bluuebunny/crossref_metadata_2025_split huggingface dataset:
The feasibility, reliability and concurrent validity of the MSReactor computerized cognitive screening tool in multiple sclerosis
Authors: Merlo Daniel , Darby David , Kalincik Tomas , Butzkueven Helmut , van der Walt Anneke 
Published: July 2019

Background: Multiple sclerosis (MS) cognitive tests are resource intensive and limited by practice effects that prevent frequent retesting. Brief, reliable and valid monitoring tools are urgently needed to detect subtle, subclinical cognitive changes in people with MS. Cognitive monitoring over time could contribute to a new definition of disease progression, supplementing routine clinical monitoring. Methods: MSReactor is a web-based battery that measures psychomotor (processing) speed, visual attention and working memory, using simple reaction time tasks. Clinic-based tasks were completed at baseline and 6 monthly with home testing 1–3 monthly. Acceptability, quality of life, depression and anxiety surveys were completed. We studied its correlation with the Symbol Digit Modalities Test, practice effects, test–retest reliability and the discriminative ability of MSReactor. Results: A total of 450 people with MS were recruited over 18 months, with 81% opting to complete home-based testing. Most participants (96%) would be happy (or neutral) to repeat the tasks again and just four reported the tasks made them ‘very anxious’. Persistence of home testing was high and practice effects stabilized within three tests. MSReactor tasks correlated with Symbol Digit Modalities Test scores and participants with MS performed slower than healthy controls. Conclusion: MSReactor is a scalable and reliable cognitive screening tool that can be used in the clinic and remotely. MSReactor task performance correlated with another highly validated cognitive test, was sensitive to MS and baseline predictors of cognitive performance were identified.
Shoulder arthroplasty in patients with upper extremity lymphedema may result in transient or permanent lymphedema worsening
Authors: Lee Julia , Nguyen Ngoc Tram V , Shukla Dave , Sperling John W , Cofield Robert H , Sanchez-Sotelo Joaquin 
Published: July 2019

Introduction Upper extremity lymphedema can complicate mastectomy, lymph node dissection, and radiation. The purpose of this study is to present the outcomes of shoulder arthroplasty in patients with lymphedema. Methods The 19 shoulders with a shoulder arthroplasty and lymphedema on the surgical side (6 anatomic, 12 reverse, 1 hemiarthroplasty) were followed for four years (1–10 years). There were 2 males and 17 females; average age was 67.8 (48–86) years. Breast carcinoma was the most common reason for lymphedema (75%). A dedicated lymphedema questionnaire could be completed for 14 shoulders. Results Pain improved from moderate or severe preoperatively to no or mild in 18 shoulders. Motion improved in elevation (55° preoperatively, 107° at last follow-up), external rotation (14°, 43°), and internal rotation (sacrum, L5). Complications included an acromion stress fracture with a deep infection (1), deep infection (1), superficial infection (1), and glenoid loosening (1). Lymphedema worsened in nine cases, but worsening was permanent in only four. Currently, lymphedema treatment is being performed by 93% of survey respondents. No patients reported lymphangitis or lymphangiosarcoma. Conclusion Shoulder arthroplasty for an upper extremity with lymphedema provides substantial improvements in pain and motion; however, infection is a concerning complication. Fifty percent of the patients will experience worsening of their lymphedema and in 20% worsening may be permanent.
Blastic natural killer cell lymphoma/leukaemia in a cat
Authors: Hirabayashi Miyuki , Chambers James K , Sugawara Mei , Ohmi Aki , Tsujimoto Hajime , Nakayama Hiroyuki , Uchida Kazuyuki 
Published: July 2019

Case summary A 7-year-old mixed-breed cat presented with subcutaneous oedema and erythema extending from the right axilla to the abdomen. Fine-needle aspiration of the subcutaneous lesion revealed large, atypical, round cells. A clonality analysis for the T-cell receptor-gamma and immunoglobulin heavy chain genes showed no clonal rearrangement. The presumed diagnosis was lymphoma and the cat was treated with prednisolone and L-asparaginase but died 78 days after initial treatment. At necropsy, an oedematous subcutaneous mass in the right axilla, hepatomegaly, splenomegaly and lymphadenopathy of the mediastinum and left axilla were observed. Histopathological examination revealed diffuse infiltration of large atypical round cells in the subcutaneous mass, liver, spleen, lymph nodes and bone marrow. Immunohistochemically, the tumour cells were strongly positive for CD56, and negative for CD3, CD20, CD79a, CD57, granzyme B and perforin. Based on these findings, the cat was diagnosed with blastic natural killer (NK) cell lymphoma/leukaemia. Relevance and novel information Here, we report the pathological and clinical findings of NK cell lymphoma/leukaemia in a cat. The antibody for human CD56, a diagnostic marker for human NK cell neoplasms, showed cross-reactivity with feline CD56 by immunohistochemistry and Western blotting analysis. The antibody could be a useful diagnostic marker for feline NK cell neoplasms.
Does Prior Anterior Cruciate Ligament Reconstruction Affect Outcomes of Subsequent Total Knee Arthroplasty? A Systematic Review
Authors: Chaudhry Zaira S. , Salem Hytham S. , Purtill James J. , Hammoud Sommer 
Published: July 2019

Background: Anterior cruciate ligament injury may accelerate knee osteoarthritis, and patients with a history of anterior cruciate ligament reconstruction (ACLR) tend to undergo total knee arthroplasty (TKA) at a greater rate than patients without a history of ACLR. Purpose: To compare clinical outcomes of TKA in patients with and without a history of ACLR through a systematic review. Study Design: Systematic review; Level of evidence, 3. Methods: A comprehensive search of the PubMed (MEDLINE), Cochrane Central, and SPORTDiscus databases from inception through November 2018 was performed to identify studies directly comparing outcomes of TKA between patients with and without a history of ipsilateral ACLR. Eligible studies were included in this review if they reported at least 1 outcome measure. Results: Included for review were 5 retrospective case-control studies collectively evaluating TKA outcomes in 318 patients (176 males, 142 females) with a history of ACLR and 455 matched controls. The mean age in the ACLR and control groups was 58.5 years and 60.9 years, respectively. The mean follow-up period after arthroplasty was 3.4 years in the ACLR group and 3.3 years in the control group. The mean time between ACLR and arthroplasty was 21.8 years. Three studies noted greater operative time in the ACLR group than in the control group. No differences in intraoperative blood loss were reported. Greater preoperative extension deficits were noted in the ACLR group in 2 studies. Two studies reported increased preoperative Knee Society Score function scores in the ACLR group, but no differences in postoperative subjective outcome scores were noted in any of the studies. One study reported increased incidence of periprosthetic joint infection and a higher total reoperation rate in the ACLR group, and another study reported an increased incidence of manipulation under anesthesia in the ACLR group. Conclusion: Short- and midterm subjective scores and functional outcomes of TKA appear to be comparable in patients with and without a history of ACLR, although the risk for reoperation after TKA may be greater in patients with prior ACLR. Surgeons should anticipate increased operative time in patients with a history of ACLR. However, the findings of this review must be interpreted within the context of its limitations.
Ultrasound findings in finger flexor tendons in systemic sclerosis: A cross-sectional pilot study
Authors: Hughes Michael , Manning Joanne , Moore Tonia , Herrick Ariane L , Chitale Sarang 
Published: July 2019

Objective: Finger flexion contractures are an important cause of disability in patients with systemic sclerosis; however, their pathophysiology is poorly understood. Our aim was to assess the feasibility of scanning finger flexor tendons in patients with systemic sclerosis and explore the ultrasound findings in these tendons, including measurement of finger flexor tendon complex. Methods: Grey-scale and power Doppler ultrasound assessment of the finger flexor tendon complex including tendon structure and surrounding soft tissue. Measurements of the finger flexor tendon complex (A1 pulley, tendon and palmar plate) were made. Feasibility was assessed by the number of fingers which could be measured. Results: We studied the second to fifth flexor tendons (n = 160) of both hands in 20 patients with systemic sclerosis, including early and established disease. We were able to assess the finger flexor tendon complex and make measurements of the flexor tendon and palmar plate in all (n = 40) and A1 pulley in almost all (n = 39) of the studied fingers. Common pathologies identified included peritendinous (n = 12) and soft tissue (n = 8) calcification. Tendon thickening was seen in six patients, but synovitis/tenosynovitis was rare. The A1 pulley was thickened in patients with systemic sclerosis (0.46 mm), in particular, those with diffuse cutaneous systemic sclerosis (0.50 mm). Conclusion: We were able to successfully assess, including making measurements of, the finger flexor tendon complex in patients with systemic sclerosis. Our study showed calcifications in the peritendinous areas and soft tissue and thickening of the A1 pulley. These findings may play a role in the pathophysiology of systemic sclerosis–hand contractures by causing mechanical impingement of the finger flexion mechanism. This pilot study will guide future research to look for potential (treatable) causes of finger flexion contractures in patients with systemic sclerosis.
Full-Thickness Macular Hole Formation After Repair of Rhegmatogenous and Tractional Retinal Detachment
Authors: Cunningham Matthew A. , Fink Samantha , Kumar Jaya B. , Mavrofrides Elias C. , Houston S.K. Steven , Jeroudi Abdallah M. , Barnard Thomas A. 
Published: July 2019

Purpose: This article reports the clinical features, associations, and outcomes of patients with full-thickness macular hole (MH) formation after pars plana vitrectomy for retinal detachment (RD). Methods: A retrospective, interventional case series is presented of consecutive patients undergoing surgical repair of MH following prior tractional or rhegmatogenous retinal detachment repair from September 2014 to October 2018 at a single vitreoretinal surgery practice. The size of the MH, presence of epiretinal membrane (ERM), rate of MH closure, and visual outcome following repair were evaluated. Results: A total of 996 cases of rhegmatogenous and tractional retinal detachment repair were identified. The average time from the RD surgery to MH diagnosis was 72 days. The incidence of subsequent MH formation in patients who underwent surgery was 0.8% (8/996). The presence of ERM prior to MH repair was noted in 50% of these cases (4/8). In cases with at least 3 months of postoperative follow-up, MH closure was achieved in 100% of eyes after a single surgery. The mean preoperative visual acuity (VA) was 2.06 logMAR (logarithm of the minimum angle of resolution) units (Snellen equivalent, 20/2296) and significantly improved to 0.72 logMAR units (Snellen, 20/104; P = .017) at the last follow-up after MH repair. All patients had improvement in VA at the final postoperative visit, with a VA of 20/200 or better achieved in 87.5% of cases. Conclusions: Although MH formation after successful RD repair is uncommon, favorable visual and anatomic results can be obtained.
Aqueous Cytokines in Sympathetic Ophthalmia Following Complications of Intravitreal Aflibercept
Authors: Juncal Verena R. , Cho Ryan , Bakshi Nupura , Ghaffar Hasan , Yucel Yeni Y. , Muni Rajeev H. 
Published: July 2019

Purpose: This article reports a case of sympathetic ophthalmia (SO) following complications from bilateral intravitreal aflibercept injections, including infectious endophthalmitis requiring vitreoretinal surgery in the left eye (OS) and sterile intraocular inflammation in the right eye (OD), and describes the aqueous cytokine profile of this patient. Methods: The patient was a 51-year-old man with SO. Cytokine levels in the aqueous humor of the sympathizing eye were measured at presentation. Results: A patient being treated with bilateral aflibercept injections for diabetic macular edema developed infectious endophthalmitis OS requiring a pars plana vitrectomy and sterile intraocular inflammation OD, which subsequently led to SO. Enucleation of the exciting eye (OS) was performed and histopathology confirmed the diagnosis. Cytokine levels in the sympathizing eye revealed high concentrations of intercellular adhesion molecule-1, inducible protein-10, and interleukin-8 and -10. Conclusions: SO can occur after vitreoretinal surgery for endophthalmitis in the exciting eye and sterile intraocular inflammation in the sympathizing eye following aflibercept injections.
Shared roles for Scl and Lyl1 in murine platelet production and function
Authors: Chiu Sung K. , Orive Stephanie L. , Moon Mitchell J. , Saw Jesslyn , Ellis Sarah , Kile Benjamin T. , Huang Yizhou , Chacon Diego , Pimanda John E. , Beck Dominik , Hamilton Justin R. , Tremblay Cedric S. , Curtis David J. 
Published: July 2019

Abstract
The stem cell leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1, and Runx1, mutations of Scl have not been observed as a cause of inherited thrombocytopenia. We postulated that functional redundancy with its closely related family member, lymphoblastic leukemia 1 (Lyl1) might explain this observation. To determine whether Lyl1 can substitute for Scl in megakaryopoiesis, we examined the platelet phenotype of mice lacking 1 or both factors in megakaryocytes. Conditional Scl knockout (KO) mice crossed with transgenic mice expressing Cre recombinase under the control of the mouse platelet factor 4 (Pf4) promoter generated megakaryocytes with markedly reduced but not absent Scl. These Pf4Sclc-KO mice had mild thrombocytopenia and subtle defects in platelet aggregation. However, Pf4Sclc-KO mice generated on an Lyl1-null background (double knockout [DKO] mice) had severe macrothrombocytopenia, abnormal megakaryocyte morphology, defective pro-platelet formation, and markedly impaired platelet aggregation. DKO megakaryocytes, but not single-knockout megakaryocytes, had reduced expression of Gata1, Fli1, Nfe2, and many other genes that cause inherited thrombocytopenia. These gene expression changes were significantly associated with shared Scl and Lyl1 E-box binding sites that were also enriched for Gata1, Ets, and Runx1 motifs. Thus, Scl and Lyl1 share functional roles in platelet production by regulating expression of partner proteins including Gata1. We propose that this functional redundancy provides one explanation for the absence of Scl and Lyl1 mutations in inherited thrombocytopenia.
A critical role of the Gas6-Mer axis in endothelial dysfunction contributing to TA-TMA associated with GVHD
Authors: Furukawa Miki , Wang Xintao , Ohkawara Hiroshi , Fukatsu Masahiko , Alkebsi Lobna , Takahashi Hiroshi , Harada-Shirado Kayo , Shichishima-Nakamura Akiko , Kimura Satoshi , Ogawa Kazuei , Ikezoe Takayuki 
Published: July 2019

Abstract
Endothelial dysfunction in the early phases of hematopoietic stem cell transplantation (HSCT) contributes to a common pathology between transplant-associated thrombotic microangiopathy (TA-TMA) and graft-versus-host disease (GVHD), which are serious complications of HSCT. Growth arrest-specific (Gas) 6 structurally belongs to the family of plasma vitamin K-dependent proteins working as a cofactor for activated protein C, and has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Serum Gas6 levels were significantly increased in HSCT patients with grade II to IV acute GVHD (aGVHD), and Gas6 and Mer expression levels were upregulated in aGVHD lesions of the large intestine and skin. The increased serum Gas6 levels were also correlated with elevated lactate dehydrogenase, d-dimer, and plasmin inhibitor complex values in HSCT patients with aGVHD. In human umbilical vein endothelial cells (ECs), exogenous Gas6 or the exposure of sera isolated from patients with grade III aGVHD to ECs induced the downregulation of thrombomodulin and the upregulation of PAI-1, as well as the upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which were inhibited by UNC2250, a selective Mer tyrosine kinase inhibitor. In mouse HSCT models, we observed hepatic GVHD with hepatocellular apoptosis, necrosis, and fibrosis, as well as TA-TMA, which is characterized pathologically by thrombosis formation in the microvasculature of the liver and kidney. Of note, intravenous administration of UNC2250 markedly suppressed GVHD and TA-TMA in these mouse HSCT models. Our findings suggest that the Gas6-Mer axis is a promising target for TA-TMA after GVHD.
Genome-wide CRISPR screens reveal genetic mediators of cereblon modulator toxicity in primary effusion lymphoma
Authors: Patil Ajinkya , Manzano Mark , Gottwein Eva 
Published: July 2019

Abstract
Genome-wide CRISPR/Cas9 screens represent a powerful approach to studying mechanisms of drug action and resistance. Cereblon modulating agents (CMs) have recently emerged as candidates for therapeutic intervention in primary effusion lymphoma (PEL), a highly aggressive cancer caused by Kaposi’s sarcoma-associated herpesvirus. CMs bind to cereblon (CRBN), the substrate receptor of the cullin-RING type E3 ubiquitin ligase CRL4CRBN, and thereby trigger the acquisition and proteasomal degradation of neosubstrates. Downstream mechanisms of CM toxicity are incompletely understood, however. To identify novel CM effectors and mechanisms of CM resistance, we performed positive selection CRISPR screens using 3 CMs with increasing toxicity in PEL: lenalidomide (LEN), pomalidomide (POM), and CC-122. Results identified several novel modulators of the activity of CRL4CRBN. The number of genes whose inactivation confers resistance decreases with increasing CM efficacy. Only inactivation of CRBN conferred complete resistance to CC-122. Inactivation of the E2 ubiquitin conjugating enzyme UBE2G1 also conferred robust resistance against LEN and POM. Inactivation of additional genes, including the Nedd8-specific protease SENP8, conferred resistance to only LEN. SENP8 inactivation indirectly increased levels of unneddylated CUL4A/B, which limits CRL4CRBN activity in a dominant negative manner. Accordingly, sensitivity of SENP8-inactivated cells to LEN is restored by overexpression of CRBN. In sum, our screens identify several novel players in CRL4CRBN function and define pathways to CM resistance in PEL. These results provide rationale for increasing CM efficacy on patient relapse from a less-efficient CM. Identified genes could finally be developed as biomarkers to predict CM efficacy in PEL and other cancers.
Evaluation of diffusion-weighted MRI and (18F) fluorothymidine-PET biomarkers for early response assessment in patients with operable non-small cell lung cancer treated with neoadjuvant chemotherapy
Authors: Carlin Dominic , Weller Alexander , Kramer Gem , Liu Yan , Waterton John C , Chiti Arturo , Sollini Martina , Joop de Langen A , O’Brien Mary E R , Urbanowicz Maria , Jacobs Bart KM , deSouza Nandita 
Published: July 2019

Objective: To correlate changes in the apparent diffusion coefficient (ADC) from diffusion-weighted (DW)-MRI and standardised uptake value (SUV) from fluorothymidine (18FLT)-PET/CT with histopathological estimates of response in patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant chemotherapy and track longitudinal changes in these biomarkers in a multicentre, multivendor setting. Methods: 14 patients with operable NSCLC recruited to a prospective, multicentre imaging trial (EORTC-1217) were treated with platinum-based neoadjuvant chemotherapy. 13 patients had DW-MRI and FLT-PET/CT at baseline (10 had both), 12 were re-imaged at Day 14 (eight dual-modality) and nine after completing chemotherapy, immediately before surgery (six dual-modality). Surgical specimens (haematoxylin-eosin and Ki67 stained) estimated the percentage of residual viable tumour/necrosis and proliferation index. Results: Despite the small numbers,significant findings were possible. ADCmedian increased (p < 0.001) and SUVmean decreased (p < 0.001) significantly between baseline and Day 14; changes between Day 14 and surgery were less marked. All responding tumours (>30% reduction in unidimensional measurement pre-surgery), showed an increase at Day 14 in ADC75th centile and reduction in total lesion proliferation (SUVmean x proliferative volume) greater than established measurement variability. Change in imaging biomarkers did not correlate with histological response (residual viable tumour, necrosis). Conclusion: Changes in ADC and FLT-SUV following neoadjuvant chemotherapy in NSCLC were measurable by Day 14 and preceded changes in unidimensional size but did not correlate with histopathological response. However, the magnitude of the changes and their utility in predicting (non-) response (tumour size/clinical outcome) remains to be established. Advances in knowledge: During treatment, ADC increase precedes size reductions, but does not reflect histopathological necrosis.
Lipidomics reveal the protective effects of a vegetable-derived isothiocyanate against retinal degeneration
Authors: Kwa Faith A. , Dulull Nabeela K. , Roessner Ute , Dias Daniel A. , Rupasinghe Thusitha W. 
Published: July 2019

Background:Age-related macular degeneration (AMD) is a leading cause of blindness in the ageing population. Without effective treatment strategies that can prevent disease progression, there is an urgent need for novel therapeutic interventions to reduce the burden of vision loss and improve patients’ quality of life. Dysfunctional innate immune responses to oxidative stress observed in AMD can be caused by the formation of oxidised lipids, whilst polyunsaturated fatty acids have shown to increase the risk of AMD and disease progression in affected individuals. Previously, our laboratory has shown that the vegetable-derived isothiocyanate, L-sulforaphane (LSF), can protect human adult pigment epithelial cells from oxidative damage by upregulating gene expression of the oxidative stress enzyme Glutathione-S-Transferase µ1. This study aims to validate the protective effects of LSF on human retinal cells under oxidative stress conditions and to reveal the key players in fatty acid and lipid metabolism that may facilitate this protection.Methods:Thein vitrooxidative stress model of AMD was based on the exposure of an adult retinal pigment epithelium-19 cell line to 200µM hydrogen peroxide. Percentage cell proliferation following LSF treatment was measured using tetrazolium salt-based assays. Untargeted fatty acid profiling was performed by gas chromatography-mass spectrometry. Untargeted lipid profiling was performed by liquid chromatography-mass spectrometry.Results:Under hydrogen peroxide-induced oxidative stress conditions, LSF treatment induced dose-dependent cell proliferation. The key fatty acids that were increased by LSF treatment of the retinal cells include oleic acid and eicosatrienoic acid. LSF treatment also increased levels of the lipid classes phosphatidylcholine, cholesteryl ester and oxo-phytodienoic acid but decreased levels of phosphatidylethanolamine lipids.Conclusions:We propose that retinal cells at risk of oxidative damage and apoptosis can be pre-conditioned with LSF to regulate levels of selected fatty acids and lipids known to be implicated in the pathogenesis and progression of AMD.