bluuebunny/crossref_metadata_2025 huggingface dataset:
Single‐cell profiles reveal distinctive immune response in atopic dermatitis in contrast to psoriasis
Authors: Zhang Bowen , Roesner Lennart M. , Traidl Stephan , Koeken Valerie A. C. M. , Xu Cheng‐Jian , Werfel Thomas , Li Yang
Published: August 2022

Background

Understanding the complex orchestrated inflammation in atopic dermatitis (AD), one of the most common chronic inflammatory diseases worldwide, is essential for therapeutic approaches. However, a comparative analysis on the single‐cell level of the inflammation signatures correlated with the severity is missing so far.

Methods

We applied single‐cell RNA and T‐cell receptor (TCR) sequencing on immune cells enriched from skin biopsies and matched blood samples of AD in comparison with psoriasis (PS) patients.

Results

Clonally propagated skin‐derived T cells showed disease‐specific TCR motifs shared between patients which was more pronounced in PS compared to AD. The disease‐specific T‐cell clusters were mostly of a Th2/Th22 sub‐population in AD and Th17/Tc17 in PS, and their numbers were associated with severity scores in both diseases. Herein, we provide for the first time a list that associates cell type‐specific gene expression with the severity of the two most common chronic inflammatory skin diseases. Investigating the cell signatures in the patients´ PBMCs and skin stromal cells, a systemic involvement of type‐3 inflammation was clearly detectable in PS circulating cells, while in AD inflammatory signatures were most pronounced in fibroblasts, pericytes, and keratinocytes. Compositional and functional analyses of myeloid cells revealed the activation of antiviral responses in macrophages in association with disease severity in both diseases.

Conclusion

Different disease‐driving cell types and subtypes which contribute to the hallmarks of type‐2 and type‐3 inflammatory signatures and are associated with disease activities could be identified by single‐cell RNA‐seq and TCR‐seq in AD and PS.
IL1RAP expression and the enrichment of IL‐33 activation signatures in severe neutrophilic asthma
Authors: Badi Yusef Eamon , Salcman Barbora , Taylor Adam , Rana Batika , Kermani Nazanin Zounemat , Riley John H. , Worsley Sally , Mumby Sharon , Dahlen Sven‐Eric , Cousins David , Bulfone‐Paus Silvia , Affleck Karen , Chung Kian Fan , Bates Stewart , Adcock Ian M.
Published: August 2022

Background

Interleukin (IL)‐33 is an upstream regulator of type 2 (T2) eosinophilic inflammation and has been proposed as a key driver of some asthma phenotypes.

Objective

To derive gene signatures from in vitro studies of IL‐33‐stimulated cells and use these to determine IL‐33‐associated enrichment patterns in asthma.

Methods

Signatures downstream of IL‐33 stimulation were derived from our in vitro study of human mast cells and from public datasets of in vitro stimulated human basophils, type 2 innate lymphoid cells (ILC2), regulatory T cells (Treg) and endothelial cells. Gene Set Variation Analysis (GSVA) was used to probe U‐BIOPRED and ADEPT sputum transcriptomics to determine enrichment scores (ES) for each signature according to asthma severity, sputum granulocyte status and previously defined molecular phenotypes.

Results

IL‐33‐activated gene signatures were cell‐specific with little gene overlap. Individual signatures, however, were associated with similar signalling pathways (TNF, NF‐κB, IL‐17 and JAK/STAT signalling) and immune cell differentiation pathways (Th17, Th1 and Th2 differentiation). ES for IL‐33‐activated gene signatures were significantly enriched in asthmatic sputum, particularly in patients with neutrophilic and mixed granulocytic phenotypes. IL‐33 mRNA expression was not elevated in asthma whereas the expression of mRNA for IL1RL1, the IL‐33 receptor, was up‐regulated in the sputum of severe eosinophilic asthma. The mRNA expression for IL1RAP, the IL1RL1 co‐receptor, was greatest in severe neutrophilic and mixed granulocytic asthma.

Conclusions

IL‐33‐activated gene signatures are elevated in neutrophilic and mixed granulocytic asthma corresponding with IL1RAP co‐receptor expression. This suggests incorporating T2‐low asthma in anti‐IL‐33 trials.
The reciprocal interplay of physical activity and health‐related quality of life in children and adolescents: Evidence for both upward and downward spirals
Authors: Groß Daniel , Schröder Ines , Wasserfall Nicola , Eschenbeck Heike , Kohlmann Carl‐Walter
Published: August 2022

Objective

This study examines the bidirectional effect between physical activity (PA) and health‐related quality of life in children and adolescents, focusing on within‐person effects.

Methods

PA and health‐related quality of life were assessed in children and adolescents (N = 685, age: M = 10.29 years, SD = 1.35, range = 8–14), via self‐report across four waves, each 6 months apart, and a random‐intercept cross‐lagged panel model with time‐invariant cross‐lagged effects was calculated.

Results

Positive cross‐lagged effects between prior PA and health‐related quality of life 6 months later (
 = 0.536, 95% CI [0.016, 1.055], p = .043, d = 0.11) and vice versa (
 = 0.015, 95% CI [0.001, 0.030], p = .039, d = 0.12) were found. Furthermore, the random intercept correlation was significant (
 = 3.622, 95% CI [2.204, 5.041], p < .001, d = 0.27).

Conclusions

The findings confirm known correlations between PA and health‐related quality of life and extends them by indicating both an upward and downward spiral of PA and health‐related quality of life in children and adolescents.
Preoperative indocyanine green fluorescence injection to accurately determine a proximal margin during robotic distal gastrectomy
Authors: Nakanishi Koki , Tanaka Chie , Kanda Mitsuro , Shimizu Dai , Furukawa Kazuhiro , Fujiwara Michitaka , Kawashima Hiroki , Kodera Yasuhiro
Published: August 2022

Introduction

Adequate surgical margins following gastrectomy for gastric cancer are required. In addition, a method for accurately detecting tumor location without palpation is needed during robotic surgery. Although several methods have been reported, most of these either lack accuracy or require increased time and effort during intraoperative detection. Herein, we introduce a new method for detecting tumor location using preoperative indocyanine green (ICG) marking and the built‐in ICG detection system of the da Vinci Xi Surgical System in robotic gastrectomy to determine appropriate surgical margins.

Materials and Surgical Technique

We used this method to determine the resection line in six patients who underwent robotic distal gastrectomy for clinical T1 gastric cancer. One to three days before surgery, ICG was diluted to 1.0 mg/mL, and 0.1 mL of this diluted ICG solution was endoscopically injected at one site into the submucosal layer of the stomach, 1 cm proximal to the tumor edge. Gastrectomy was performed using the da Vinci Xi surgical platform, equipped with a near‐infrared fluorescence imaging system (Firefly®). The diameter of the fluorescent signal during gastrectomy was estimated to be approximately 2 cm. The resection line was determined on the outer edge of the fluorescent signal, which ensured a tumor‐free margin of ≥2 cm. Fluorescent signals were successfully observed in all cases. Moreover, the required 2‐cm surgical margin was achieved in all cases.

Discussion

We could successfully determine proximal margins using preoperative ICG injection marking during robotic distal gastrectomy for gastric cancer.
Association of income and educational levels on initiation of oral anticoagulant therapy in patients with incident atrial fibrillation: A Finnish nationwide cohort study
Authors: Teppo Konsta , Jaakkola Jussi , Biancari Fausto , Halminen Olli , Linna Miika , Haukka Jari , Putaala Jukka , Mustonen Pirjo , Kinnunen Janne , Hartikainen Juha , Airaksinen K. E. Juhani , Lehto Mika
Published: August 2022

Aims

Socioeconomic disparities have been reported in the outcomes of patients with atrial fibrillation (AF). We assessed the hypothesis that AF patients with higher income or educational level are more frequently initiated with oral anticoagulant (OAC) therapy for stroke prevention.

Methods

The nationwide registry‐based Finnish AntiCoagulation in Atrial Fibrillation cohort covers all patients with AF from all levels of care in Finland. Patients were divided into income quartiles according to their highest annual income during 2004‐2018 and into three categories based on educational attainment. The outcome was the first redeemed OAC prescription.

Results

We identified 239 222 patients (mean age 72.7 ± 13.2 years, 49.8% female) with incident AF during 2007‐2018. Higher income was associated with higher OAC initiation rate: compared to the lowest income quartile the adjusted SHRs (95% CI) for OAC initiation were 1.09 (1.07‐1.10), 1.13 (1.11‐1.14) and 1.13 (1.12‐1.15) in the second, third and fourth income quartiles, respectively. Patients in the highest educational category had a slightly lower OAC initiation rate than patients in the lowest educational category (adjusted SHR 0.92 [95% CI 0.90‐0.93]). Income‐related disparities were larger and education‐related disparities only marginal among patients at high risk of ischemic stroke. The socioeconomic disparities in OAC initiation within 1‐year follow‐up decreased from 2007 to 2018. The adoption of direct OACs as the initial anticoagulant was faster among patients with higher income or educational levels.

Conclusion

These findings highlight potential missed opportunities in stroke prevention, especially among AF patients with low income, whereas the education‐related disparities in OAC initiation appear controversial.
Is routine laboratory testing in healthy young patients taking isotretinoin necessary: a critically appraised topic
Authors: Affleck Andrew , Jackson David , Williams Hywel C. , Chavez Patricia , Albrecht Joerg
Published: August 2022

Clinical question

Is monitoring of liver function, lipids and full blood count necessary in healthy people taking isotretinoin?

Background

Routine blood testing was recommended in the original licence for Roaccutane™ (isotretinoin) in 1983. In recent years, less frequent monitoring has been suggested by various authors.

Data sources

We performed four individual systematic searches of the MEDLINE database, via PubMed, from origin to 2 May 2021, supplemented by a hand search of all references in the identified papers.

Study selection

Inclusion criteria were any description of clinical symptoms, laboratory abnormalities and/or physical findings, and any paper that explicitly described the patients as asymptomatic, during treatment with oral isotretinoin.

Data extraction

Two independent reviewers (J.A. and D.J.) assessed articles for eligibility of inclusion. Evaluation of the data was done also by two of the authors (A.A., D.J. and J.A.) for each section, with the aim to use the presented evidence including guidelines, databases, case series, case reports, cohort studies and randomized clinical trials to delineate the clinical presentation and frequency of adverse events that might be amenable to laboratory monitoring.

Results

We identified 407 papers in our searches and reviewed 125 papers in four sections. Overall, reported adverse events were very rare (< 1 in 10 000) and were either idiosyncratic or not preventable by monitoring, accompanied by symptoms, or seen in identifiable predisposed individuals who might benefit from monitoring because of pre-existing conditions.

Recommendation for clinical care

We could not find evidence to support the benefit of monitoring to detect adverse events. We suggest that in healthy young people laboratory monitoring for oral isotretinoin is unnecessary and risks detecting nonserious biochemical abnormalities. However, we recognize that new information about adverse events may change that recommendation.
Management of small testicular masses: outcomes from a single‐centre specialist multidisciplinary team
Authors: Wardak Shafi , Pang Karl H. , Castiglione Fabio , Lindsay Jamie , Walkden Miles , Ho Dan Heffernan , Kirkham Alex , Hadway Paul , Nigam Raj , Rees Rowland , Alifrangis Constantine , Alnajjar Hussain M. , Muneer Asif
Published: August 2022

Objectives

To report the management outcomes of men with ≤20‐mm small testicular masses (STMs) and to identify clinical and histopathological factors associated with malignancy.

Patients and methods

A retrospective analysis of men managed at a single centre between January 2010 and December 2020 with a STM ≤20 mm in size was performed.

Results

Overall, 307 men with a median (interquartile range [IQR]) age of 36 (30–44) years were included. Of these, 161 (52.4%), 82 (26.7%), 62 (20.2%) and 2 men (0.7%) underwent surveillance with interval ultrasonography (USS), primary excisional testicular biopsy (TBx) or primary radical orchidectomy (RO), or were discharged, respectively. The median (IQR) surveillance duration was 6 (3–18) months. The majority of men who underwent surveillance had lesions <5 mm (59.0%) and no lesion vascularity (67.1%) on USS. Thirty‐three (20.5%) men undergoing surveillance had a TBx based on changes on interval USS or patient choice; seven (21.2%) were found to be malignant. The overall rate of malignancy in the surveillance cohort was 4.3%. The majority of men who underwent primary RO had lesions ≥10 mm (85.5%) and the presence of vascularity (61.7%) on USS. Nineteen men (23.2%) who underwent primary TBx (median lesion size 6 mm) had a malignancy confirmed on biopsy and underwent RO. A total of 88 men (28.7%) underwent RO, and malignancy was confirmed in 73 (83.0%) of them. The overall malignancy rate in the whole STM cohort was 23.8%. Malignant RO specimens had significantly larger lesion sizes (median [IQR] 11 [8–15] mm, vs benign: median [IQR] 8 [5–10] mm; P = 0.04).

Conclusions

Small testicular masses can be stratified and managed based on lesion size and USS features. The overall malignancy rate in men with an STM was 23.8% (4.3% in the surveillance group). Surveillance should be considered in lesions <10 mm in size, with a TBx or frozen‐section examination offered prior to RO in order to preserve testicular function.
Contributions of climate, vegetation and soil to the alpine sediment carbon accumulation rate in central China since the Middle Holocene
Authors: Cheng Ying , Liu Hongyan , Wang Hongya , Hao Qian , Duan Keqin , Dong Zhibao
Published: August 2022

Large amounts of carbon in alpine sediments have been expected to be sensitive to climate change, but how carbon accumulation responds to climate change remains unclear. Thus, we explored the impact of different factors on the carbon accumulation rate (CAR) of alpine sediments by combining a variety of climatic variables, vegetation data and erosion indicators based on two alpine sediment successions on Taibai Mountain, the highest peak in central and eastern mainland China. One succession is near the modern treeline (Paomaliang Swamp, PML) and the other is located at the upper forest line (Sanqing Chi, SQC, a small lake). We used our previously published organic carbon content data and for the first time calculated the CAR, and further used pollen and physicochemical indicators to quantify the contributions from climate, vegetation and soil. We found that their contributions varied during different periods and between the two sediment successions. For the PML succession, from 5850 to 4000 calendar years before present (cal. a BP), the CAR was low, which was related to low annual temperatures, low vegetation cover and strong soil erosion. From 4000 to 2400 cal. a BP, a high CAR coincided with high annual temperatures, high vegetation cover and weak soil erosion. From 2400 to 200 cal. a BP, the CAR decreased, mainly attributed to low vegetation cover. Local vegetation cover had major impacts on the CAR in the SQC succession during the Middle–Late Holocene. In general, the local factor interpretation rate in SQC (83%) was higher than that of PML (47%), related to the vegetation stability of continuous forest and the treeline. This study highlights the important role of the local environment in determining carbon accumulation in the alpine region.
A novel chemokine‐based signature for prediction of prognosis and therapeutic response in glioma
Authors: Fan Wenhua , Wang Di , Li Guanzhang , Xu Jianbao , Ren Changyuan , Sun Zhiyan , Wang Zhiliang , Ma Wenping , Zhao Zheng , Bao Zhaoshi , Jiang Tao , Zhang Ying
Published: August 2022

Aims

Gliomas are the primary malignant brain tumor and characterized as the striking cellular heterogeneity and intricate tumor microenvironment (TME), where chemokines regulate immune cell trafficking by shaping local networks. This study aimed to construct a chemokine‐based gene signature to evaluate the prognosis and therapeutic response in glioma.

Methods

In this study, 1024 patients (699 from TCGA and 325 from CGGA database) with clinicopathological information and mRNA sequencing data were enrolled. A chemokine gene signature was constructed by combining LASSO and SVM‐RFE algorithm. GO, KEGG, and GSVA analyses were performed for function annotations of the chemokine signature. Candidate mRNAs were subsequently verified through qRT‐PCR in an independent cohort including 28 glioma samples. Then, through immunohistochemical staining (IHC), we detected the expression of immunosuppressive markers and explore the role of this gene signature in immunotherapy for glioma. Lastly, the Genomics of Drug Sensitivity in Cancer (GDSC) were leveraged to predict the potential drug related to the gene signature in glioma.

Results

A constructed chemokine gene signature was significantly associated with poorer survival, especially in glioblastoma, IDH wildtype. It also played an independent prognostic factor in both datasets. Moreover, biological function annotations of the predictive signature indicated the gene signature was positively associated with immune‐relevant pathways, and the immunosuppressive protein expressions (PD‐L1, IBA1, TMEM119, CD68, CSF1R, and TGFB1) were enriched in the high‐risk group. In an immunotherapy of glioblastoma cohort, we confirmed the chemokine signature showed a good predictor for patients' response. Lastly, we predicted twelve potential agents for glioma patients with higher riskscore.

Conclusion

In all, our results highlighted a potential 4‐chemokine signature for predicting prognosis in glioma and reflected the intricate immune landscape in glioma. It also threw light on integrating tailored risk stratification with precision therapy for glioblastoma.
Navigating a shifting agri‐environment policy landscape to conserve butterflies
Authors: Stewart Linnea B. , Bonsall Michael B. , Cusworth George , Corrigan Christopher , Dicks Lynn V. , Hall Jilly , Plackett Jenny , Spray Martin , Strevens Chloë
Published: August 2022

For decades, agri‐environment schemes (AES) within the United Kingdom have served as a policy tool for conserving butterflies. However, the UK's 2016 decision to leave the European Union (EU) means the overarching framework for AES, the EU Common Agriculture Policy (CAP), is being replaced by a new independent agri‐environment policy, the Environmental Land Management (ELM) scheme. Here, we examine the shift from CAP towards ELM and explore its implications for butterfly conservation across England, as a devolved administration, within the United Kingdom. We identify the key changes between the current Countryside Stewardship scheme and the incoming ELM scheme and present recommendations for policymakers to ensure policy design and delivery can benefit efforts to conserve butterflies, and indeed wildlife more generally, in England. This is an opportune moment to contribute to discussions on the emerging agri‐environment scheme policy within the United Kingdom as the ELM scheme is trialed, revised, and implemented.
Pharmacokinetics, pharmacodynamics, and exposure–efficacy of dupilumab in adults with atopic dermatitis
Authors: Kamal Mohamed A. , Davis John D. , Kovalenko Pavel , Srinivasan Kamal , Simpson Eric L. , Nakahara Takeshi , Sugaya Makoto , Igarashi Atsuyuki , Ardeleanu Marius , Xu Christine , Arima Kazuhiko
Published: August 2022

The pharmacokinetics (PKs) and exposure–efficacy of dupilumab have not been fully described for adults with atopic dermatitis (AD). Our objectives were to analyze the PKs and exposure–efficacy of dupilumab in adults with AD and compare the results of Japanese and overall populations. Adults with moderate‐to‐severe AD were randomly assigned to dupilumab (300 mg weekly [qw] or every 2 weeks [q2w], 200 mg q2w, 300 mg every 4 weeks [q4w], or 100 mg q4w) or placebo for 16 weeks in a randomized, double‐blind, placebo‐controlled, dose‐ranging phase IIb trial (NCT01859988). This analysis included 379 patients (58 Japanese). Functional dupilumab concentrations increased in a dose‐dependent manner; at lower concentrations, increases were greater than dose‐proportional because of nonlinear, target‐mediated clearance. Dupilumab pharmacokinetics were comparable in Japanese and non‐Japanese patients with similar body weights. Week 16 efficacy parameters, including Investigator’s Global Assessment score 0/1, greater than or equal to 75% reduction from baseline in the Eczema Area and Severity Index (EASI), and percentage change from baseline in EASI and pruritus Numerical Rating Scale, generally increased with week 16 trough concentration; the plateau of these exposure–efficacy relationships occurred for most patients at exposures associated with the 300 mg q2w and 300 mg qw regimens. Japanese ethnicity did not remain in the population PK model as covariate with or without accounting for body weight differences. In Japanese and non‐Japanese patients, efficacy responses increased with week 16 dupilumab trough concentrations in a similar manner. Dupilumab 300 mg qw and q2w regimens were recommended for further evaluation in larger phase III studies.
Global mortality of diabetic foot ulcer: A systematic review and meta‐analysis of observational studies
Authors: Chen Lihong , Sun Shiyi , Gao Yunyi , Ran Xingwu
Published: August 2022

Aim

To estimate the long‐term mortality and risk factors in patients with diabetic foot ulcer (DFU).

Methods

We systematically searched Medline (PubMed), Embase, Scopus, Web of Science, Cochrane Library, China Science and Technology Journal Database (CQVIP), China National Knowledge Infrastructure, the Chinese Biomedical Literature Database (SinoMed) and Wanfang Data from 1 January 2011 to 31 July 2022. All observational studies that reported long‐term mortality of patients with DFU were included. Random effect models were used to pool the reconstructed participant data from Kaplan–Meier curves. The primary outcome was the long‐term survival of patients with DFU. An aggregate data meta‐analysis was also performed.

Results

We identified 34 studies, with 124 376 participants representing 16 countries, among whom there were 51 386 deaths. Of these, 27 studies with 21 171 patients were included in the Kaplan–Meier‐based meta‐analysis. The estimated Kaplan–Meier‐based survival rates were 86.9% (95% confidence interval [CI] 82.6%‐91.5%) at 1 year, 66.9% (95% CI 59.3%‐75.6%) at 3 years, 50.9% (95% CI 42.0%‐61.7%) at 5 years and 23.1% (95% CI 15.2%‐34.9%) at 10 years. The results of the aggregate data‐based meta‐analysis were similar. Cardiovascular disease and infection were the most common causes of death, accounting for 46.6% (95% CI 33.5%‐59.7%) and 24.8% (95% CI 16.0%‐33.5%), respectively. Patients with older age (per 1 year, hazard ratio [HR] 1.054, 95% CI 1.045‐1.063), peripheral artery disease (HR 1.882, 95% CI 1.592‐2.225), chronic kidney disease (HR 1.535, 95% CI 1.227‐1.919), end‐stage renal disease (HR 3.586, 95% CI 1.333‐9.643), amputation (HR 2.415, 95% CI 1.323‐4.408) and history of cardiovascular disease (HR 1.449, 95% CI 1.276‐1.645) had higher mortality risk.

Conclusions

This meta‐analysis found that the overall mortality of DFU was high, with nearly 50% mortality within 5 years. Cardiovascular disease and infection were the two leading causes of death.
Associations of microvascular complications with all‐cause death in patients with diabetes andCOVID‐19: TheCORONADO,ABCDCOVID‐19 UK national audit andAMERICADOstudy groups
Authors: Hadjadj Samy , Saulnier Pierre‐Jean , Ruan Yue , Zhu Xu , Pekmezaris Renee , Marre Michel , Halimi Jean Michel , Wargny Matthieu , Rea Rustam , Gourdy Pierre , Cariou Bertrand , Myers Alyson K. , Khunti Kamlesh ,   for the CORONADO, the ABCD COVID‐19 diabetes national audit and AMERICADO investigators
Published: August 2022

Aim

To provide a detailled analysis of the microvascular burden in patients with diabetes hopitalized for COVD‐19.

Materials and Methods

We analysed data from the French CORONADO initiative and the UK Association of British Clinical Diabetologists (ABCD) COVID‐19 audit, two nationwide multicentre studies, and the AMERICADO, a multicentre study conducted in New York area. We assessed the association between risk of all‐cause death during hospital stay and the following microvascular complications in patients with diabetes hospitalized for COVID‐19: diabetic retinopathy and/or diabetic kidney disease and/or history of diabetic foot ulcer.

Results

Among 2951 CORONADO, 3387 ABCD COVID‐19 audit and 9327 AMERICADO participants, microvascular diabetic complications status was ascertained for 1314 (44.5%), 1809 (53.4%) and 7367 (79.0%) patients, respectively: 1010, 1059 and 1800, respectively, had ≥1 severe microvascular complication(s) and 304, 750 and 5567, respectively, were free of any complications. The patients with isolated diabetic kidney disease had an increased risk of all‐cause death during hospital stay: odds ratio [OR] 2.53 (95% confidence interval [CI] 1.66‐3.83), OR 1.24 (95% CI 1.00‐1.56) and OR 1.66 (95% CI 1.40‐1.95) in the CORONADO, the ABCD COVID‐19 national audit and the AMERICADO studies, respectively. After adjustment for age, sex, hypertension and cardiovascular disease (CVD), compared to those without microvascular complications, patients with microvascular complications had an increased risk of all‐cause death during hospital stay in the CORONADO, the ABCD COVID‐19 diabetes national audit and the AMERICADO studies: adjusted OR (adjOR) 2.57 (95% CI 1.69‐3.92),adjOR 1.22 (95% CI 1.00‐1.52) andadjOR 1.33 (95% CI 1.15‐1.53), respectively. In meta‐analysis of the three studies, compared to patients free of complications, those with microvascular complications had an unadjusted OR for all‐cause death during hospital stay of 2.05 (95% CI 1.42‐2.97), which decreased to 1.62 (95% CI 1.19‐2.119) after adjustment for age and sex, and to 1.50 (1.12‐2.02) after hypertension and CVD were further added to the model.

Conclusion

Microvascular burden is associated with an increased risk of death in patients hospitalized for COVID‐19.
Clinical implications of vascular dysfunction in acute and convalescent COVID‐19: A systematic review
Authors: Mavraganis Georgios , Dimopoulou Maria‐Angeliki , Delialis Dimitrios , Bampatsias Dimitrios , Patras Raphael , Sianis Alexandros , Maneta Eleni , Stamatelopoulos Kimon , Georgiopoulos Georgios
Published: August 2022

Background

Accumulating evidence suggests that endothelial dysfunction is implicated in the pathogenesis and severity of coronavirus disease 2019 (COVID‐19). In this context, vascular impairment in COVID‐19 might be associated with clinical manifestations and could refine risk stratification in these patients.

Methods

This systematic review aims to synthesize current evidence on the frequency and the prognostic value of vascular dysfunction during acute and post‐recovery COVID‐19. After systematically searching the MEDLINE, clinicaltrials.gov and the Cochrane Library from 1 December 2019 until 05 March 2022, we identified 24 eligible studies with laboratory confirmed COVID‐19 and a thorough examination of vascular function. Flow‐mediated dilation (FMD) was assessed in 5 and 12 studies in acute and post‐recovery phase respectively; pulse wave velocity (PWV) was the marker of interest in three studies in the acute and four studies in the post‐recovery phase.

Results

All studies except for one in the acute and in the post‐recovery phase showed positive association between vascular dysfunction and COVID‐19 infection. Endothelial dysfunction in two studies and increased arterial stiffness in three studies were related to inferior survival in COVID‐19.

Discussion

Overall, a detrimental effect of COVID‐19 on markers of endothelial function and arterial stiffness that could persist even for months after the resolution of the infection and provide prognostic value was congruent across published studies. Further research is warranted to elucidate clinical implications of this association.
Ambulatory central BP and arterial stiffness in patients with and without intradialytic hypertension
Authors: Theodorakopoulou Marieta P. , Karagiannidis Artemios G. , Alexandrou Maria‐Eleni , Iatridi Fotini , Christodoulou Michalis , Dimitroulas Theodoros , Papagianni Aikaterini , Sarafidis Pantelis A.
Published: August 2022

Background

Increased arterial stiffness is suggested to be involved in the pathogenesis of intradialytic‐hypertension (IDH). Ambulatory pulse‐wave‐velocity (PWV) is an independent predictor for all‐cause‐mortality in haemodialysis and its prognostic power is better than office PWV. This is the first study examining ambulatory central blood pressure (BP) and arterial stiffness parameters in patients with and without IDH.

Methods

This study examined 45 patients with IDH (SBP rise ≥10 mmHg from pre‐ to post‐dialysis and post‐dialysis SBP ≥150 mmHg) in comparison with 197 patients without IDH. All participants underwent 48‐h ABPM with Mobil‐O‐Graph‐NG; parameters of central haemodynamics, wave reflection and PWV were estimated.

Results

Age, dialysis vintage and interdialytic weight gain did not differ between‐groups. IDH patients had higher 48‐h cSBP (131.7 ± 16.2 vs. 119.2 ± 15.2 mmHg, p < 0.001), 48‐h cDBP (86.7 ± 12.7 vs. 79.6 ± 11.5 mmHg, p < 0.001) and 48‐h cPP (45.5 ± 10.4 vs. 39.8 ± 10.0 mmHg, p = 0.001) compared to patients without IDH. Similarly, during day‐ and nighttime periods, cSBP/cDBP and cPP levels were higher in IDH‐patients compared to non‐IDH. Forty‐eight‐hour augmentation pressure and index, but not AIx(75) were higher in IDH patients; 48‐h PWV (10.0 ± 2.0 vs. 9.2 ± 2.1 m/s, p = 0.017) was significantly higher in patients with IDH. The two study groups displayed different trajectories in central BP and PWV over the course of the recording; IDH patients had steadily high values of the above variables during the 2 days of the interdialytic‐interval, whereas non‐IDH patients showed a gradual elevation, with significant increases from the 1st to 2nd 24 h.

Conclusions

IDH patients have significantly higher levels of ambulatory central BP and arterial stiffness parameters and a different course over the 48‐h period compared with non‐IDH patients. Increased arterial stiffness could be a prominent factor associated with the high burden of cardiovascular disease in this population.
Life history adaptations to fluctuating environments: Combined effects of demographic buffering and lability
Authors: Le Coeur Christie , Yoccoz Nigel G. , Salguero‐Gómez Roberto , Vindenes Yngvild
Published: August 2022

Demographic buffering and lability have been identified as adaptive strategies to optimise fitness in a fluctuating environment. These are not mutually exclusive, however, we lack efficient methods to measure their relative importance for a given life history. Here, we decompose the stochastic growth rate (fitness) into components arising from nonlinear responses and variance–covariance of demographic parameters to an environmental driver, which allows studying joint effects of buffering and lability. We apply this decomposition for 154 animal matrix population models under different scenarios to explore how these main fitness components vary across life histories. Faster‐living species appear more responsive to environmental fluctuations, either positively or negatively. They have the highest potential for strong adaptive demographic lability, while demographic buffering is a main strategy in slow‐living species. Our decomposition provides a comprehensive framework to study how organisms adapt to variability through buffering and lability, and to predict species responses to climate change.
The EICA is dead? Long live the EICA!
Authors: Callaway Ragan M. , Lucero Jacob E. , Hierro José L. , Lortie C. J.
Published: August 2022

An important hypothesis for how plants respond to introduction to new ranges is the evolution of increased competitive ability (EICA). EICA predicts that biogeographical release from natural enemies initiates a trade‐off in which exotic species in non‐native ranges become larger and more competitive, but invest less in consumer defences, relative to populations in native ranges. This trade‐off is exceptionally complex because detecting concomitant biogeographical shifts in competitive ability and consumer defence depends upon which traits are targeted, how competition is measured, the defence chemicals quantified, whether defence chemicals do more than defend, whether ‘herbivory’ is artificial or natural, and where consumers fall on the generalist‐specialist spectrum. Previous meta‐analyses have successfully identified patterns but have yet to fully disentangle this complexity. We used meta‐analysis to reevaluate traditional metrics used to test EICA theory and then expanded on these metrics by partitioning competitive effect and competitive tolerance measures and testing Leaf‐Specific Mass in detail as a response trait. Unlike previous syntheses, our meta‐analyses detected evidence consistent with the classic trade‐off inherent to EICA. Plants from non‐native ranges imposed greater competitive effects than plants from native ranges and were less quantitatively defended than plants from native ranges. Our results for defence were not based on complex leaf chemistry, but instead were estimated from tannins, toughness traits and primarily Leaf‐Specific Mass. Species specificity occurred but did not influence the general patterns. As for all evidence for EICA‐like trade‐offs, we do not know if the biogeographical differences we found were caused by trade‐offs per se, but they are consistent with predictions derived from the overarching hypothesis. Underestimating physical leaf structure may have contributed to two decades of tepid perspectives on the trade‐offs fundamental to EICA.
Eco‐evolutionary dynamics of interference competition
Authors: Grether Gregory F. , Okamoto Kenichi W.
Published: August 2022

Theorists have identified several mechanisms through which species that compete exploitatively for resources could coexist. By contrast, under the current theory, interference competitors could coexist only in rare circumstances. Yet, some types of interference competition, such as interspecific territoriality, are common. This mismatch between theory and nature inspired us to model interference competition in an eco‐evolutionary framework. We based the model on the life cycle of territorial birds and ran simulations to examine whether natural selection could rescue a superior interference competitor from extinction without driving a superior exploitative competitor extinct. We found that coexistence between interference competitors can occur over a wide range of ecologically plausible scenarios, and up to the highest levels of resource overlap. An important caveat is that coexistence requires the species to co‐evolve. Reductions in population size and levels of genetic variation could destabilise coexistence between interference competitors, and thereby increase extinction rates over current estimates.
GluN2C selective inhibition is a target to develop new antiepileptic compounds
Authors: Gataullina Svetlana , Galvani Gilles , Touchet Sabrina , Nous Caroline , Lemaire Éric , Laschet Jacques , Chiron Catherine , Dulac Olivier , Dossi Elena , Brion Jean‐Daniel , Messaoudi Samir , Alami Mouad , Huberfeld Gilles
Published: August 2022

Objective

Many early‐onset epilepsies present as developmental and epileptic encephalopathy associated with refractory seizures, altered psychomotor development, and disorganized interictal cortical activity. Abnormal upregulation of specific N‐methyl‐d‐aspartate receptor (NMDA‐R) subunits is being disentangled as one of the mechanisms of severe early‐onset epilepsies. In tuberous sclerosis complex (TSC), upregulation of the GluN2C subunit of the NMDA‐R with slow deactivation kinetic results in increased neuronal excitation and synchronization.

Methods

Starting from an available GluN2C/D antagonist, NMDA‐R–modulating compounds were developed and screened using a patch clamp on neuronal culture to select those with the strongest inhibitory effect on glutamatergic NMDA currents. For these selected compounds, blood pharmacokinetics and passage through the blood–brain barrier were studied. We tested the effect of the most promising compounds on epileptic activity in Tsc1+/− mice brain slices with multielectrode array, and then in vivo at postnatal ages P14–P17, comparable with the usual age at epilepsy onset in human TSC.

Results

Using a double‐electrode voltage clamp on isolated NMDA currents, we identified the most prominent antagonists of the GluN2C subunit with no effect on GluN2A as a means of preventing side effects. The best compound passing through the blood–brain barrier was selected. Applied in vivo in six Tsc1+/− mice at P14–P17, this compound reduced or completely stopped spontaneous seizures in four of them, and decreased the background activity disorganization. Furthermore, ictal‐like discharges stopped on a human brain sample from an infant with epilepsy due to TSC.

Interpretation

Subunit‐selective inhibition is a valuable target for developing drugs for severe epilepsies resulting from an upregulation of NMDA‐R subunit–mediated transmission.
Contrasting population genetic responses to migration barriers in two native and an invasive freshwater fish
Authors: Deflem Io S. , Calboli Federico C. F. , Christiansen Henrik , Hellemans Bart , Raeymaekers Joost A. M. , Volckaert Filip A. M.
Published: August 2022

Habitat fragmentation impacts the distribution of genetic diversity and population genetic structure. Therefore, protecting the evolutionary potential of species, especially in the context of the current rate of human‐induced environmental change, is an important goal. In riverine ecosystems, migration barriers affect the genetic structure of native species, while also influencing the spread of invasive species. In this study, we compare genetic patterns of two native and one highly invasive riverine fish species in a Belgian river basin, namely the native three‐spined stickleback (Gasterosteus aculeatus) and stone loach (Barbatula barbatula), and the non‐native and invasive topmouth gudgeon (Pseudorasbora parva). We aimed to characterize both natural and anthropogenic determinants of genetic diversity and population genetic connectivity. Genetic diversity was highest in topmouth gudgeon, followed by stone loach and three‐spined stickleback. The correlation between downstream distance and genetic diversity, a pattern often observed in riverine systems, was only marginally significant in stone loach and three‐spined stickleback, while genetic diversity strongly declined with increasing number of barriers in topmouth gudgeon. An Isolation‐By‐Distance pattern characterizes the population genetic structure of each species. Population differentiation was only associated with migration barriers in the invasive topmouth gudgeon, while genetic composition of all species seemed at least partially determined by the presence of migration barriers. Among the six barrier types considered (watermills, sluices, tunnels, weirs, riverbed obstructions, and others), the presence of watermills was the strongest driver of genetic structure and composition. Our results indicate that conservation and restoration actions, focusing on conserving genetic patterns, cannot be generalized across species. Moreover, measures might target either on restoring connectivity, while risking a rapid spread of the invasive topmouth gudgeon, or not restoring connectivity, while risking native species extinction in upstream populations.
Introduction to special section: Federally funded, community‐based healthy marriage and responsible fatherhood program impact studies
Authors: Rhoades Galena K. , Doss Brian D. , Carlson Ryan G.
Published: August 2022

The focus of this special section is impact studies that were conducted as part of the Administration for Children and Families' Healthy Marriage and Responsible Fatherhood initiative. This initiative has led to more than 2 million people receiving relationship education and fatherhood programs across the United States over the last two decades. Community organizations develop these programs, select their curricula and content, and run these programs in their local communities. Many programs funded in the 2015–2020 cohort of grantees included randomized controlled trials of program effectiveness; some of these studies are presented in this issue, with the goal of marrying the field of program evaluation and family science.
Sex‐specific role of the circadian transcription factor NPAS2 in opioid tolerance, withdrawal and analgesia
Authors: Puig Stephanie , Shelton Micah A. , Barko Kelly , Seney Marianne L. , Logan Ryan W.
Published: August 2022

Opioids like fentanyl remain the mainstay treatment for chronic pain. Unfortunately, opioid's high dependence liability has led to the current opioid crisis, in part, because of side‐effects that develop during long‐term use, including analgesic tolerance and physical dependence. Both tolerance and dependence to opioids may lead to escalation of required doses to achieve previous therapeutic efficacy. Additionally, altered sleep and circadian rhythms are common in people on opioid therapy. Opioids impact sleep and circadian rhythms, while disruptions to sleep and circadian rhythms likely mediate the effects of opioids. However, the mechanisms underlying these bidirectional relationships between circadian rhythms and opioids remain largely unknown. The circadian protein, neuronal PAS domain protein 2 (NPAS2), regulates circadian‐dependent gene transcription in structure of the central nervous system that modulate opioids and pain. Here, male and female wild‐type and NPAS2‐deficient (NPAS2−/−) mice were used to investigate the role of NPAS2 in fentanyl analgesia, tolerance, hyperalgesia and physical dependence. Overall, thermal pain thresholds, acute analgesia and tolerance to a fixed dose of fentanyl were largely similar between wild‐type and NPAS2−/− mice. However, female NPAS2−/− exhibited augmented analgesic tolerance and significantly more behavioral symptoms of physical dependence to fentanyl. Only male NPAS2−/− mice had increased fentanyl‐induced hypersensitivity, when compared with wild‐type males. Together, our findings suggest sex‐specific effects of NPAS2 signaling in the regulation of fentanyl‐induced tolerance, hyperalgesia and dependence.
Generational perspective on asthma self‐management in the Bangladeshi and Pakistani community in the United Kingdom: A qualitative study
Authors: Ahmed Salina , Pinnock Hilary , Dowrick Anna , Steed Liz
Published: August 2022

Background

Self‐management strategies improve asthma outcomes, although interventions for South Asian populations have been less effective than in White populations. Both self‐management and culture are dynamic, and factors such as acculturation and generation have not always been adequately reflected in existing cultural interventions. We aimed to explore the perspectives of Bangladeshi and Pakistani people in the United Kingdom, across multiple generations (first, second and third/fourth), on how they self‐manage their asthma, with a view to suggesting recommendations for cultural interventions.

Methods

We purposively recruited Bangladeshi and Pakistani participants, with an active diagnosis of asthma from healthcare settings. Semi‐structured interviews in the participants' choice of language (English, Sylheti, Standard Bengali or Urdu) were conducted, and data were analysed thematically.

Results

Twenty‐seven participants (13 Bangladeshi and 14 Pakistani) were interviewed. There were generational differences in self‐management, influenced by complex cultural processes experienced by South Asians as part of being an ethnic minority group. Individuals from the first generation used self‐management strategies congruent to traditional beliefs such as ‘sweating’ and often chose to travel to South Asian countries. Generations born and raised in the United Kingdom learnt and experimented with self‐management based on their fused identities and modified their approach depending on whether they were in familial or peer settings. Acculturative stress, which was typically higher in first generations who had migration‐related stressors, influenced the priority given to asthma self‐management throughout generations. The amount and type of available asthma information as well as social discussions within the community and with healthcare professionals also shaped asthma self‐management.

Conclusions

Recognizing cultural diversity and its influence of asthma self‐management can help develop effective interventions tailored to the lives of South Asian people.

Patient or Public Contribution

Patient and Public Involvement colleagues were consulted throughout to ensure that the study and its materials were fit for purpose.
What adults with ADHD want to know: A Delphi consensus study on the psychoeducational needs of experts by experience
Authors: Seery Christina , Wrigley Margo , O'Riordan Fiona , Kilbride Ken , Bramham Jessica
Published: August 2022

Introduction

A lack of knowledge about attention‐deficit/hyperactivity disorder (ADHD) can contribute to feelings of distress and difficulty in seeking and accepting an ADHD diagnosis. The present study uses a Delphi consensus design to investigate the psychoeducational needs of adults with ADHD and the information about ADHD they would like included in digital health interventions for adults with ADHD. Inclusion of perspectives of service users in developing such interventions ensures that they are evidence based and addresses the risks of engagement barriers.

Methods

The expert panel consisted of 43 adults with ADHD (age range: 23–67 years). Panel members were asked to rate the importance of the proposed topics and provide additional suggestions. Suggested topics and topics that did not achieve consensus were included for ranking in the second round.

Results

Interquartile ratings were used to determine consensus. A high consensus was achieved in both rounds, with an agreement on 94% of topics in the first round and 98% in the second round. Most topics were rated as important or essential.

Conclusions

The findings highlighted that adults with ADHD want to learn about many different aspects of ADHD and the importance of considering their perspectives when developing psychosocial interventions. Findings can be applied when creating psychoeducational content for adult ADHD.

Patient or Public Contribution

Adults with ADHD were recruited to the Delphi panel to use an experts‐by‐experience approach. In doing so, we are engaging service users in the development of a psychoeducational smartphone app. The evaluation of the app will involve interviews with app users. Additionally, the present study was developed and conducted with ADHD Ireland, a charity based in Ireland that advocates for people with ADHD.