bluuebunny/crossref_metadata_2025_split huggingface dataset:
The heritability of amyloid burden in older adults: the Older Australian Twins Study
Authors: Koncz Rebecca , Thalamuthu Anbupalam , Wen Wei , Catts Vibeke S , Dore Vincent , Lee Teresa , Mather Karen A , Slavin Melissa J , Wegner Eva A , Jiang Jiyang , Trollor Julian N , Ames David , Villemagne Victor L , Rowe Christopher C , Sachdev Perminder S 
Published: December 2021

ObjectiveTo determine the proportional genetic contribution to the variability of cerebral β-amyloid load in older adults using the classic twin design.MethodsParticipants (n=206) comprising 61 monozygotic (MZ) twin pairs (68 (55.74%) females; mean age (SD): 71.98 (6.43) years), and 42 dizygotic (DZ) twin pairs (56 (66.67%) females; mean age: 71.14 (5.15) years) were drawn from the Older Australian Twins Study. Participants underwent detailed clinical and neuropsychological evaluations, as well as MRI, diffusion tensor imaging (DTI) and amyloid PET scans. Fifty-eight participants (17 MZ pairs, 12 DZ pairs) had PET scans with 11Carbon-Pittsburgh Compound B, and 148 participants (44 MZ pairs, 30 DZ pairs) with 18Fluorine-NAV4694. Cortical amyloid burden was quantified using the centiloid scale globally, as well as the standardised uptake value ratio (SUVR) globally and in specific brain regions. Small vessel disease (SVD) was quantified using total white matter hyperintensity volume on MRI, and peak width of skeletonised mean diffusivity on DTI. Heritability (h2) and genetic correlations were measured with structural equation modelling under the best fit model, controlling for age, sex, tracer and scanner.ResultsThe heritability of global amyloid burden was moderate (0.41 using SUVR; 0.52 using the centiloid scale) and ranged from 0.20 to 0.54 across different brain regions. There were no significant genetic or environmental correlations between global amyloid burden and markers of SVD.ConclusionAmyloid deposition, the hallmark early feature of Alzheimer’s disease, is under moderate genetic influence, suggesting a major environmental contribution that may be amenable to intervention.
Recognising and managing eating disorders in the emergency department
Authors: Jafar Anisa Jabeen Nasir , Jafar Wisam Jalal Jawad , Everitt Emma Kathleen , Gill Ian , Sait Hannah Maria , Tan Jacinta 
Published: December 2021

Abstract
Compared with other mental health conditions or psychiatric presentations, such as self-harm, which may be seen in emergency departments, eating disorders can seem relatively rare. However, they have the highest mortality across the spectrum of mental health, with high rates of medical complications and risk, ranging from hypoglycaemia and electrolyte disturbances to cardiac abnormalities. People with eating disorders may not disclose their diagnosis when they see healthcare professionals. This can be due to denial of the condition itself, a wish to avoid treatment for a condition which may be valued, or because of the stigma attached to mental health. As a result their diagnosis can be easily missed by healthcare professionals and thus the prevalence is underappreciated. This article presents eating disorders to emergency and acute medicine practitioners from a new perspective using the combined emergency, psychiatric, nutrition and psychology lens. It focuses on the most serious acute pathology which can develop from the more common presentations; highlights indicators of hidden disease; discusses screening; suggests key acute management considerations and explores the challenge of mental capacity in a group of high-risk patients who, with the right treatment, can make a good recovery.
Identification of biological risk factors for persistent postoperative pain after total knee arthroplasty
Authors: Sideris Alexandra , Malahias Michael-Alexander , Birch George , Zhong Haoyan , Rotundo Valeria , Like Brian J , Otero Miguel , Sculco Peter K , Kirksey Meghan 
Published: December 2021

BackgroundThere is growing evidence that cytokines and adipokines are associated with osteoarthritis (OA) severity, progression, and severity of associated pain. However, the cytokine response to total knee arthroplasty (TKA) and its association with persistent postoperative pain is not well understood. This study aims to describe the perioperative systemic (plasma) and local (synovial fluid) cytokine profiles of patients who do and do not develop persistent pain after TKA.MethodsPatients undergoing primary unilateral TKA for end-stage OA were prospectively enrolled. Demographic and clinical data were gathered preoperatively and postoperatively. Synovial fluid was collected pre arthrotomy and plasma was collected at multiple time points before and after surgery. Persistent postoperative pain (PPP) was defined as Numerical Rating Score≥4 at 6 months. Cytokine levels were measured using the V-Plex Human Cytokine 30-Plex Panel (Mesoscale—Rockville, Maryland, USA). Cytokine levels were compared between PPP and minimal pain groups. Given that the study outcomes are exploratory, no adjustment was performed for multiple testing.ResultsIncidence of persistent pain at 6 months post TKA was 15/162 (9.3%). Postoperative plasma levels of four cytokines were significantly different in patients who developed persistent postoperative pain: interleukin (IL)-10, IL-1β, vascular endothelial growth factor, and IL12/IL23p40. Significantly lower IL-10 levels in the prearthrotomy synovial fluid were associated with development of postoperative persistent pain.ConclusionsThis prospective cohort study described a distinct acute perioperative inflammatory response profile in patients who developed persistent post-TKA pain, characterized by significant differences in four cytokines over the first 2 postoperative days. These results support the growing evidence that the patient-specific biologic response to surgery may influence longer-term clinical outcomes after TKA.Trial registration numberClinicaltrials.gov NCT02626533.
Volcano-sedimentary processes at Las Derrumbadas rhyolitic twin domes, Serdán-Oriental Basin, Eastern Trans-Mexican Volcanic Belt
Authors: Guilbaud Marie-Noëlle , Chédeville Corentin , Molina-Guadarrama Ángel Nahir , Pineda-Serrano Julio Cesar , Siebe Claus 
Published: December 2021

Abstract

The eruption of the
c.
10 km
3
rhyolitic Las Derrumbadas twin domes about 2000 years ago generated a wide range of volcano-sedimentary deposits in the Serdán-Oriental lacustrine basin, Trans-Mexican Volcanic Belt. Some of these deposits have been quarried, creating excellent exposures. In this paper we describe the domes and related products and interpret their mode of formation, reconstructing the main phases of the eruption as well as syn- and post-eruptive erosional processes. After an initial phreatomagmatic phase that built a tuff ring, the domes grew as an upheaved plug, lifting a thick sedimentary pile from the basin floor. During uplift, the domes collapsed repeatedly to form a first generation of hetero-lithologic hummocky debris avalanche deposits. Subsequent dome growth produced a thick talus and pyroclastic density currents. Later, the hydrothermally altered over-steepened dome peaks fell to generate second-generation, mono-lithologic avalanches. Subsequently, small domes grew in the collapse scars. From the end of the main eruptive episode onwards, heavy rains remobilized parts of the dome carapaces and talus, depositing lahar aprons. The Las Derrumbadas domes are still an important source of sediments in the basin, and ongoing mass-wasting processes are associated with hazards that should be assessed, given their potential impact on nearby populations.
Tectonic control on the palaeogeographical evolution of the Miocene Seaway along the Western Alpine foreland basin
Authors: Kalifi Amir , Sorrel Philippe , Leloup Philippe-Hervé , Galy Albert , Spina Vincenzo , Huet Bastien , Russo Séverine , Pittet Bernard , Rubino Jean-Loup 
Published: December 2021

Abstract

The Miocene of the Western Alpine foreland basin were deposited in a north–south seaway along the active alpine orogenic front. In the subalpine massifs and the southern Jura mountains, the revised Miocene stratigraphy documents a detailed chronology of thrust propagation at the western alpine front, where tectonic activity had a primary influence on seaway palaeogeographical evolution. Here we propose nine palaeogeographical maps during the Miocene, the first of which depicts the initial Miocene transgression at
c.
21.0 Ma. Between
c.
18.05 and
c.
12.0 Ma, a westward retreat of the Miocene Sea occurred in response to activation of the basal thrust of the Belledonne massif, which in turn triggered successive fault zones from east to west. At
c.
10.0 Ma, a major uplift phase intervened and induced a rapid southward retreat of the Miocene Sea. The reconstructed palaeogeographical maps outline the main controls on the foreland basin seaway evolution: (1) the timing of the main thrusts; (2) the inherited palaeotopography; and (3) eustatic sea-level changes during the Miocene. These reconstructions are integrated at the basin scale, highlighting the southward- to westward-directed seaway migration in response to the Belledonne thrust activity that deeply shaped the palaeogeographical evolution during the early to middle Miocene.
Targeting Ribonucleotide Reductase Induces Synthetic Lethality in PP2A-Deficient Uterine Serous Carcinoma
Authors: O'Connor Caitlin M. , Taylor Sarah E. , Miller Kathryn M. , Hurst Lauren , Haanen Terrance J. , Suhan Tahra K. , Zawacki Kaitlin P. , Noto Fallon K. , Trako Jonida , Mohan Arathi , Sangodkar Jaya , Zamarin Dmitriy , DiFeo Analisa , Narla Goutham 
Published: December 2021

Abstract

Uterine serous carcinoma (USC) is a highly aggressive endometrial cancer subtype with limited therapeutic options and a lack of targeted therapies. While mutations to PPP2R1A, which encodes the predominant protein phosphatase 2A (PP2A) scaffolding protein Aα, occur in 30% to 40% of USC cases, the clinical actionability of these mutations has not been studied. Using a high-throughput screening approach, we showed that mutations in Aα results in synthetic lethality following treatment with inhibitors of ribonucleotide reductase (RNR). In vivo, multiple models of Aα mutant uterine serous tumors were sensitive to clofarabine, an RNR inhibitor (RNRi). Aα-mutant cells displayed impaired checkpoint signaling upon RNRi treatment and subsequently accumulated more DNA damage than wild-type (WT) cells. Consistently, inhibition of PP2A activity using LB-100, a catalytic inhibitor, sensitized WT USC cells to RNRi. Analysis of The Cancer Genome Atlas data indicated that inactivation of PP2A, through loss of PP2A subunit expression, was prevalent in USC, with 88% of patients with USC harboring loss of at least one PP2A gene. In contrast, loss of PP2A subunit expression was rare in uterine endometrioid carcinomas. While RNRi are not routinely used for uterine cancers, a retrospective analysis of patients treated with gemcitabine as a second- or later-line therapy revealed a trend for improved outcomes in patients with USC treated with RNRi gemcitabine compared with patients with endometrioid histology. Overall, our data provide experimental evidence to support the use of ribonucleotide reductase inhibitors for the treatment of USC.

Significance:
A drug repurposing screen identifies synthetic lethal interactions in PP2A-deficient uterine serous carcinoma, providing potential therapeutic avenues for treating this deadly endometrial cancer.
Dissecting the Oncogenic Roles of Keratin 17 in the Hallmarks of Cancer
Authors: Baraks Gabriella , Tseng Robert , Pan Chun-Hao , Kasliwal Saumya , Leiton Cindy V. , Shroyer Kenneth R. , Escobar-Hoyos Luisa F. 
Published: December 2021

AbstractThere is an unmet need to identify and validate tumor-specific therapeutic targets to enable more effective treatments for cancer. Heterogeneity in patient clinical characteristics as well as biological and genetic features of tumors present major challenges for the optimization of therapeutic interventions, including the development of novel and more effective precision medicine. The expression of keratin 17 (K17) is a hallmark of the most aggressive forms of cancer across a wide range of anatomical sites and histological types. K17 correlates with shorter patient survival, predicts resistance to specific chemotherapeutic agents, and harbors functional domains that suggest it could be therapeutically targeted. Here, we explore the role of K17 in the hallmarks of cancer and summarize evidence to date for K17-mediated mechanisms involved in each hallmark, elucidating functional roles that warrant further investigation to guide the development of novel therapeutic strategies.
Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis
Authors: Fitzpatrick Amanda , Iravani Marjan , Mills Adam , Childs Lucy , Alaguthurai Thanussuyah , Clifford Angela , Garcia-Murillas Isaac , Van Laere Steven , Dirix Luc , Harries Mark , Okines Alicia , Turner Nicholas C. , Haider Syed , Tutt Andrew N.J. , Isacke Clare M. 
Published: December 2021

Abstract

Purpose:
Cerebrospinal fluid (CSF) cytology is the gold standard diagnostic test for breast cancer leptomeningeal metastasis (BCLM), but has impaired sensitivity, often necessitating repeated lumbar puncture to confirm or refute diagnosis. Further, there is no quantitative response tool to assess response or progression during BCLM treatment.

Experimental Design:
Facing the challenge of working with small-volume samples and the lack of common recurrent mutations in breast cancers, cell-free DNA was extracted from the CSF and plasma of patients undergoing investigation for BCLM (n = 30). ctDNA fraction was assessed by ultra-low-pass whole genome sequencing (ulpWGS), which does not require prior tumor sequencing.

Results:
In this proof-of-concept study, ctDNA was detected (fraction ≥0.10) in the CSF of all 24 patients with BCLM+ (median ctDNA fraction, 0.57), regardless of negative cytology or borderline MRI imaging, whereas CSF ctDNA was not detected in the six patients with BCLM− (median ctDNA fraction 0.03, P &lt; 0.0001). Plasma ctDNA was only detected in patients with extracranial disease progression or who had previously received whole brain radiotherapy. ctDNA fraction was highly concordant with mutant allele fraction measured by tumor mutation-specific ddPCR assays (r = 0.852; P &lt; 0.0001). During intrathecal treatment, serial monitoring (n = 12 patients) showed that suppression of CSF ctDNA fraction was associated with longer BCLM survival (P = 0.034), and rising ctDNA fraction was detectable up to 12 weeks before clinical progression.

Conclusions:
Measuring ctDNA fraction by ulpWGS is a quantitative marker demonstrating potential for timely and accurate BCLM diagnosis and therapy response monitoring, with the ultimate aim to improve management of this poor-prognosis patient group.
Biomarkers of Angiogenesis and Clinical Outcomes to Cabozantinib and Everolimus in Patients with Metastatic Renal Cell Carcinoma from the Phase III METEOR Trial
Authors: Denize Thomas , Farah Subrina , Cimadamore Alessia , Flaifel Abdallah , Walton Emily , Sticco-Ivins Maura A. , Labaki Chris , Braun David A. , Sun Maxine , Wang Evelyn , Xie Wanling , Choueiri Toni K. , Signoretti Sabina 
Published: December 2021

Abstract

Purpose:
Antiangiogenic VEGF receptor (VEGFR) inhibitors are approved for metastatic clear cell renal cell carcinoma (mccRCC) and their efficacy is higher in high angiogenic tumors. As cabozantinib inhibits multiple tyrosine kinase receptors, including VEGFRs, we tested whether markers of angiogenesis, including microvascular density (MVD) and mast cell density (MCD), could predict benefit from cabozantinib versus everolimus, using RCC samples from the METEOR (NCT01865747) trial.

Experimental Design:
MVD and MCD were studied in 430 patients (cabozantinib = 216, everolimus = 214) by double immunohistochemistry for CD31 (vascular marker) and tryptase (mast cell marker) coupled with automated image analysis. Results from evaluable cases (MVD = 360, MCD = 325) were correlated with progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

Results:
MVD was positively correlated with MCD. In the whole cohort, high MVD and high MCD were associated with longer PFS; improved PFS was most evident in patients with high levels of both MCD and MVD. Cabozantinib was associated with improved PFS, OS, and ORR compared with everolimus, irrespective of MVD levels. Cabozantinib was also associated with improved ORR compared with everolimus, irrespective of MCD levels. For PFS and OS, the treatment effect for cabozantinib versus everolimus tended to be greater in tumors with low MCD.

Conclusions:
High MVD and high MCD are associated with improved outcome in mccRCC but do not predict efficacy to cabozantinib versus everolimus. The high efficacy of cabozantinib in low angiogenic tumors allows us to speculate that its antitumor activity is not exclusively mediated by VEGFR inhibition.
Racial Disparities in Invasive Management for Patients With Acute Myocardial Infarction With Chronic Kidney Disease
Authors: Rymer Jennifer A. , Li Shuang , Pun Patrick H. , Thomas Laine , Wang Tracy Y. 
Published: December 2021

Background:
Due to increased risks of contrast nephropathy, chronic kidney disease (CKD) can deter consideration of invasive management for patients with myocardial infarction (MI). Black patients have a higher prevalence of CKD. Whether racial disparities exist in the use of invasive MI management for patients with CKD presenting with MI is unknown.

Methods:

We examined 717 012 White and 99 882 Black patients with MI treated from 2008 to 2017 at 914 hospitals in the National Cardiovascular Data Registry Chest Pain—MI Registry. CKD status was defined as estimated glomerular filtration rate (eGFR) ≥90 mL/(min·1.73 m
2
; no CKD), eGFR <90 but ≥60 (mild), eGFR <60 but ≥30 (moderate), and eGFR <30 or dialysis (severe). We used multivariable logistic regression models to examine the interaction of race and CKD severity in invasive MI management.

Results:

Among those with MI, Black patients were more likely than White patients to have CKD (eGFR <90; 61.4% versus 58.5%;
P
<0.001). Among those with MI and CKD, Black patients were more likely than White patients to have severe CKD (21.2% versus 12.4%;
P
<0.001). Patients with CKD were more likely than those without CKD to have diabetes or heart failure; Black patients with CKD were more likely to have these comorbidities when compared with White patients with CKD (all
P
<0.0001). Black race and CKD were associated with a lower likelihood of invasive management (adjusted odds ratio, 0.78 [95% CI, 0.75–0.81]; adjusted odds ratio, 0.72 [95% CI, 0.70–0.74];
P
<0.001 for both). At eGFR levels ≥10, Black patients were significantly less likely than White patients to undergo invasive management.

Conclusions:
Black patients with MI and mild or moderate CKD were less likely to undergo invasive management compared with White patients with similar CKD severity. National efforts are needed to address racial disparities that may remain in the invasive management of MI.
‘This is a Call of God … or is it?’: Narratives about Humans, God and Eschatology in the Dutch Reformed Pietist Community during the COVID-19 Outbreak
Authors: Cinjee Tobias , Schaap-Jonker Hanneke 
Published: December 2021

Abstract
In this study, we examine which narratives were put forward by key figures of the Dutch reformed pietist community during the COVID-19 pandemic. We analyse sermons and news articles from the period March–November 2020. We find, as expected, a dominant narrative of COVID-19 as God’s judgment, a calling to repentance and an event which emphasizes the need for prayer. Although the pandemic was seen as a call by God, the systematic origin of the virus (God/Satan/natural phenomena) remained rather ambiguous. More often it was stated that ‘everything falls under His providence’. The earthly origin of the virus remained mostly unaddressed, as well as eschatological interpretations, contrary to our expectations. We conclude that the main narrative is a general message of repentance, rather than a concrete theological application to the dynamic of the virus, its origins and its subsequent spread. In some cases, virus ‘jargon’ even was used as a tool just to further accentuate general tendencies of reformed pietist theology.
Who Are Protected by the Fundamental Guarantees under International Humanitarian Law? Part 2: Breaking with the Control Requirement in Light of the icc Case Law
Authors: van Steenberghe Raphaël 
Published: December 2021

Abstract
International humanitarian law provides for fundamental guarantees, the content of which is similar irrespective of the nature of the armed conflict and which apply to individuals even if they do not fall into the categories of specifically protected persons under the Geneva Conventions. Those guarantees, all of which derive from the general requirement of human treatment, include prohibitions of specific conduct against persons, such as murder, cruel treatment, torture, sexual violence, or against property, such as pillaging. However, it is traditionally held that the entitlement to those guarantees depends upon two requirements: the ‘status requirement’, which basically means that the concerned persons must not or no longer take a direct part in hostilities, and the ‘control requirement’, which basically means that the concerned persons or properties must be under the control of a party to the armed conflict. This study argues in favour of breaking with these two requirements in light of the existing icc case law. That study is divided into two parts, with each part devoted to one requirement and made the object of a specific paper. The two papers follow the same structure. They start with general observations on the requirement concerned, examine the relevant icc case law and put forward several arguments in favour of an extensive approach to the personal scope of the fundamental guarantees. The first paper, which was published in the previous issue of this journal, dealt with the status requirement. It especially delved into the icc decisions in the Ntaganda case with respect to the issue of protection against intra-party violence. It advocated the applicability of the fundamental guarantees in such a context by rejecting the requirement of a legal status, on the basis of several arguments. Those arguments relied on ihl provisions protecting specific persons as well as on the potential for humanizing ihl on the matter and also on the approach making the status requirement relevant only when the fundamental guarantees apply in the conduct of hostilities. The second paper, which is published here, deals with the control requirement. It examines several icc cases in detail, including the Katanga and Ntaganda cases, in relation to the issue of the applicability of the fundamental guarantees in the conduct of hostilities. It is argued that the entitlement to those guarantees is not dependent upon any general control requirement, and that, as a result, some of these guarantees may apply in the conduct of hostilities. This concerns mainly those guarantees whose application or constitutive elements do not imply any physical control over the concerned persons or properties.