Survey and Future Research Opportunities*
Authors: Cunningham Lauren M. , Leidner Jacob J.
Published: October 2021

As part of its goal to monitor and enhance the quality of information available to investors, the SEC reviews companies' filings to ensure compliance with applicable financial reporting and disclosure requirements. Increased public interest and the substantial costs for both the SEC in reviewing and the companies in responding have led to a rapidly growing body of accounting literature that examines the filing review process. We survey and comment on 80 published and unpublished academic research papers in this literature and identify significant gaps that future research should address. We also summarize the institutional features of the filing review process, aiming to inform future academic studies. Our survey should be of interest to both academics and market participants evaluating the effectiveness and efficiency of the filing review process.
Network Analysis of Audit Partner Rotation†
Authors: Pittman Jeffrey , Wang Lin , Wu Donghui
Published: October 2021

Focusing on mandatory partner rotations, we examine the importance of within‐firm network connections to the selection of successor partners and the impact of those connections on post‐rotation audit performance. Using data from China, we track partners' history and identify incumbent‐successor connections stemming from jointly conducted prior engagements. Although these connections can enhance incumbent‐successor information transfers and thus post‐rotation audit performance, they may also pose a threat to quality by compromising the successor's independence. Among the pool of replacement candidates, we find that individuals with stronger connections with the incumbent are more likely to be appointed as successors. This finding is more pronounced when the audit engagement is more complex, client‐specific knowledge is not readily available to the succeeding partner, and the engagement is more valuable to the audit firm. We also document that successor‐incumbent connections are associated with equal or better post‐rotation audit quality and fewer client defections. These results suggest that the benefits of network‐based successor selection may outweigh its costs. By enriching our understanding of the partner transition process, this study contributes to the public policy discourse on partner rotation.
Balancing the story of fetal alcohol spectrum disorder: A narrative review of the literature on strengths
Authors: Flannigan Katherine , Wrath Andrew , Ritter Chantel , McLachlan Kaitlyn , Harding Kelly D. , Campbell Alanna , Reid Dorothy , Pei Jacqueline
Published: October 2021

For many years, researchers have explored the complex challenges experienced by individuals with fetal alcohol spectrum disorder (FASD). This research has been important for documenting the brain‐ and body‐based impacts of prenatal alcohol exposure and the psychosocial vulnerabilities and environmental adversities frequently associated with FASD. It has also supported advocacy efforts and highlighted the necessity of providing FASD services and supports. However, with the focus on deficits and needs, there is a considerable gap in the literature on the strengths and successes of individuals with FASD. The lack of strengths‐based FASD research has likely perpetuated the stress and stigma experienced by individuals with FASD and their families. Thus, there is a critical need to shift the direction of the field. Here we provide a narrative review of the literature on strengths in FASD. Our goals are to: (1) understand the state of strengths‐based research related to individuals with FASD across the lifespan, and (2) describe positive characteristics, talents, and abilities of individuals with FASD that may be cultivated to promote their fulfillment and well‐being. We identified a total of 19 studies, most of which were conducted to explore the lived experiences of adults with FASD. This preliminary but critical body of evidence highlights the intrinsic strengths of individuals with FASD, including strong self‐awareness, receptiveness to support, capacity for human connection, perseverance through challenges, and hope for the future. Despite the importance of this emerging evidence, appraisal of the literature indicates a need for more intentional, methodologically rigorous, participatory, and theory‐driven research in this area. Findings from this study, including the identified gaps in the literature, can be used to inform research, practice, and policy to meaningfully advance the field of FASD and promote positive outcomes in this population.
Moderate blood alcohol and brain neurovulnerability: Selective depletion of calcium‐independent phospholipase A2, omega‐3 docosahexaenoic acid, and its synaptamide derivative as a potential harbinger of deficits in anti‐inflammatory reserve
Authors: Schreiber Jennifer A. , Tajuddin Nuzhath F. , Kouzoukas Dimitrios E. , Kevala Karl , Kim Hee‐Yong , Collins Michael A.
Published: November 2021

Background

Repetitive, highly elevated blood alcohol (ethanol) concentrations (BACs) of 350 to 450 mg/dl over several days cause brain neurodegeneration and coincident neuroinflammation in adult rats localized in the hippocampus (HC), temporal cortex (especially the entorhinal cortex; ECX), and olfactory bulb (OB). The profuse neuroinflammation involves microgliosis, increased proinflammatory cytokines, and elevations of Ca+2‐dependent phospholipase A2 (cPLA2) and secretory PLA2 (sPLA2), which both mobilize proinflammatory ω‐6 arachidonic acid (ARA). In contrast, Ca+2‐independent PLA2 (iPLA2) and anti‐inflammatory ω‐3 docosahexaenoic acid (DHA), a polyunsaturated fatty acid regulated primarily by iPLA2, are diminished. Furthermore, supplemented DHA exerts neuroprotection. Given uncertainties about the possible effects of lower circulating BACs that are common occurring during short‐ term binges, we examined how moderate BACs affected the above inflammatory events, and the impact of supplemented DHA.

Methods and results

Young adult male rats sustaining upper‐moderate BACs (~150 mg/dl) from once‐daily alcohol intubations were sacrificed with appropriate controls after 1 week. The HC, ECX and OB were quantitatively examined using immunoblotting, neurodegeneration staining, and lipidomics assays. Whereas neurodegeneration, increases in cPLA2 IVA, sPLA2 IIA, and ARA, and microglial activation were not detected, the HC and ECX regions demonstrated significantly reduced iPLA2 levels. Levels of DHA and synaptamide, its anti‐inflammatory N‐docosahexaenoylethanolamide derivative, also were lower in HC, and DHA supplementation prevented the iPLA2 decrements in HC. Additionally, adult mice maintaining upper‐moderate BACs from limited alcohol binges had reduced midbrain iPLA2 levels.

Conclusions

The apparently selective depletion by moderate BACs of the metabolically linked anti‐inflammatory triad of hippocampal iPLA2, DHA, and synaptamide, and of iPLA2 in the ECX, potentially indicates an unappreciated deficit in brain anti‐inflammatory reserve that may be a harbinger of regional neurovulnerability.
Political and economic determinants of export restrictions in the agricultural and food sector
Authors: He Xi
Published: November 2021

Utilizing a rich export restriction database that covers 527 agricultural products at the six‐digit Harmonized System (HS) code level in 168 countries from 2005 to 2015, this article investigates the political and economic determinants of countries’ export restriction decisions. Empirical analysis shows that a one standard deviation increase in a commodity's market power increases the probability of an export restriction on that commodity by 5.5%, and a one standard deviation increase in a country's number of Regional Trade Agreement (RTA) partners decreases the probability of an export restriction by 6.0%. There is also evidence that higher market power of the downstream sector, which purchases inputs from the upstream sector, leads to a higher probability of export restrictions in the upstream sector. Macroeconomic variables, including urbanization rate, agricultural land per capita, and weather variables, are also important determinants of export restrictions. This article highlights the potential role of RTAs and competitive market structure in both the sector of interest and its downstream sector in disciplining export restrictions.
Circ_0037078 promotes trophoblast cell proliferation, migration, invasion and angiogenesis by miR‐576‐5p/IL1RAP axis
Authors: Zou Hong , Mao Qinghua
Published: November 2021

Background

Preeclampsia (PE) is a common hypertensive disorder of pregnancy. Recent studies have suggested that circular RNAs (circRNAs) play a pathological role in PE. Herein, this study aimed to investigate the action and mechanism of circ_0037078 in PE process.

Methods

The quantitative real‐time PCR (qRT‐PCR) and Western blot were used to determine the expression levels of RNAs and genes. Cell proliferation, migration, invasion and angiogenesis were evaluated by using cell counting kit‐8 (CCK‐8), colony formation, transwell, and tube formation assays, respectively. The target relation between miR‐576‐5p and IL1RAP (Interleukin‐1 receptor accessory protein) and circ_0037078 was predicted by bioinformatics analysis and verified by dual‐luciferase reporter and RNA immunoprecipitation (RIP) assays.

Results

Circ_0037078 expression was higher in placental tissues of patients with PE than that of normal control. Knockdown of circ_0037078 led to an enhancement of the proliferation, migration, invasion, and angiogenesis in trophoblast cells. Mechanistically, circ_0037078 acted as a sponge for miR‐576‐5p, thus elevating the expression of IL1RAP, which was targeted by IL1RAP. Further rescue experiments suggested that miR‐576‐5p inhibition reversed the effects of circ_0037078 knockdown on above behaviors of trophoblast cells. Moreover, miR‐576‐5p overexpression enhanced the proliferative, migratory, invasive, angiogenic phenotypes of trophoblast cells, which were attenuated by IL1RAP up‐regulation.

Conclusion

Circ_0037078 knockdown promotes trophoblast cell proliferation, migration, invasion, and angiogenesis in vitro by miR‐576‐5p/IL1RAP axis, providing a novel insight into the etiology of PE.
miR‐146a enhances regulatory T‐cell differentiation and function in allergic rhinitis by targeting STAT5b
Authors: Zhang Yu , Yang Yujuan , Guo Jing , Cui Limei , Yang Liping , Li Yumei , Mou Yakui , Jia Chuanliang , Zhang Luo , Song Xicheng
Published: October 2021

Background

MicroRNA (miR)‐146a, as an important immune regulatory factor with an anti‐inflammatory effect, plays a crucial role in regulatory T‐cell (Tregs) differentiation and function in allergic rhinitis (AR). The present study aimed to investigate the regulatory mechanism employed by miR‐146a to control Treg differentiation and function in AR.

Methods

Expression of miR‐146a and STAT5b in peripheral blood mononuclear cells (PBMCs) and nasal mucosa from patients with AR was detected by qPCR and Western blotting. Tregs were quantified by flow cytometry in miR‐146a knockdown or STAT5b knockdown PBMCs. FOXP3, IL‐10, and TGF‐β levels were detected by Western blotting or ELISA in miR‐146a knockdown or STAT5b overexpressing PBMCs, as well as in STAT5b knockdown PBMCs overexpressing miR‐146a. The effect of miR‐146a on STAT5b was observed by luciferase assay and knockdown experiments.

Results

Levels of miR146a and STAT5b in the nasal mucosa or PBMCs were significantly lower in the AR group than in the control group. There were significantly fewer Tregs in miR‐146a knockdown or STAT5b knockdown PBMCs compared to control PBMCs. Expression of FOXP3, IL‐10, and TGF‐β was decreased in the miR‐146a knockdown group but increased in the STAT5b overexpression group. In contrast, miR‐146a overexpression increased the levels of these factors, but knockdown of STAT5b significantly inhibited this effect. Luciferase assay and knockdown experiments showed that miR‐146a bound directly to STAT5b.

Conclusions

miR‐146a enhances Treg differentiation and function in AR by positively targeting STAT5b.
Performance, clinical utility, and cost‐effectiveness of selective use of staging investigations in early breast cancers
Authors: James Justin , Teo Melanie , Ramachandran Vivekananda , Law Michael , Cheng Michael
Published: November 2021

Background

International guidelines do not recommend routine staging of EBCs. However, most clinicians still perform staging investigations (SI) selectively for several reasons. We examined our practice of selective use of SI to determine its performance, clinical utility, and cost‐effectiveness.

Methods

We performed this retrospective study on patients who had treatment for AJCC stage I or stage II breast cancer through Eastern health Breast and cancer centre, Melbourne, for 50 months from January 2012.

Result

Our practice of selective use resulted in SI in 41% of all EBCs (95% CI 37–46%). Overall yield was 3% (95% CI 0.4–5.4%) with a false positive rate of 22% (95% CI 1628%) and a false‐negative rate of 45% (95% CI 11–79%). The sensitivity of SI is 55% (95% CI 21–89%) with a negative predictive value of 97% (95% CI 94.8–99.9%). None of the treatment components was found to be significantly changed based on findings on SI. There was no significant difference in all‐cause mortality or new distant recurrence in the staged and non‐staged groups. Identification of six new metastases cost at least 422 021 AUD. The approximate cost to stage one EBC is 2069 AUD. ‘Number needed to scan’ to detect one new metastasis is 34 at the expense of 70337AUD.

Conclusion

Selective use of SI results in better yield. However, the clinical utility of these results is not significant. It is debatable if this level of expenditure is cost‐effective. Our results point to a need for change in practice.
Long‐term colorectal cancer incidence and mortality after adenoma removal in women and men
Authors: Jodal Henriette C. , Klotz Dagmar , Herfindal Magnhild , Barua Ishita , Tag Petter , Helsingen Lise M. , Refsum Erle , Holme Øyvind , Adami Hans‐Olov , Bretthauer Michael , Kalager Mette , Løberg Magnus
Published: October 2021

Background

Women and men with colorectal adenomas are at increased risk of colorectal cancer and colonoscopic surveillance is recommended. However, the long‐term cancer risk remains unknown.

Aims

To investigate colorectal cancer incidence and mortality after adenoma removal in women and men

Methods

We identified all individuals who had adenomas removed in Norway from 1993 to 2007, with follow‐up through 2018. We calculated standardized incidence ratios (SIR) and incidence‐based mortality ratios (SMR) with 95% confidence intervals (CI) for colorectal cancer in women and men using the female and male population for comparison. We defined high‐risk adenomas as ≥2 adenomas, villous component, or high‐grade dysplasia.

Results

The cohort comprised 40 293 individuals. During median follow‐up of 13.0 years, 1079 women (5.5%) and 866 men (4.2%) developed colorectal cancer; 328 women (1.7%) and 275 men (1.3%) died of colorectal cancer. Colorectal cancer incidence was more increased in women (SIR 1.64, 95% CI 1.54‐1.74) than in men (SIR 1.12, 95% CI 1.05‐1.19). Colorectal cancer mortality was increased in women (SMR 1.13, 95% CI 1.02‐1.26) and reduced in men (SMR 0.79, 95% CI 0.71‐0.89). Women with high‐risk adenomas had an increased risk of colorectal cancer death (SMR 1.37, 95% CI 1.19‐1.57); women with low‐risk adenomas (SMR 0.90, 95% CI 0.76‐1.07) and men with high‐risk adenomas had a similar risk (SMR 0.89, 95% CI 0.76‐1.04), while men with low‐risk adenomas had reduced risk (SMR 0.70, 95% CI 0.59‐0.84).

Conclusions

After adenoma removal, women had an increased risk of colorectal cancer death, while men had reduced risk, compared to the general female and male populations. Sex‐specific surveillance recommendations after adenoma removal should be considered.
Influence of fibrolytic enzymes in total mixed ration containing urea‐molasses‐treated sugarcane bagasse on the performance of lactating Holstein–Friesian crossbred cows
Authors: Lunsin Ratchataporn , Pilajun Ruangyote , Cherdthong Anusorn , Wanapat Metha , Duanyai Somporn , Sombatsri Prapatsorn
Published: October 2021

The aim of this study was to determine the effect of different levels of fibrolytic enzyme on nutrient utilization and milk production in dairy cows. Four multiparous early‐to‐mid‐lactation Holstein–Friesian crossbred cows were randomly allocated in a 4 × 4 Latin square design. Cows were fed a balanced total mixed ration (TMR) on a dry matter (DM) basis containing 0, 1.2, 2.4, and 3.6 g/kg DM of fibrolytic enzyme in TMR, where the TMR comprises 60% concentrate supplemented with a fibrolytic enzyme at 0, 2, 4, and 6 g/kg DM of concentrate, and 40% urea‐molasses‐treated sugarcane bagasse (UMSB) was used as a roughage source. Fibrolytic enzyme supplementation in TMR containing UMSB did not affect dry matter intake (DMI) of dairy cows (p > 0.05). There was a quadratic effect of fibrolytic enzyme levels on the digestibility of DM, organic matter (OM), neutral detergent fiber (NDF), and acid detergent fiber (ADF) (p < 0.05), and the maximal response was reached at 1.2–2.4 g/kg DM of fibrolytic enzyme added in the TMR. Furthermore, 3.5% fat‐corrected milk, milk fat, total volatile fatty acids, and propionic acid were greater in a cow fed with 1.2–2.4 g/kg DM of fibrolytic enzyme, resulting in a lower ratio of acetic acid to propionic acid (p < 0.05). In conclusion, adding a fibrolytic enzyme in TMR containing UMSB improved nutrient utilization, rumen fermentation, and milk production of lactating dairy cows.
‘Faking it’: Exploring adolescent perceptions of depression (in)authenticity and ‘attention seeking’
Authors: Dixon‐Ward Katharina C. , Chan Stella W. Y.
Published: October 2021

Objectives

Attitudes towards peers who are not perceived to be legitimately depressed, or whose depression ‘authenticity’ is questioned, represent a current gap in adolescent depression stigma research. This research study, therefore, investigated how perceptions of depression inauthenticity are framed in adolescent Reddit communities.

Methods

This observational study used an internet‐mediated, qualitative methodology to analyse forum posts from April 2019 to January 2020 on three adolescent‐based subreddits. Posts were extracted using the Baumgartner Reddit Corpus. Identifiable information was removed to protect anonymity.

Results

Inductive thematic analysis identified two overarching themes, namely, public stigma and self‐stigma associated with depression inauthenticity. Public stigma could be further dissected into five subthemes: (i) dichotomy between ‘real’ and ‘fake depression’; (ii) aggression towards ‘fakers’; (iii) stereotypes; (iv) attention; and (v) diagnosis. On the other hand, the theme of self‐stigma consisted of subthemes: (i) self‐doubt and (ii) validation and invalidation.

Conclusions

Adolescents framed a dichotomy between so‐called ‘real’ and ‘fake depression’, with hostility directed at peers perceived to be ‘fake depressed’. Perceptions of depression inauthenticity were confused and inconsistent. Public and self‐stigma towards depression inauthenticity enforced barriers to help‐seeking. While future research should investigate to what extent these observations based on online forums mimic stigma in real‐life settings, our findings have highlighted the needs for ‘fake depression’ stigma to be addressed by adolescent depression literacy and stigma interventions. Recent movements towards reconceptualizing depression as a dimensional construct may help to challenge these stigmatizing views of a dichotomy between ‘real’ and ‘fake’ depression.

Practitioner points

There is widespread stigma concerning perceived inauthenticity related to depression in these online adolescent communities, with vitriol targeted at peers perceived to be so‐called ‘fake depressed’.

Adolescent depression literacy and stigma programmes should tackle stigma towards perceived inauthenticity and promote the message that all adolescent distress deserves attention and help. This involves challenging perceptions that only supposedly ‘authentic’, diagnosed, or diagnosable, depression is worthy of attention and support.

Prevention Programmes should work to mitigate barriers to help‐seeking posed by misunderstandings that distress which is kept secret is more ‘authentic’, and tackle gender and age stereotypes surrounding perceived inauthenticity.

There is a need for clinically approved online resources targeted at adolescents who feel unsure about whether their symptoms could be indicators of depression, and to make professional advice and help more accessible for young people.
The role of dialecticism in objective and subjective attitudinal ambivalence
Authors: Luttrell Andrew , Petty Richard E. , Chang Jen‐Ho , Togans LaCount J.
Published: November 2021

Although attitudes are often considered positive or negative evaluations, people often have both positive and negative associations with a target object or issue, and when people are ambivalent, they are typically presumed to find the experience aversive because they are motivated to hold clear, univalent attitudes. Cross‐cultural research, however, has shown cultural variation in the propensity for dialectical thinking, which is characterized by a tolerance for contradiction. Two studies examined the role of dialectical thinking tendencies in the occurrence of attitudinal ambivalence and how much people subjectively experience their state of ambivalence. Study 1 measured individual differences in dialectical thinking within a culture, and Study 2 compared participants across two cultures (United States and Taiwan) that differ in dialecticism. Across studies, greater dialectical thinking was associated with holding both positive and negative evaluations of the same topic (objective ambivalence) and weaker correlations between objective ambivalence and subjective reports of being conflicted (subjective ambivalence).
The influence of tectonic activity on clathrate destabilisation: Microthermometry and Raman insights from seep carbonates in the Alps‐Apennines tectonic knot
Authors: Ceriani Andrea , Arboit Francesco , Di Giulio Andrea , Decarlis Alessandro , Steuber Thomas , Amadori Chiara , Al Suwaidi Aisha
Published: October 2021

The formation of carbonate build‐ups associated with seafloor methane vents – where microbially mediated sulphate‐dependent anaerobic oxidation of methane produces alkalinity – is well documented in modern marine environments and in the geologic record. However, the triggering event(s) behind the processes leading to hydrocarbon disequilibrium, seeping and consequent deposition of seep‐carbonates remain poorly constrained. This contribution characterises the salinity, geochemistry and temperature framework of a suit of fluid inclusions from hydrocarbon‐derived seep‐carbonate veins, collected from the Marmorito Formation in the Monferrato Hills, NW Italy. The datasets yield evidence of three different precipitation events, which comprise porous structures composed of well bladed calcites and aggregated spherules of aragonite. Fluid inclusions analysis shows the presence of a heterogeneous entrapment of immiscible fluids proving the paleo‐dissolution of a suite of complex hydrocarbons, which have a wide range of closing temperature starting at ca. 60°C. These physical and chemical conditions are considered to indicate seep‐carbonate deposition driven by disequilibrium of hydrocarbon‐bearing compounds at temperatures much warmer than the background ambient bottom waters (ca. 1 to 5°C) due to the influence of the Late Oligocene to Early Miocene tectonic compression at the junction of the southern Alps and Apennines.
Late Paleozoic supradetachment basin configuration in the southwestern Barents Sea—Intrabasement seismic facies of the Fingerdjupet Subbasin
Authors: Gresseth Julie L. S. , Braathen Alvar , Serck Christopher S. , Faleide Jan Inge , Osmundsen Per Terje
Published: October 2021

Late to post‐Caledonian, Devonian extension remains unresolved in the SW Barents Sea, despite considerable knowledge from onshore Norway, East Greenland and Svalbard. We analyse intrabasement seismic facies in high‐resolution 3D and reprocessed 2D data to investigate evidence for Caledonian deformation and post‐Caledonian detachment faulting in the central SW Barents Sea. These results are compared to published potential field models and analogue field studies from onshore Svalbard and Bjørnøya, substantiating that structures inherited from post‐orogenic extension influenced the Late Paleozoic and Mesozoic basin evolution. The Late Paleozoic Fingerdjupet Subbasin is underlain by a NNE‐striking, ESE‐dipping extensional detachment fault that records a minimum eastwards displacement of 22 km. The detachment fault and associated shear zone(s) separate post‐orogenic metamorphic core complexes from the syn‐tectonic deposits of a presumed Devonian supradetachment basin. Spatial variability in isostatically induced doming likely governed Devonian basin configurations. Pronounced footwall corrugations and faults splaying from the detachment indicate eastward extensional transport. This ultimately led to two interacting but subsequent, east‐stepping detachments. Local reactivation of the detachment systems controlled the extent of Carboniferous carbonate and evaporite basins in the Bjarmeland Platform area. Further, the Mesozoic Terningen Fault Complex and Randi Fault Set testify to how the inherited Devonian structural template continued to control spatial localisation and extent of rift structures during subsequent periods of extensional faulting in the Fingerdjupet Subbasin.
Efficacy and safety of standard of care with/without bevacizumab for platinum‐resistant ovarian/fallopian tube/peritoneal cancer previously treated with bevacizumab: The Japanese Gynecologic Oncology Group study JGOG3023
Authors: Shoji Tadahiro , Enomoto Takayuki , Abe Masakazu , Okamoto Aikou , Nagasawa Takayuki , Oishi Tetsuro , Nagase Satoru , Mori Masahiko , Inokuchi Yuki , Kamiura Shoji , Komiyama Shinichi , Takeshima Nobuhiro , Sugiyama Toru
Published: October 2021

We investigated the efficacy and safety of further bevacizumab therapy in patients with platinum‐resistant ovarian cancer whose disease had progressed after bevacizumab plus chemotherapy. In this multicenter, open‐label, phase II trial (JGOG3023), patients were randomized 1:1 to a single‐agent chemotherapy alone (either pegylated liposomal doxorubicin [40 or 50 mg/m2 administered intravenously], topotecan [1.25 mg/m2 intravenously], paclitaxel [80 mg/m2 intravenously], or gemcitabine [1000 mg/m2 intravenously]) or single‐agent chemotherapy + bevacizumab (15 mg/m2 intravenously). The primary endpoint was investigator‐assessed progression‐free survival (PFS) according to RECIST version 1.1. Secondary endpoints were overall survival (OS), objective response rate (ORR), and response rate according to Gynecological Cancer Intergroup cancer antigen 125 criteria. In total, 103 patients were allocated to chemotherapy (n = 51) or chemotherapy + bevacizumab (n = 52). Median investigator‐assessed PFS was 3.1 and 4.0 mo in each group, respectively (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.32‐0.90, P = .0082). Median OS was 11.3 and 15.3 mo in each group, respectively (HR = 0.67, 95% CI: 0.38‐1.17, P = .1556). Respective ORRs were 13.7% and 25.0% (P = .0599) and response rates were 16.7% and 21.4% (P = .8273). The incidence of grade ≥3 treatment‐related AEs was 42.0% in the chemotherapy group and 54.9% in the chemotherapy + bevacizumab group; AEs were well tolerated, with only 2 and 12 events leading to discontinuation of therapy, respectively. Bevacizumab was effective beyond progressive disease and AEs were manageable. The observed improvement in PFS requires further verification.
Alteration of the immune environment in bone marrow from children with recurrent B cell precursor acute lymphoblastic leukemia
Authors: Mikami Takashi , Kato Itaru , Wing James Badger , Ueno Hiroo , Tasaka Keiji , Tanaka Kuniaki , Kubota Hirohito , Saida Satoshi , Umeda Katsutsugu , Hiramatsu Hidefumi , Isobe Tomoya , Hiwatari Mitsuteru , Okada Ai , Chiba Kenichi , Shiraishi Yuichi , Tanaka Hiroko , Miyano Satoru , Arakawa Yuki , Oshima Koichi , Koh Katsuyoshi , Adachi Souichi , Iwaisako Keiko , Ogawa Seishi , Sakaguchi Shimon , Takita Junko
Published: October 2021

Due to the considerable success of cancer immunotherapy for leukemia, the tumor immune environment has become a focus of intense research; however, there are few reports on the dynamics of the tumor immune environment in leukemia. Here, we analyzed the tumor immune environment in pediatric B cell precursor acute lymphoblastic leukemia by analyzing serial bone marrow samples from nine patients with primary and recurrent disease by mass cytometry using 39 immunophenotype markers, and transcriptome analysis. High‐dimensional single‐cell mass cytometry analysis elucidated a dynamic shift of T cells from naïve to effector subsets, and clarified that, during relapse, the tumor immune environment comprised a T helper 1‐polarized immune profile, together with an increased number of effector regulatory T cells. These results were confirmed in a validation cohort using conventional flow cytometry. Furthermore, RNA transcriptome analysis identified the upregulation of immune‐related pathways in B cell precursor acute lymphoblastic leukemia cells during relapse, suggesting interaction with the surrounding environment. In conclusion, a tumor immune environment characterized by a T helper 1‐polarized immune profile, with an increased number of effector regulatory T cells, could contribute to the pathophysiology of recurrent B cell precursor acute lymphoblastic leukemia. This information could contribute to the development of effective immunotherapeutic approaches against B cell precursor acute lymphoblastic leukemia relapse.
Merkel cell polyomavirus–negative Merkel cell carcinoma is associated with JAK‐STAT and MEK‐ERK pathway activation
Authors: Iwasaki Takeshi , Hayashi Kazuhiko , Matsushita Michiko , Nonaka Daisuke , Kohashi Kenichi , Kuwamoto Satoshi , Umekita Yoshihisa , Oda Yoshinao
Published: November 2021

Merkel cell polyomavirus (MCPyV) is monoclonally integrated into the genomes of approximately 80% of Merkel cell carcinomas (MCCs). While the presence of MCPyV affects the clinicopathological features of MCC, the molecular mechanisms of MCC pathogenesis after MCPyV infection are unclear. This study investigates the association between MCPyV infection and activation of the MEK‐ERK and JAK‐STAT signaling pathways in MCC to identify new molecular targets for MCC treatment. The clinicopathological characteristics of 30 MCPyV‐positive and 20 MCPyV‐negative MCC cases were analyzed. The phosphorylation status of MEK, ERK, JAK, and STAT was determined by immunohistochemical analysis. The activation status of the MEK‐ERK and JAK‐STAT pathways and the effects of a JAK inhibitor (ruxolitinib) was analyzed in MCC cell lines. Immunohistochemically, the expression of pJAK2 (P = .038) and pERK1/2 (P = .019) was significantly higher in MCPyV‐negative than in MCPyV‐positive MCCs. Male gender (hazard ratio [HR] 2.882, P = .039), older age (HR 1.137, P < .001), negative MCPyV status (HR 0.324, P = .013), and advanced cancer stage (HR 2.672, P = .041) were identified as unfavorable prognostic factors; however, the phosphorylation states of JAK2, STAT3, MEK1/2, and ERK1/2 were unrelated to the prognosis. The inhibition of cell proliferation by ruxolitinib was greater in MCPyV‐negative MCC cell lines than in an MCPyV‐positive MCC cell line. The expression of pERK1/2 and pMEK was higher in MCPyV‐negative than in MCPyV‐positive cell lines. These results suggest that activation of the JAK2 and MEK‐ERK pathways was more prevalent in MCPyV‐negative than in MCPyV‐positive MCC and the JAK inhibitor ruxolitinib inhibited MEK‐ERK pathway activation. Consequently, the JAK‐STAT and MEK‐ERK signaling pathways may be potential targets for MCPyV‐negative MCC treatment.
Technical aspects of the use of cytopathological specimens for diagnosis and predictive testing in malignant epithelial neoplasms of the lung
Authors: Maddox Anthony , Smart Louise M.
Published: October 2021

Lung cancer is a leading cause of cancer mortality worldwide but recent years have seen a rapidly rising proportion of cases of advanced non‐small cell carcinoma amenable to increasingly targeted therapy, initially based on the differential response to systemic treatment of tumours of squamous or glandular differentiation. In two‐thirds of the cases, where patients present with advanced disease, both primary pathological diagnosis and biomarker testing is based on small biopsies and cytopathological specimens. The framework of this article is an overview of the technical aspect of each stage of the specimen pathway with emphasis on maximising potential for success when using small cytology samples. It brings together the current literature addressing pre‐analytical and analytical aspects of specimen acquisition, performing rapid onsite evaluation, and undertaking diagnostic and predictive testing using immunocytochemistry and molecular platforms. The advantages and drawbacks of performing analysis on cell block and non‐cell block specimen preparations is discussed.
Emerging texture and color enhancement imaging in early gastric cancer
Authors: Abe Seiichiro , Makiguchi Mai Ego , Nonaka Satoru , Suzuki Haruhisa , Yoshinaga Shigetaka , Saito Yutaka
Published: October 2021

Screening endoscopy improves detection and prognosis of patients with gastric cancer. However, even expert endoscopists can miss early gastric cancer under standard white light imaging. Texture and color enhancement imaging (TXI) is an image‐enhanced endoscopy that enhances brightness, surface irregularities such elevation or depression, and subtle color changes. A few image‐oriented studies have compared the gastric color differences between neoplastic and peripheral areas under both white light imaging and TXI. The results not only suggested that the overall color differences to be more pronounced in TXI, but also that TXI mode 1 was superior to white light imaging in the visibility of early gastric cancer. Despite the promising results in these initial studies, it is unclear whether the superiority of the image‐enhanced endoscopy will translate into an improvement in early gastric cancer detection in real practice. Therefore, large‐scale prospective studies are necessary to investigate the efficacy of this new technology in the evaluation of patients undergoing screening endoscopy.
The many faces of the E3 ubiquitin ligase, RNF220, in neural development and beyond
Authors: Ma Pengcheng , Mao Bingyu
Published: October 2021

Ubiquitin modification plays important roles in many cellular processes that are fundamental for vertebrate embryo development, such as cell division, differentiation, and migration. Aberrant function or deregulation of ubiquitination enzymes can cause developmental disorders, cancer progression, and neurodegenerative diseases in humans. RING finger protein 220 (RNF220) is an evolutionarily conserved RING‐type ubiquitin E3 ligase. Recent studies have revealed the roles and mechanisms of RNF220 and its partner protein, zinc finger C4H2‐type containing protein (ZC4H2), in embryonic development and human diseases. Using mouse and zebrafish models, it has been shown that RNF220 regulates sonic hedgehog (Shh) signaling via Gli and embryonic ectoderm development (EED), a polycomb repressive complex 2 (PRC2) component, during ventral neural patterning and cerebellum development. In addition, RNF220 also regulates the development and functions of central noradrenergic and motor neurons in mice. By stabilizing β‐catenin and signal transducer and activator of transcription 1 (STAT1), RNF220 is also involved in Wnt and interferon (IFN)–STAT1 signaling and thus the regulation of tumorigenesis and immune response, respectively. In humans, both RNF220 and ZC4H2 mutations have been reported to be associated with diseases accompanied by complicated neural defects. In this review, we summarize the current knowledge of RNF220 with special emphasis on its roles and mechanisms of action in signal transduction, vertebrate neural development, and related human disorders.
Dung beetles can sow: the potential of secondary seed dispersers to assist ecological restoration
Authors: Almeida Hernani A. , Antonini Yasmine , Tavares Junior Cláudio , Braga Rodrigo F. , da Silva Pedro G. , Beiroz Wallace
Published: October 2021

1. Restoration of disturbed environments in which soil surface layers have been removed is challenging and its success depends on the characteristics of the exposed soil layers and neighbour organisms. Dung beetles are important elements in the restoration of degraded habitats as secondary seed dispersers.

2. In this study, we first assessed how the removal of upper soil layers affected the assemblage of dung beetle compared to adjacent reference areas without soil removal. We also evaluated the efficiency of dung beetles as secondary seed dispersers by experimentally testing their effect on the germination of wolf apple seeds (Solanum lycocarpum).

3. Degraded areas harboured a different dung beetle assemblage compared to the reference area, with a predominance of habitat generalist species. In addition, we found higher abundance and richness of dung beetles in the degraded than in reference areas. Despite dung removal being similar between areas, more seeds were removed in the reference area.

4. Dung beetles, especially rollers, positively influenced the probability of wolf apple seed germination in the degraded environment by up to 5%; germination occurred in 27% of treatments with dung beetle presence and no germination occurred when beetles were excluded.

5. Therefore, promoting the attraction of dung beetles from reference areas, together with other techniques that enhance primary seed dispersion, mainly by mammals and birds, could potentially increase the success of projects to restore areas with degraded soil.
The impact of persistent social anxiety on social functioning and health‐related quality of life in young people with remitted first‐episode psychosis
Authors: González‐Blanch César , Gleeson John F. , McEnery Carla , O'Sullivan Shaunagh , Ayesa‐Arriola Rosa , D'Alfonso Simon , Valentine Lee , Tremain Hailey , Bell Imogen , Bendall Sarah , Alvarez‐Jimenez Mario
Published: October 2021

Objective

Comorbid social anxiety is common in psychotic disorders and is associated with multiple negative consequences. However, the long‐term effects of persistent social anxiety versus fluctuating or no anxiety on social functioning and health‐related quality of life (HR‐QoL) have received scant attention. Therefore, we aimed to examine the prevalence of persistent social anxiety to determine its effect on social functioning and HR‐QoL in first‐episode psychosis (FEP).

Methods

One hundred and eight individuals with remitted FEP were classified into three groups (persistent, fluctuating or no social anxiety) according to the Social Interaction Anxiety Scale over an 18‐month follow‐up period. The three groups were then compared at 18 months follow‐up to assess the influence of social anxiety on social functioning and HR‐QoL before and after controlling for confounders.

Results

Of the 108 individuals with FEP, 25 (23.1%) had persistent social anxiety. This group presented lower social functioning and HR‐QoL levels compared to the groups with fluctuating or no anxiety symptoms. The effect on HR‐QoL remained significant after controlling for positive psychotic and depressive symptoms.

Conclusions

In this study, nearly one‐quarter of young people with remitted FEP experienced persistent social anxiety symptoms, which had a negative impact on HR‐QoL. Thus, individuals with persistent social anxiety constitute a highly vulnerable group and may require targeted interventions to improve their social functioning and HR‐QoL.