bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feline comorbidities: Recognition, diagnosis and management of the cushingoid diabetic
Authors: Cook Audrey K , Evans Jeremy B 
Published: January 2021

Practical relevance: Diabetes mellitus (DM) is a common feline endocrinopathy, and is often driven by underlying insulin resistance with associated pancreatic beta (β)-cell dysfunction. Although spontaneous hyperadrenocorticism (HAC) with hypercortisolemia (hypercortisolism) is relatively uncommon in cats, it is a well-established cause of insulin resistance and is routinely associated with DM in this species. Clinical challenges: Many of the clinical signs associated with feline HAC are subtle and may be attributed to concurrent DM or the aging process. Failure to recognize HAC in the diabetic cat can impact patient wellbeing and predispose the patient to progressive compromise. Unfortunately, it can be difficult to establish a diagnosis of HAC, as test results may be influenced by poor diabetic regulation, and protocols are different to those used in canine patients. Treatment options depend on the underlying cause, and often require careful, ongoing assessment and modulation of both adrenal function and insulin requirements. However, various approaches have been shown to either improve glycemic control in cats with sustained insulin dependence, or facilitate diabetic remission. Evidence base: This review summarizes the current literature on feline HAC, with a particular focus on cats with concurrent DM. The clinical findings that suggest HAC are discussed, along with an outline of diagnostic options and their limitations. Published outcomes for various medical options, surgical procedures and radiation therapy are provided. The authors also share their thoughts on the safe and effective management of cats with HAC and DM, with an emphasis on the anticipation and recognition of changing insulin requirements.
Congenital central corneal dermoid: A rare entity
Authors: Hameed Syed , Kaur Inderjeet , Singh Vivek , Mishra Dilip C , Reddy Jagadesh C 
Published: January 2021

Background: To understand the pathogenesis of a central corneal dermoid (CD) in a 12-day-old child, a comparison of CD specimen was done with limbal dermoid (LD) and cadaveric corneal (CC) specimens by immuno-histochemical staining. Methods: The child underwent penetrating keratoplasty for visual rehabilitation. The corneal tissue was sent for histo-pathological and immunochemistry evaluation. The corneal specimen obtained was compared the origin of central CD with LD and CC based on their antigenic expression profile. Results: Clinically over a period of 75 months post operatively the child maintained a clear graft. Hematoxylin and Eosin staining of LD had a typical morphology including stratified keratinized epithelium, hair shaft with pilo sebaceous glands, eccrine sweat glands, lymphocytes, and blood vessels. Immuno-histochemical staining showed positive stain for Cytokeratin 3 epithelial marker in the epithelium of CC, LD, and CD. Smooth muscle maker (SMA) was identified in LD and CD but not in the CC as it is devoid of blood vessels. Limbal stem cell maker (P63) was detected only in LD. Vimentin, a mesenchymal stem cell marker stained positively in all three tissues of CC, LD, and CD. Conclusions: Corneal dermoid showed positive staining for mesodermal tissue components compared to both ectodermal and mesodermal components in limbal dermoid suggesting possibly a different origin of corneal dermoid
Acts of pedagogical resistance: Marking out an ethical boundary against human technologies
Authors: McNair Lynn J , Blaisdell Caralyn , Davis John M , Addison Luke J 
Published: January 2021

This article highlights an action research project that sparked transformation regarding how early years practitioners documented children’s learning. The dominant discourse of standardisation and narrowing of early childhood education, encapsulated in the Organisation for Economic Co-operation and Development’s International Early Learning Study, has resulted in the ‘shaping’ and ‘testing’ of young children around the globe. The OECD has become very interested in early childhood education and is a very instrumental player today (Moss, 2018). Consequently, the testing of young children has been instigated by governments to ensure children gain the accepted knowledge, skills and dispositions required to be successful learners. Situated within this context of testing and standardisation, this article will share knowledge gained from a small action research project that took place in one Scottish early years setting. The study was stimulated by the early years practitioners of the setting, who strongly opposed the ‘reductionist’ formal ‘tick-box’ assessments produced by their local authority. These types of didactic formal assessments suggest that pedagogy is underpinned by a desire to tame, predict, prepare, supervise and evaluate learning. This article is of critical importance as it examines the imposition of didactic assessment from the practitioners’ perspective. The practitioners in the study contested that ‘tick-box’ assessments diminished children’s identities down to a list of judgements about their academic abilities, or lack thereof. The introduction of the ‘tick-box’ assessments presented a dilemma for the practitioners, in terms of the different views of the government and practitioners of what knowledge is worth knowing and what individuals and groups are able to learn. Many of the practitioners from the early childcare and learning setting positioned themselves and their work as being consciously different from what was going on in the wider sector. The early childcare and learning setting employed in this article introduced a new method to capture children’s learning, which they named the ‘Lived Story’ approach. In this article, we argue that Lived Stories are a form of narrative assessment which are designed to track children’s progress whilst respecting the complexity of their learning, their position within the learning process, the flow/fluidity of their ways of being and their ability to act in radical, creative and innovative ways. We conclude that by using ‘Lived Stories’ practitioners were able to lessen the surety of the language we use. The article highlights that as practitioners write Lived Stories and assess children’s progress they are freed to use language such as ‘wondering, puzzling, thinking, exploring’. In turn, we demonstrate that this language, and the ideas it enables, are on a continuum; a journey that spans a lifetime.
KRAS/BRAF mutations in brain arteriovenous malformations: A systematic review and meta-analysis
Authors: Bameri Omid , Salarzaei Morteza , Parooie Fateme 
Published: January 2021

Introduction Somatic KRAS mutations have been identified in the majority of brain arteriovenous malformations (AVM) specimens. The aim of our study was to evaluate the prevalence of Kirsten rat sarcoma (KRAS)/murine sarcoma viral oncogene homolog B1 (BRAF) mutations in brain AVM. Methods A systematic literature review was performed in November 2019. We reviewed MEDLINE/PubMed, Cochrane Library, and ClinicalTrials.gov for citation or ongoing trials from January 2010 to March 2020. Results 6 studies were identified as meeting the inclusion criteria of this review. The total frequency of KRAS mutations in 1726 patients with AVM was 55%. The prevalence of BRAF mutation was 7.5%. The prevalence of AVMs with grade 2 was the most (39%). Frontal and parietal lobes were the commonest sites of AVMs (21%). the most prevalent presentation of patients with AVM was hemorrhage (62%). Conclusion Our findings support a high prevalence of somatic activating mutations in KRAS and less commonly, BRAF in the overwhelming majority of brain AVMs. Practically and importantly, this pathway homogeneity in CNS arteriovenous malformations also supports the development of targeted therapies with RAS/RAF pathway inhibitors. However, more studies are needed to confirm this hypothesis.
Major post-prostate biopsy complications under antibiotic augmentation prophylaxis protocol
Authors: Rodrigues Antônio Antunes , Muglia Valdair , de Albuquerque Emanuel Veras , Mori Rafael Ribeiro , Feres Rafael Neuppmann , Nogueira André Beluso , e Almeida Vanessa Soares de Oliveira , Freire Guilherme Carvalho , Santos Henrique Amorim , dos Santos Sandra Conceição , Cologna Adauto José , Tucci Jr Silvio , dos Reis Rodolfo Borges 
Published: January 2021

Objective: To identify risk factors for major post-biopsy complications under augmented prophylaxis protocol. The risk factors already described mainly comprise outdated antibiotic prophylaxis protocols. Material and methods: This retrospective cohort study included patients that underwent transrectal ultrasound-guided biopsies, from 2011 to 2016. All patients had received antibiotic prophylaxis with ciprofloxacin and gentamicin. Patients were grouped according to the presence or absence of post-biopsy complications. Demographic variables and possible risk factors based on routine clinical assessment were registered. Correlation tests, univariate and multivariate analyses were used to identify risk factors for post-biopsy complications. Results: Of the 404 patients that were included, 25 (6.2%) presented 27 post-biopsy complications, distributed as follows: acute urinary retention ( n = 14, 3.5%), infections ( n = 11, 2.7%) and hemorrhage ( n = 2, 0.5%). On univariate analysis, patients who presented complications showed higher body mass index and post-voiding residual volumes. Multivariate analysis identified ethnicity and prostate-specific antigen (PSA) density as possible risk factors for biopsy complications. The presence of bacterial resistance identified by rectal swabs did not correlate with the incidence of complications and infections. Conclusions: Non-infectious post-biopsy complications were more frequent than infectious ones in this cohort. Higher post-voiding residual volumes and PSA density, that indicates prostate enlargement, were identified as risk factors and interpreted as secondary to bladder outlet obstruction. The higher body mass index and ethnicity were also identified as risk factors and attributed to the heterogeneity of the patients included. Level of evidence: Not applicable for this multicentre audit.
Anatomic reconstruction of the anterior cruciate ligament of the knee with or without reconstruction of the anterolateral ligament: A meta-analysis
Authors: Yin Jianjian , Yang Kaiyuan , Zheng Dong , Xu Nanwei 
Published: January 2021

Purpose: To systematically analyze the effectiveness between combined anterior cruciate ligament and anterolateral ligament reconstruction (ACL+ALLR) and isolated anterior cruciate ligament reconstruction (ACLR) for treatment of patients with injured ACL. Methods: We performed a systematic search in MEDLINE, EMBASE, PubMed, Web of Science, Cochrane databases, Chinese Biomedical Literature Database, CNKI, and Wanfang Data for all relevant studies. All statistical analysis was performed using Review Manager version 5.3. Results: A total of six articles with 460 study subjects were included, with 193 patients in ACL+ALL reconstruction group and 267 patients in ACL reconstruction group. The results of the meta-analysis showed that the ACL+ALL reconstruction group had significantly lower KT measured value (P < 0.00001), Lachman test positive-rate (P = 0.02), Pivot-shift test positive-rate (P < 0.00001) and graft rupture rate (P = 0.02) compared with the ACL reconstruction group. Higher IKDC score ( P < 0.00001) and Lysholm score ( P < 0.00001) were measured in ACL+ALL reconstruction group, while infection rate ( P = 0.86) and other complications rate ( P = 0.29) showed no significant differences between the two groups. Conclusions: Anatomic reconstruction of the ACL of the knee with reconstruction of the ALL indicates better postoperative knee function and clinical outcomes compared with isolated ACL reconstruction. The infection rate and other complications rate showed no significant difference between two groups.
Interleukin-6, C-reactive protein, fibrinogen, and risk of recurrence after ischaemic stroke: Systematic review and meta-analysis
Authors: McCabe JJ , O’Reilly E , Coveney S , Collins R , Healy L , McManus J , Mulcahy R , Moynihan B , Cassidy T , Hsu F , Worrall B , Murphy S , O’Donnell M , Kelly PJ 
Published: January 2021

Background Recent randomised trials showed benefit for anti-inflammatory therapies in coronary disease but excluded stroke. The prognostic value of blood inflammatory markers after stroke is uncertain and guidelines do not recommend their routine measurement for risk stratification. Methods We performed a systematic review and meta-analysis of studies investigating the association of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen and risk of recurrent stroke or major vascular events (MVEs). We searched EMBASE and Ovid Medline until 10/1/19. Random-effects meta-analysis was performed for studies reporting comparable effect measures. Results Of 2,515 reports identified, 39 met eligibility criteria (IL-6, n = 10; CRP, n = 33; fibrinogen, n = 16). An association with recurrent stroke was reported in 12/26 studies (CRP), 2/11 (fibrinogen) and 3/6 (IL-6). On random-effects meta-analysis of comparable studies, CRP was associated with an increased risk of recurrent stroke [pooled hazard ratio (HR) per 1 standard-deviation (SD) increase in loge-CRP (1.14, 95% CI 1.06–1.22, p < 0.01)] and MVEs (pooled HR 1.21, CI 1.10–1.34, p < 0.01). Fibrinogen was also associated with recurrent stroke (HR 1.26, CI 1.07–1.47, p < 0.01) and MVEs (HR 1.31, 95% CI 1.15–1.49, p < 0.01). Trends were identified for IL-6 for recurrent stroke (HR per 1-SD increase 1.17, CI 0.97–1.41, p = 0.10) and MVEs (HR 1.22, CI 0.96–1.55, p = 0.10). Conclusion Despite evidence suggesting an association between inflammatory markers and post-stroke vascular recurrence, substantial methodological heterogeneity was apparent between studies. Individual-patient pooled analysis and standardisation of methods are needed to determine the prognostic role of blood inflammatory markers and to improve patient selection for randomised trials of inflammatory therapies.
Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI
Authors: Assmann Julian C. , Farthing Don E. , Saito Keita , Maglakelidze Natella , Oliver Brittany , Warrick Kathrynne A. , Sourbier Carole , Ricketts Christopher J. , Meyer Thomas J. , Pavletic Steven Z. , Linehan W. Marston , Krishna Murali C. , Gress Ronald E. , Buxbaum Nataliya P. 
Published: January 2021

Abstract
Graft-versus-host disease (GVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (AHSCT). Definitive diagnosis of GVHD is invasive, and biopsies of involved tissues pose a high risk of bleeding and infection. T cells are central to GVHD pathogenesis, and our previous studies in a chronic GVHD mouse model showed that alloreactive CD4+ T cells traffic to the target organs ahead of overt symptoms. Because increased glycolysis is an early feature of T-cell activation, we hypothesized that in vivo metabolic imaging of glycolysis would allow noninvasive detection of liver GVHD as activated CD4+ T cells traffic into the organ. Indeed, hyperpolarized 13C-pyruvate magnetic resonance imaging detected high rates of conversion of pyruvate to lactate in the liver ahead of animals becoming symptomatic, but not during subsequent overt chronic GVHD. Concomitantly, CD4+ T effector memory cells, the predominant pathogenic CD4+ T-cell subset, were confirmed to be highly glycolytic by transcriptomic, protein, metabolite, and ex vivo metabolic activity analyses. Preliminary data from single-cell sequencing of circulating T cells in patients undergoing AHSCT also suggested that increased glycolysis may be a feature of incipient acute GVHD. Metabolic imaging is being increasingly used in the clinic and may be useful in the post-AHSCT setting for noninvasive early detection of GVHD.
TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target
Authors: Kennedy Emma , Coulter Eve , Halliwell Emma , Profitos-Peleja Nuria , Walsby Elisabeth , Clark Barnaby , Phillips Elizabeth H. , Burley Thomas A. , Mitchell Simon , Devereux Stephen , Fegan Christopher D. , Jones Christopher I. , Johnston Rosalynd , Chevassut Tim , Schulz Ralph , Seiffert Martina , Agathanggelou Angelo , Oldreive Ceri , Davies Nicholas , Stankovic Tatjana , Liloglou Triantafillos , Pepper Chris , Pepper Andrea G. S. 
Published: January 2021

Abstract
Chronic lymphocytic leukemia (CLL) remains incurable despite B-cell receptor–targeted inhibitors revolutionizing treatment. This suggests that other signaling molecules are involved in disease escape mechanisms and resistance. Toll-like receptor 9 (TLR9) is a promising candidate that is activated by unmethylated cytosine guanine dinucleotide–DNA. Here, we show that plasma from patients with CLL contains significantly more unmethylated DNA than plasma from healthy control subjects (P &lt; .0001) and that cell-free DNA levels correlate with the prognostic markers CD38, β2-microglobulin, and lymphocyte doubling time. Furthermore, elevated cell-free DNA was associated with shorter time to first treatment (hazard ratio, 4.0; P = .003). We also show that TLR9 expression was associated with in vitro CLL cell migration (P &lt; .001), and intracellular endosomal TLR9 strongly correlated with aberrant surface expression (sTLR9; r = 0.9). In addition, lymph node–derived CLL cells exhibited increased sTLR9 (P = .016), and RNA-sequencing of paired sTLR9hi and sTLR9lo CLL cells revealed differential transcription of genes involved in TLR signaling, adhesion, motility, and inflammation in sTLR9hi cells. Mechanistically, a TLR9 agonist, ODN2006, promoted CLL cell migration (P &lt; .001) that was mediated by p65 NF-κB and STAT3 transcription factor activation. Importantly, autologous plasma induced the same effects, which were reversed by a TLR9 antagonist. Furthermore, high TLR9 expression promoted engraftment and rapid disease progression in a NOD/Shi-scid/IL-2Rγnull mouse xenograft model. Finally, we showed that dual targeting of TLR9 and Bruton’s tyrosine kinase (BTK) was strongly synergistic (median combination index, 0.2 at half maximal effective dose), which highlights the distinct role for TLR9 signaling in CLL and the potential for combined targeting of TLR9 and BTK as a more effective treatment strategy in this incurable disease.
CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1
Authors: Belizaire Roger , Koochaki Sebastian H. J. , Udeshi Namrata D. , Vedder Alexis , Sun Lei , Svinkina Tanya , Hartigan Christina , McConkey Marie , Kovalcik Veronica , Bizuayehu Amanuel , Stanclift Caroline , Schenone Monica , Carr Steven A. , Padron Eric , Ebert Benjamin L. 
Published: January 2021

Abstract
Casitas B-lineage lymphoma (CBL) encodes an E3 ubiquitin ligase and signaling adaptor that regulates receptor and nonreceptor tyrosine kinases. Recurrent CBL mutations occur in myeloid neoplasms, including 10% to 20% of chronic myelomonocytic leukemia (CMML) cases, and selectively disrupt the protein’s E3 ubiquitin ligase activity. CBL mutations have been associated with poor prognosis, but the oncogenic mechanisms and therapeutic implications of CBL mutations remain incompletely understood. We combined functional assays and global mass spectrometry to define the phosphoproteome, CBL interactome, and mechanism of signaling activation in a panel of cell lines expressing an allelic series of CBL mutations. Our analyses revealed that increased LYN activation and interaction with mutant CBL are key drivers of enhanced CBL phosphorylation, phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) recruitment, and downstream phosphatidylinositol 3-kinase (PI3K)/AKT signaling in CBL-mutant cells. Signaling adaptor domains of CBL, including the tyrosine kinase–binding domain, proline-rich region, and C-terminal phosphotyrosine sites, were all required for the oncogenic function of CBL mutants. Genetic ablation or dasatinib-mediated inhibition of LYN reduced CBL phosphorylation, CBL-PIK3R1 interaction, and PI3K/AKT signaling. Furthermore, we demonstrated in vitro and in vivo antiproliferative efficacy of dasatinib in CBL-mutant cell lines and primary CMML. Overall, these mechanistic insights into the molecular function of CBL mutations provide rationale to explore the therapeutic potential of LYN inhibition in CBL-mutant myeloid malignancies.
Tryptophan metabolism is dysregulated in individuals with Fanconi anemia
Authors: Bartlett Allison L. , Romick-Rosendale Lindsey , Nelson Adam , Abdullah Sheyar , Luebbering Nathan , Bartlett Jamen , Brusadelli Marion , Palumbo Joseph S. , Lake Kelly , Litts Bridget , Duell Alexandra , Urbanski Annette , Lane Adam , Myers Kasiani C. , Wells Susanne I. , Davies Stella M. 
Published: January 2021

AbstractFanconi anemia (FA) is a complex genetic disorder associated with progressive marrow failure and a strong predisposition to malignancy. FA is associated with metabolic disturbances such as short stature, insulin resistance, thyroid dysfunction, abnormal body mass index (BMI), and dyslipidemia. We studied tryptophan metabolism in FA by examining tryptophan and its metabolites before and during the stress of hematopoietic stem cell transplant (HSCT). Tryptophan is an essential amino acid that can be converted to serotonin and kynurenine. We report here that serotonin levels are markedly elevated 14 days after HSCT in individuals with FA, in contrast to individuals without FA. Kynurenine levels are significantly reduced in individuals with FA compared with individuals without FA, before and after HSCT. Most peripheral serotonin is made in the bowel. However, serotonin levels in stool decreased in individuals with FA after transplant, similar to individuals without FA. Instead, we detected serotonin production in the skin in individuals with FA, whereas none was seen in individuals without FA. As expected, serotonin and transforming growth factor β (TGF-β) levels were closely correlated with platelet count before and after HSCT in persons without FA. In FA, neither baseline serotonin nor TGF-B correlated with baseline platelet count (host-derived platelets), only TGF-B correlated 14 days after transplant (blood bank-derived platelets). BMI was negatively correlated with serotonin in individuals with FA, suggesting that hyperserotonemia may contribute to growth failure in FA. Serotonin is a potential therapeutic target, and currently available drugs might be beneficial in restoring metabolic balance in individuals with FA.