bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk factors of disease flares in a Chinese lupus cohort with low-grade disease activity
Authors: Sun Fangfang , Zhao Liling , Wang Haiting , Zhang Danting , Chen Jie , Wang Xiaodong , Li Ting , Ye Shuang 
Published: May 2022

ObjectiveRecurrent disease flare is one of the key problems in lupus patients. A Chinese Flare-Prevention Lupus Initiative Cohort (FLIC) was established. Risk factors of disease flare were evaluated accordingly.MethodsPatients with low-grade disease activity (the Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) =≤6, daily prednisone ≤20 mg, no British Isles Lupus Assessment Group A or no more than one B organ domain score) from January 2014 to August 2020 were included in the FLIC. Disease flares were defined by the modified SELENA-­SLEDAI Flare Index. Low disease activity status (LDAS) and remission were also assessed. The cumulative flare rate was estimated by an event per 100 person-years analysis. Cox proportional hazards models were performed to identify risk factors of subsequent disease flares after adjusting clinical confounders. Survival was assessed with the Kaplan-Meier method.Results448 eligible patients with low-grade disease activity were included in FLIC. During a mean follow-up of 30.4 months, 170 patients flared. The cumulative lupus flare rate was 22.2 events per 100 patient-years. Compared with patients without flare, those with lupus flares were taking more prednisone, had higher disease activity index and with less patients attained LDAS/remission at baseline. They also had higher rates of antiphospholipid antibodies (aPLs) and antiribosomal P antibody. Cox regression analysis confirmed that attainment of either LDAS or remission at baseline were independent protective factors against subsequent disease flare (LDAS but not in remission: HR 0.58, 95% CI 0.38~0.88; remission: HR 0.46, 95% CI 0.30~0.69), while aPL was a risk factor of lupus flares (HR 1.95, 95% CI 1.36~2.78). Kaplan-Meier curves indicated that attaining LDAS or remission and absence of aPL at baseline had the least flare risk.ConclusionsIn our real-world cohort study, not attaining LDAS or remission at baseline and aPL positivity was associated with higher risk of disease flares in patients with low-grade SLE.
Two kinds of embryo research: four case examples
Authors: Savulescu Julian , Labude Markus , Barcellona Capucine , Huang Zhongwei , Leverentz Michael Karl , Xafis Vicki , Lysaght Tamra 
Published: May 2022

There are ethical obligations to conduct research that contributes to generalisable knowledge and improves reproductive health, and this should include embryo research in jurisdictions where it is permitted. Often, the controversial nature of embryo research can alarm ethics committee members, which can unnecessarily delay important research that can potentially improve fertility for patients and society. Such delay is ethically unjustified. Moreover, countries such as the UK, Australia and Singapore have legislation which unnecessarily captures low-risk research, such as observational research, in an often cumbersome and protracted review process. Such countries should revise such legislation to better facilitate low-risk embryo research.We introduce a philosophical distinction to help decision-makers more efficiently identify higher risk embryo research from that which presents no more risks to persons than other types of tissue research. That distinction is between future person embryo research and non-future person embryo research. We apply this distinction to four examples of embryo research that might be presented to ethics committees.Embryo research is most controversial and deserving of detailed scrutiny when it potentially affects a future person. Where it does not, it should generally require less ethical scrutiny. We explore a variety of ways in which research can affect a future person, including by deriving information about that person, and manipulating eggs or sperm before an embryo is created.
Clinical law: what do clinicians want to know? The demography of clinical law
Authors: Wheeler Robert , Hall Nigel 
Published: May 2022

This is the first description of the questions that clinicians ask a department of clinical law, relating to the legal rules applicable to the care of their patients.ObjectivesTo describe in detail the demography of clinical legal enquiries made by clinicians of all professions concerning the care of their patients. To collate and categorise the varieties of enquiry, to identify phenotypic patterns. To provide colleges, regulators, commissioners, educators and the NHS with an insight into hitherto undescribed subject matter, better to understand and respond to this aspect of clinical practice.DesignProspective collection of all clinical legal referrals recorded in writing over 12 years by a department of clinical law.SettingAn English Tertiary Hospital NHS Trust.ParticipantsClinical staff of the regulated professions, all seeking to have their clinical legal enquiries answered.Main outcome measuresThe description of the demography of clinical law.Results1251 written records were identified and reviewed. These were divided into nine broad clinical legal subject areas (domains): mental disorders, parents and children, incapacity, consent for treatment, disclosure of private information, other statutory, regulated practice, professional practice, clinical practice. Within these, 149 clinical legal phenotypes were identified to which each case could be assigned.ConclusionsAmong a broad range of enquiries, recognisable clinical legal phenotypes exist and have for the first time been described and categorised. These are clinical situations which clinicians need to be able to recognise and equipped to deal with. Doing so will likely facilitate timely and better treatment.
Combined anterior and posterior circulation approach for stent-assisted coiling of a recurrent basilar tip aneurysm
Authors: Domingo Ricardo A , Ramos-Fresnedo Andres , Ravindran Krishnan , Tawk Rabih G 
Published: May 2022

Endovascular treatment of recurrent basilar aneurysms is challenging due to significant changes in the configuration of the aneurysm and adjacent vessels from prior interventions.1 Coil compaction is a common cause of recurrence and alters the aneurysm morphology significantly.2–4 Stenting of the basilar artery into a posterior cerebral artery modifies the angles between these vessels.5 In this video, we discuss a combined approach via the anterior and posterior circulation for stent-assisted coiling of a recurrent basilar tip aneurysm (Video 1) . A patient in their 40s with a history of ruptured aneurysm underwent multiple endovascular interventions including coiling, stent-assisted coiling, and Woven Endobridge (WEB) device. The patient presented with worsening headaches and underwent treatment with stent-assisted coiling for recurrence. After encountering challenges with direct access from the basilar artery, a combined anterior and posterior circulation approach was used.6 The stent was deployed through the posterior communicating artery and a snare was used to navigate the complex anatomy.Video 1
Comparison of cancer incidence and mortality in the Norwegian Fire Departments Cohort, 1960–2018
Authors: Marjerrison Niki , Jakobsen Jarle , Demers Paul A , Grimsrud Tom K , Hansen Johnni , Martinsen Jan Ivar , Nordby Karl-Christian , Veierød Marit B , Kjærheim Kristina 
Published: May 2022

ObjectivesElevated risk of cancer at several sites has been reported among firefighters, although with mixed findings. The purpose of this study was to calculate standardised incidence ratios (SIRs) and standardised mortality ratios (SMRs) for cancer and compare them to assess whether use of the different measures could be a source of inconsistencies in findings.MethodsThe Norwegian Fire Departments Cohort, comprising 4295 male employees who worked at 15 fire departments across Norway, was linked to health outcome registries for the period 1960–2018. SIRs and SMRs were derived using national reference rates.ResultsOverall, we observed elevated incidence of colon cancer (SIR, 95% CI 1.27, 1.01 to 1.58), mesothelioma (2.59, 1.12 to 5.11), prostate cancer (1.18, 1.03 to 1.34) and all sites combined (1.15, 1.08 to 1.23). Smaller, non-significant elevations were found for mortality of colon cancer (SMR, 95% CI 1.20, 0.84 to 1.67) and mesothelioma (1.66, 0.34 to 4.86), while SMR for prostate cancer was at unity. Potential errors were observed in some of the mortality data, notably for mesothelioma cases. Among those who died of cancer, 3.7% (n=14) did not have a prior diagnosis of malignancy at the same site group.ConclusionsAssessment of incidence or mortality did not greatly influence the interpretation of results. The most prominent differences in SIR and SMR appeared to be due to inconsistencies between sites of cancer diagnosis and cause of death. The difference in SIR and SMR for prostate cancer suggested a detection bias from differential screening practices.
Mendelian randomisation of eosinophils and other cell types in relation to lung function and disease
Authors: Guyatt Anna , John Catherine , Williams Alexander T , Shrine Nick , Reeve Nicola F ,   SpiroMeta consortium, Sayers Ian , Hall Ian , Wain Louise V , Sheehan Nuala , Dudbridge Frank , Tobin Martin D 
Published: May 2022

RationaleEosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil counts. However, whether raised eosinophils are causally related to chronic obstructive pulmonary disease (COPD) and other respiratory phenotypes is not well understood.ObjectivesWe investigated causality between eosinophils and: lung function, acute exacerbations of COPD, asthma-COPD overlap (ACO), moderate-to-severe asthma and respiratory infections.MethodsWe performed Mendelian randomisation (MR) using 151 variants from genome-wide association studies of blood eosinophils in UK Biobank/INTERVAL, and respiratory traits in UK Biobank/SpiroMeta, using methods relying on different assumptions for validity. We performed multivariable analyses using eight cell types where there was possible evidence of causation by eosinophils.Measurements and main resultsCausal estimates derived from individual variants were highly heterogeneous, which may arise from pleiotropy. The average effect of raising eosinophils was to increase risk of ACO (weighted median OR per SD eosinophils, 1.44 (95%CI 1.19 to 1.74)), and moderate-severe asthma (weighted median OR 1.50 (95%CI 1.23 to 1.83)), and to reduce forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1(weighted median estimator, SD FEV1/FVC: −0.054 (95% CI −0.078 to −0.029), effect only prominent in individuals with asthma).ConclusionsBroad consistency across MR methods may suggest causation by eosinophils (although of uncertain magnitude), yet heterogeneity necessitates caution: other important mechanisms may be responsible for the impairment of respiratory health by these eosinophil-raising variants. These results could suggest that anti-IL5 agents (designed to lower eosinophils) may be valuable in treating other respiratory conditions, including people with overlapping features of asthma and COPD.
Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis
Authors: Kraven Luke M , Taylor Adam R , Molyneaux Philip L , Maher Toby M , McDonough John E , Mura Marco , Yang Ivana V , Schwartz David A , Huang Yong , Noth Imre , Ma Shwu Fan , Yeo Astrid J , Fahy William A , Jenkins R Gisli , Wain Louise V 
Published: May 2022

BackgroundConsiderable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes.MethodsWe co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases).FindingsWe identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10−5).InterpretationWe have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.
Lifetime hormone profiles for a long-lived teleost: opercula reveal novel estimates of age-specific reproductive parameters and stress trends in yelloweye rockfish (Sebastes ruberrimus)
Authors: Charapata Patrick , Oxman Dion , McNeel Kevin , Keith Alexa , Mansouri Farzaneh , Trumble Stephen 
Published: May 2022

Fisheries management relies on accurate population models for estimating biomass and setting harvest goals; however, physiological data for estimating reproductive parameters in population models are difficult to acquire. Here, lifetime reproductive (progesterone and estradiol) and stress-related (cortisol) hormones were measured in annually deposited growth increments in female yelloweye rockfish ( Sebastes ruberrimus) opercula ( N = 22 females, sampled ages 1–90 years). Analyses of these profiles (∼1-year resolution) provided estimates of physiological (complete puberty) and functional age of sexual maturity (females spawn and contribute larvae to the population) and spawning frequency, with lifetime trends of reproduction and stress. The descriptive mean age of physiological sexual maturity was 11 ± 1 years (standard error (SE)), whereas functional age of maturity was 17 ± 2 years. The estimate of marginal mean spawning frequency was 45.1% ± 5.1%. Stress data (∼15% of females experienced distress events) suggested that females were potentially resilient or not exposed to chronic stressors. Although preliminary, we provide a novel method to estimate age-specific reproductive parameters for proper age-based population modeling of a human-targeted teleost.
Non-invasive measurement of nuclear relative stiffness from quantitative analysis of microscopy data
Authors: Villa Stefano , Palamidessi Andrea , Frittoli Emanuela , Scita Giorgio , Cerbino Roberto , Giavazzi Fabio 
Published: May 2022

Abstract
The connection between the properties of a cell tissue and those of the single constituent cells remains to be elucidated. At the purely mechanical level, the degree of rigidity of different cellular components, such as the nucleus and the cytoplasm, modulates the interplay between the cell inner processes and the external environment, while simultaneously mediating the mechanical interactions between neighboring cells. Being able to quantify the correlation between single-cell and tissue properties would improve our mechanobiological understanding of cell tissues. Here we develop a methodology to quantitatively extract a set of structural and motility parameters from the analysis of time-lapse movies of nuclei belonging to jammed and flocking cell monolayers. We then study in detail the correlation between the dynamical state of the tissue and the deformation of the nuclei. We observe that the nuclear deformation rate linearly correlates with the local divergence of the velocity field, which leads to a non-invasive estimate of the elastic modulus of the nucleus relative to the one of the cytoplasm. We also find that nuclei belonging to flocking monolayers, subjected to larger mechanical perturbations, are about two time stiffer than nuclei belonging to dynamically arrested monolayers, in agreement with atomic force microscopy results. Our results demonstrate a non-invasive route to the determination of nuclear relative stiffness for cells in a monolayer.

Graphic abstract
Late Holocene climate variability and its impact on cultural dynamics in central India
Authors: Behera Diptimayee , Mishra Praveen K. , Sabale Pandurang , Bhattacharya Sharmila , Anoop Ambili 
Published: May 2022

Abstract

An understanding of long-term climate variability may provide a valuable perspective on the possible response of human societies to modern climate change. The present study, based on geochemical and sedimentological analyses on well dated (using AMS
14
C and optically stimulated luminescence (OSL) dates) alluvial sediments from Sina River basin (in Maharashtra, central India), provides a detailed understanding of the complex interplay between climate and cultural dynamics during the Late Holocene. The radiocarbon dates of the organic residues from the potsherds represent the Medieval period (
c.
1.6–0.95 cal ka BP), whereas the OSL sample shows an age of
c.
7.5 ± 0.4 ka. Further, several cultural objects (e.g. potsherds, shell bangles, and copper artefacts) available at the site were also investigated in order to understand the extent of human activity in the region. The temporal changes in the proxies along with the abundance of cultural materials in the fluvial section during the Medieval period suggest that the human population attempted to adapt against the fluctuating climate conditions. The regional comparison of geo-archaeological datasets shows that the pronounced weakening of the monsoonal rainfall during the Late Holocene coincides with the disruption, migration and resettlement of indigenous societies, deciphering the possible impact of climate on human settlement.
Eight-Year Depressive Symptom Trajectories and Incident Stroke: A 10-Year Follow-Up of the HRS (Health and Retirement Study)
Authors: Soh Yenee , Tiemeier Henning , Kawachi Ichiro , Berkman Lisa F. , Kubzansky Laura D. 
Published: May 2022

Background:
Evidence suggests a link between depressive symptoms and risk of subsequent stroke. However, most studies assess depressive symptoms at only one timepoint, with few examining this relationship using repeatedly measured depressive symptoms. This study aimed to examine the relationship between depressive symptom trajectories and risk of incident stroke.

Methods:
This prospective cohort included 12 520 US individuals aged ≥50 years enrolled in the Health and Retirement Study, free of stroke at study baseline (1998). We used the 8-item Center for Epidemiologic Studies Depression scale to assess depressive symptoms (high defined as ≥3 symptoms; low <3 symptoms) at 4 consecutive, biennial timepoints from 1998 to 2004. We assigned individuals to 5 predefined trajectories based on their scores at each timepoint (consistently low, decreasing, fluctuating, increasing, and consistently high). Using self-reported doctors’ diagnoses, we assessed incident stroke over a subsequent 10-year period from 2006 to 2016. Cox regression models estimated the association of depressive symptom trajectories with risk of incident stroke, adjusting for demographics, health behaviors, and health conditions.

Results:
During follow-up, 1434 incident strokes occurred. Compared with individuals with consistently low symptoms, individuals with consistently high depressive symptoms (adjusted hazard ratio, 1.18 [95% CI, 1.02–1.36]), increasing symptoms (adjusted hazard ratio, 1.31 [95% CI, 1.10–1.57]), and fluctuating symptoms (adjusted hazard ratio, 1.21 [95% CI, 1.01–1.46]) all had higher hazards of stroke onset. Individuals in the decreasing symptom trajectory group did not show increased stroke risk.

Conclusions:
Depressive symptom trajectories characterized by high symptoms at multiple timepoints were associated with increased stroke risk. However, a trajectory with depressive symptoms that started high but decreased over time was not associated with higher stroke risk. Given the remitting-relapsing nature of depressive symptoms, it is important to understand the relationship between depressive symptoms and stroke risk over time through repeated assessments.
Characterizing Reasons for Stroke Thrombectomy Ineligibility Among Potential Candidates Transferred in a Hub‐and‐Spoke Network
Authors: Regenhardt Robert W. , Awad Amine , Kraft Andrew W. , Rosenthal Joseph A. , Dmytriw Adam A. , Vranic Justin E. , Bonkhoff Anna K. , Bretzner Martin , Etherton Mark R. , Hirsch Joshua A. , Rabinov James D. , Singhal Aneesh B. , Rost Natalia S. , Stapleton Christopher J. , Leslie‐Mazwi Thabele M. , Patel Aman B. 
Published: May 2022

Background
Access to endovascular thrombectomy (EVT) is relatively limited. Hub‐and‐spoke networks seek to transfer appropriate large‐vessel occlusion stroke candidates to EVT‐capable hubs. However, some patients are ineligible upon hub arrival, and factors that drive transfer inefficiencies are not well described. We sought to quantify EVT transfer efficiency and identify reasons for EVT ineligibility.

Methods
Consecutive EVT candidates presenting to 25 spokes from 2018 to 2020 with pretransfer computed tomography angiography‐defined large‐vessel occlusion and Alberta Stroke Program Early Computed Tomography Score of ≥6 were identified from a prospectively maintained database. Outcomes of interest included hub EVT, reasons for EVT ineligibility, and 90‐day modified Rankin scale score of ≤2.

Results

Among 258 patients, the median age was 70 years (interquartile range, 60–81 years); 50% were women. A total of 56% were ineligible for EVT after hub arrival. Cited reasons were large established infarct (49%), mild symptoms (33%), recanalization (6%), distal occlusion (5%), subocclusive lesion (3%), and goals of care (3%). Late window patients (last known well >6 hours) were more likely to be ineligible (67% versus 43%;
P
<0.0001). EVT‐ineligible patients were older (73 versus 68 years;
P
=0.04), had lower National Institutes of Health Stroke Scale score (10 versus 16;
P
<0.0001), had longer last known well‐to‐hub arrival time (8.4 versus 4.6 hours;
P
<0.0001), had longer spoke Telestroke consult‐to‐hub arrival time (2.8 versus 2.2 hours;
P
<0.0001), and received less intravenous thrombolysis (32% versus 45%;
P
=0.04) compared with eligible patients. EVT ineligibility independently reduced the odds of 90‐day modified Rankin scale score of ≤2 (adjusted odds ratio, 0.26; 95% CI, 0.12–0.56;
P
=0.001) when controlling for age, National Institutes of Health Stroke Scale score, and last known well‐to‐hub arrival time.

Conclusions
Among patients transferred for EVT, there are multiple reasons for ineligibility upon hub arrival, with most excluded for infarct growth and mild symptoms. Understanding factors that drive transfer inefficiencies is important to improve EVT access and outcomes.