bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three-antibody classifier for muscle invasive urothelial carcinoma and its correlation with p53 expression
Authors: Olkhov-Mitsel Ekaterina , Hodgson Anjelica , Liu Stanley K , Vesprini Danny , Xu Bin , Downes Michelle R 
Published: June 2021

AimsTo assess the utility of a three-antibody immunohistochemistry panel to classify muscle invasive bladder cancers (MIBCs) in correlation with morphological features and p53 status.MethodsA retrospective review of 243 chemotherapy naïve MIBC cystectomy specimens was performed to assess morphological features. A tissue microarray was sequentially stained with CK5/6, GATA-3 and p16. Subgroups were assigned as basal-like (CK5/6+, GATA3−) and luminal (CK5/6−, GATA3+), with the latter subdivided into genomically unstable (GU, p16+) and urothelial like (Uro, p16−) subgroups. p53 staining was assessed as abnormal/wild type. Cases from the The Cancer Genome Atlas (TCGA) portal were assessed as external validation.ResultsWe identified 78.8% luminal, 21.2% basal cases within our cohort and 63.4% luminal, 36.6% basal in the TCGA dataset. Divergent differentiation (p<0.001) was significantly associated with basal-subtype cases in both cohorts. Within the luminal subgroup (n=186), 81 cases were classified as GU and 105 as Uro. Abnormal p53 staining was noted in 48.0% of basal, 80.2% GU and 38.1% Uro cases. Further, basal-subtype tumours significantly correlated with disease-specific death compared with Uro cases in multivariate survival analysis.ConclusionsThis retrospective study demonstrates the potential utility of a three-antibody immunohistochemistry panel to differentiate luminal and basal MIBC.
Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma
Authors: Lynch Kevin T , Young Samuel J , Meneveau Max O , Wages Nolan A , Engelhard Victor H , Slingluff Jr Craig L , Mauldin Ileana S 
Published: June 2021

BackgroundTertiary lymphoid structures (TLSs) are immune aggregates in peripheral tissues that may support adaptive immune responses. Their presence has been associated with clinical response to checkpoint blockade therapy (CBT), but it is unknown whether TLS have prognostic significance independent of CBT in melanoma. We hypothesized that TLS in melanoma metastases would be associated with increased intratumoral lymphocyte infiltration, but that the intra-TLS immunological milieu would be distinct from the intratumoral immunological milieu. We also hypothesized that the presence of TLS would be associated with improved survival, and that TLS maturation or intra-TLS lymphocyte activity would also correlate with survival.MethodsCutaneous melanoma metastases (CMM) from 64 patients were evaluated by multiplex immunofluorescence for the presence and maturation status of TLS. Intra-TLS lymphocyte density, proliferation and B-cell Ig somatic hypermutation (AID+) were analyzed, as were markers of T-cell exhaustion and Th1/Tc1 differentiation. Associations between TLS maturation and intra-TLS immunologic activity were assessed, as well as associations with intratumoral immune cell infiltration. Independent associations with overall survival (OS) were assessed using log-rank tests and Cox proportional hazards models.ResultsTLS were identified in 30 (47%) of 64 CMM (TLS+) and were associated with increased intratumoral lymphocyte infiltration. However, proliferation of intra-TLS lymphocytes did not correlate with intratumoral lymphocyte proliferation. Most were early TLS; however, subsets of primary or secondary follicle-like TLS were also present. TLS+ lesions were associated with lower risk of tumor recurrence after metastasectomy and with improved OS in multivariate analyses (HR 0.51, p=0.04). OS was longer for TLS with low fractions of CD21+ B-cells (HR 0.29, p=0.02) and shorter for those with low AID+ fraction of B-cells (HR 2.74, p=0.03).ConclusionsThe presence of TLS in CMMs is associated with improved OS in patients treated with surgery before CBT, but TLS vary widely in maturation state, in proportions of proliferating T and B cells, and in markers of B cell function, including AID and CD21. Importantly, these features have additional prognostic significance, which suggest that some TLS may have regulatory function, while others functioning to support antigen-driven immune responses, depending on the cellular composition and activation status.
Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases
Authors: Grunseich Christopher , Sarkar Nathan , Lu Joyce , Owen Mallory , Schindler Alice , Calabresi Peter A , Sumner Charlotte J , Roda Ricardo H , Chaudhry Vinay , Lloyd Thomas E , Crawford Thomas O , Subramony S H , Oh Shin J , Richardson Perry , Tanji Kurenai , Kwan Justin Y , Fischbeck Kenneth H , Mankodi Ami 
Published: June 2021

BackgroundWe used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres.MethodsWES was performed on 66 individuals with neurogenetic diseases using candidate gene filters and stringent algorithms for assessing sequence variants. Pathogenic or likely pathogenic missense variants were interpreted using in silico prediction tools, family segregation analysis, previous publications of disease association and relevant biological assays.ResultsMolecular diagnosis was achieved in 39% (n=26) including 59% of childhood-onset cases and 27% of late-onset cases. Overall, 37% (10/27) of myopathy, 41% (9/22) of neuropathy, 22% (2/9) of MND and 63% (5/8) of complex phenotypes were given genetic diagnosis. Twenty-seven disease-associated variants were identified including ten novel variants inFBXO38, LAMA2, MFN2, MYH7, PNPLA6, SH3TC2andSPTLC1. Single-nucleotide variants (n=10) affected conserved residues within functional domains and previously identified mutation hot-spots. Established pathogenic variants (n=16) presented with atypical features, such as optic neuropathy in adult polyglucosan body disease, facial dysmorphism and skeletal anomalies in cerebrotendinous xanthomatosis, steroid-responsive weakness in congenital myasthenia syndrome 10. Potentially treatable rare diseases were diagnosed, improving the quality of life in some patients.ConclusionsIntegrating deep phenotyping, gene filter algorithms and biological assays increased diagnostic yield of exome sequencing, identified novel pathogenic variants and extended phenotypes of difficult to diagnose rare neurogenetic disorders in an outpatient clinic setting.
TNF-α inhibitors used as steroid-sparing maintenance monotherapy in parenchymal CNS sarcoidosis
Authors: Hilezian Frédéric , Maarouf Adil , Boutiere Clemence , Rico Audrey , Demortiere Sarah , Kerschen Philippe , Sene Thomas , Bensa-Koscher Caroline , Giannesini Claire , Capron Jean , Mekinian Arsene , Camdessanché Jean-Philippe , Androdias Géraldine , Marignier Romain , Collongues Nicolas , Casez Olivier , Coclitu Catalina , Vaillant Mathieu , Mathey Guillaume , Ciron Jonathan , Pelletier Jean , Audoin Bertrand 
Published: June 2021

ObjectiveTo assess the efficacy of tumour necrosis factor-α (TNF-α) inhibitors used as steroid-sparing monotherapy in central nervous system (CNS) parenchymal sarcoidosis.MethodsThe French Multiple Sclerosis and Neuroinflammation Centers retrospectively identified patients with definite or probable CNS sarcoidosis treated with TNF-α inhibitors as steroid-sparing monotherapy. Only patients with CNS parenchymal involvement demonstrated by MRI and imaging follow-up were included. The primary outcome was the minimum dose of steroids reached that was not associated with clinical or imaging worsening during a minimum of 3 months after dosing change.ResultsOf the identified 38 patients with CNS sarcoidosis treated with TNF-α inhibitors, 23 fulfilled all criteria (13 females). Treatments were infliximab (n=22) or adalimumab (n=1) for a median (IQR) of 24 (17–40) months. At treatment initiation, the mean (SD) age was 41.5 (10.5) years and median (IQR) disease duration 22 (14–49.5) months. Overall, 60% of patients received other immunosuppressive agents before a TNF-α inhibitor. The mean (SD) minimum dose of steroids was 31.5 (33) mg before TNF-α inhibitor initiation and 6.5 (5.5) mg after (p=0.001). In all, 65% of patients achieved steroids dosing <6 mg/day; 61% showed clinical improvement, 30% stability and 9% disease worsening. Imaging revealed improvement in 74% of patients and stability in 26%.ConclusionTNF-α inhibitors can greatly reduce steroids dosing in patients with CNS parenchymal sarcoidosis, even refractory.Classification of evidenceThis study provides Class IV evidence that TNF-α inhibitor used as steroid-sparing monotherapy is effective for patients with CNS parenchymal sarcoidosis.
Intravenous immunoglobulin treatment for mild Guillain-Barré syndrome: an international observational study
Authors: Verboon Christine , Harbo Thomas , Cornblath David R , Hughes Richard A C , van Doorn Pieter A , Lunn Michael P , Gorson Kenneth C , Barroso Fabio , Kuwabara Satoshi , Galassi Giuliana , Lehmann Helmar C , Kusunoki Susumu , Reisin Ricardo C , Binda Davide , Cavaletti Guido , Jacobs Bart C 
Published: June 2021

ObjectiveTo compare the disease course in patients with mild Guillain-Barré syndrome (GBS) who were treated with intravenous immunoglobulin (IVIg) or supportive care only.MethodsWe selected patients from the prospective observational International GBS Outcome Study (IGOS) who were able to walk independently at study entry (mild GBS), treated with one IVIg course or supportive care. The primary endpoint was the GBS disability score four weeks after study entry, assessed by multivariable ordinal regression analysis.ResultsOf 188 eligible patients, 148 (79%) were treated with IVIg and 40 (21%) with supportive care. The IVIg group was more disabled at baseline. IVIg treatment was not associated with lower GBS disability scores at 4 weeks (adjusted OR (aOR) 1.62, 95% CI 0.63 to 4.13). Nearly all secondary endpoints showed no benefit from IVIg, although the time to regain full muscle strength was shorter (28 vs 56 days, p=0.03) and reported pain at 26 weeks was lower (n=26/121, 22% vs n=12/30, 40%, p=0.04) in the IVIg treated patients. In the subanalysis with persistent mild GBS in the first 2 weeks, the aOR for a lower GBS disability score at 4 weeks was 2.32 (95% CI 0.76 to 7.13). At 1 year, 40% of all patients had residual symptoms.ConclusionIn patients with mild GBS, one course of IVIg did not improve the overall disease course. The certainty of this conclusion is limited by confounding factors, selection bias and wide confidence limits. Residual symptoms were often present after one year, indicating the need for better treatments in mild GBS.
Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias
Authors: Alcolea Daniel , Delaby Constance , Muñoz Laia , Torres Soraya , Estellés Teresa , Zhu Nuole , Barroeta Isabel , Carmona-Iragui María , Illán-Gala Ignacio , Santos-Santos Miguel Ángel , Altuna Miren , Sala Isabel , Sánchez-Saudinós Mª Belén , Videla Laura , Valldeneu Sílvia , Subirana Andrea , Pegueroles Jordi , Hirtz Christophe , Vialaret Jérôme , Lehmann Sylvain , Karikari Thomas K , Ashton Nicholas J , Blennow Kaj , Zetterberg Henrik , Belbin Olivia , Blesa Rafael , Clarimón Jordi , Fortea Juan , Lleó Alberto 
Published: June 2021

ObjectivesAll categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer’s disease (AD) through an easy and minimally invasive approach.MethodsWe measured Aβ, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination.ResultsThe plasma Aβ composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A–T– participants. There was a moderate correlation between plasma Aβ composite and CSF Aβ1–42/Aβ1–40 (Rho=−0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001).ConclusionsPlasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach.
Sofosbuvir with daclatasvir and the outcomes of patients with COVID-19: a systematic review and meta-analysis with GRADE assessment
Authors: Zein Ahmad Fariz Malvi Zamzam , Sulistiyana Catur Setiya , Raffaello Wilson Matthew , Wibowo Arief , Pranata Raymond 
Published: June 2021

AbstractPurposeThis systematic review and meta-analysis aimed to evaluate the effect of sofosbuvir/daclatasvir (SOF/DCV) on mortality, the need for intensive care unit (ICU) admission or invasive mechanical ventilation (IMV) and clinical recovery in patients with COVID-19.MethodsWe performed a systematic literature search through the PubMed, Scopus and Embase from the inception of databases until 6 April 2021. The intervention group was SOF/DCV, and the control group was standard of care. The primary outcome was mortality, defined as clinically validated death. The secondary outcomes were (1) the need for ICU admission or IMV and (2) clinical recovery. The pooled effect estimates were reported as risk ratios (RRs).ResultsThere were four studies with a total of 231 patients in this meta-analysis. Three studies were randomised controlled trial, and one study was non-randomised. SOF/DCV was associated with lower mortality (RR: 0.31 (0.12, 0.78); p=0.013; I2: 0%) and reduced need for ICU admission or IMV (RR: 0.35 (0.18, 0.69); p=0.002; I2: 0%). Clinical recovery was achieved more frequently in the SOF/DCV (RR: 1.20 (1.04, 1.37); p=0.011; I2: 21.1%). There was a moderate certainty of evidence for mortality and need for ICU/IMV outcome, and a low certainty of evidence for clinical recovery. The absolute risk reductions were 140 fewer per 1000 for mortality and 186 fewer per 1000 for the need for ICU/IMV. The increase in clinical recovery was 146 more per 1000.ConclusionSOF/DCV may reduce mortality rate and need for ICU/IMV in patients with COVID-19 while increasing the chance for clinical recovery.Protocol registrationPROSPERO: CRD42021247510.
Efficacy and safety of intra-articular therapies in rheumatic and musculoskeletal diseases: an overview of systematic reviews
Authors: Rodriguez-García Sebastián Cruz , Castellanos-Moreira Raul , Uson Jacqueline , Naredo Esperanza , O'Neill Terence W , Doherty Michael , Boesen Mikael , Pandit Hemant , Möller Parera Ingrid , Vardanyan Valentina , Terslev Lene , Kampen Will Uwe , D'Agostino Maria Antonieta , Berenbaum Francis , Nikiphorou Elena , Pitsillidou Irene , de la Torre-Aboki Jenny , Carmona Loreto 
Published: June 2021

ObjectiveTo summarise the evidence on intra-articular therapies (IAT) to inform the 2020 EULAR recommendations.MethodsAn overview of systematic reviews (SR) including randomised-controlled trials (RCTs) of IAT in adults with arthropathies was performed up to July 2020. Pain, function, and frequency of adverse events were the main efficacy and safety outcomes, respectively. Quality was assessed with the A MeaSurement Tool to Assess Systematic Reviews (AMSTAR)-2 tool.ResultsOf 184 references identified, 16 met the inclusion criteria, and a search of their reference lists identified 16 additional SRs. After quality assessment, 29 were finally included. Of these, 18 focused on knee osteoarthritis (KOA), 6 on hip osteoarthritis (HOA), 3 on shoulder capsulitis (SC), and 3 on rheumatoid arthritis. Overall, hyaluronic acid showed a small effect on pain and function in KOA but not in HOA or shoulder capsulitis. Intra-articular glucocorticoids showed a small effect in pain and function in KOA and function in HOA and SC. Platelet-rich plasma showed benefit in pain and function in KOA but not in HOA. Mesenchymal stem cells behaved similarly. Most SR results were of moderate quality and RCTs included often presented a high risk of bias, mainly due to inadequate blinding and heterogeneous results. All interventions were well tolerated with no clear safety differences.ConclusionsThis overview underlines that most IAT currently used in KOA, HOA, and SC exert small effects and are well tolerated. However, no firm conclusions can be drawn for inflammatory arthritis due to the limited data found.
Semi-synthesis of novel buprenorphine derivatives and their anti-nociceptive properties and dependency potential
Authors: Hasanpour Zahra , Salehi Peyman , Bunch Lennart , Khoramjouy Mona , Bararjanian Morteza , Staerk Dan , Faizi Mehrdad 
Published: June 2021

Novel 1,2,3-triazole-tethered N-norbuprenorphine derivatives with an OMe or OH group at the C3 position were synthesized alongside with evaluation of their analgesic properties. The analgesic activities of the resulting library were investigated via tail flick test in mice. Our results indicated that 10b and 10e were as effective as the starting compounds 8 and 9 with ED50 equal to 16.59 and 19.44 mg/kg, respectively. To investigate the effect of a methyl group at C3 on biological properties, the most active compounds were O-demethylated and their anti-nociceptive effects were assessed. The new O-demethylated derivatives (11b and 11e) showed better analgesic properties than the parent compounds with ED50 of 14.73 and 15.80 mg/kg, respectively. Naloxone prevented the analgesic effect of the synthesized compounds, indicating that the opioid receptors are highly involved in the anti-nociceptive effects. The potential dependency effects of the most potent derivatives were studied by condition place preference test in mice and compared with morphine and buprenorphine. Interestingly, 10b, 10e, 11b, and 11e did not show any dependency effect, similar to buprenorphine.
Effect of gravitational wave on shadow of a Schwarzschild black hole
Authors: Wang Mingzhi , Chen Songbai , Jing Jiliang 
Published: June 2021

AbstractWe have studied the shadows of a Schwarzschild black hole under a special polar gravitational perturbation, which is a particular solution of Einstein equations expanded up to first order. It is shown that the black hole shadow changes periodically with time and the change of shadow depends on the Legendre polynomial order parameter l and the frequency $$\sigma $$
σ
of gravitational wave. For the odd order of Legendre polynomial, the center of shadow oscillates along the direction which is vertical to equatorial plane. For even l, the center of shadow does not move, but the shadow alternately stretches and squeezes with time along the vertical direction. Moreover, the presence of the gravitational wave leads to the self-similar fractal structures appearing in the boundary of the black hole shadow. We also find that this special gravitational wave has a greater influence on the vertical direction of black hole shadow.
Expressiveness and Nash Equilibrium in Iterated Boolean Games
Authors: Gutierrez Julian , Harrenstein Paul , Perelli Giuseppe , Wooldridge Michael 
Published: June 2021

We define and investigate a novel notion of expressiveness for temporal logics that is based on game theoretic equilibria of multi-agent systems. We use
iterated Boolean games
as our abstract model of multi-agent systems [Gutierrez et al. 2013, 2015a]. In such a game, each agent

has a goal

, represented using (a fragment of)

Linear Temporal Logic (

)

. The goal

captures agent

’s preferences, in the sense that the models of

represent system behaviours that would satisfy

. Each player controls a subset of Boolean variables

, and at each round in the game, player

is at liberty to choose values for variables

in any way that she sees fit. Play continues for an infinite sequence of rounds, and so as players act they collectively trace out a model for

, which for every player will either satisfy or fail to satisfy their goal. Players are assumed to act strategically, taking into account the goals of other players, in an attempt to bring about computations satisfying their goal. In this setting, we apply the standard game-theoretic concept of (pure) Nash equilibria. The (possibly empty) set of Nash equilibria of an iterated Boolean game can be understood as inducing a set of computations, each computation representing one way the system could evolve if players chose strategies that together constitute a Nash equilibrium. Such a set of equilibrium computations expresses a temporal property—which may or may not be expressible within a particular

fragment. The new notion of expressiveness that we formally define and investigate is then as follows:

What temporal properties are characterised by the Nash equilibria of games in which agent goals are expressed in specific fragments of

? We formally define and investigate this notion of expressiveness for a range of

fragments. For example, a very natural question is the following:

Suppose we have an iterated Boolean game in which every goal is represented using a particular fragment

of

: is it then always the case that the equilibria of the game can be characterised within

?

We show that this is not true in general.
Twizzler: A
Data-centric
OS for Non-volatile Memory
Authors: Bittman Daniel , Alvaro Peter , Mehra Pankaj , Long Darrell D. E. , Miller Ethan L. 
Published: June 2021

Byte-addressable, non-volatile memory (NVM) presents an opportunity to rethink the entire system stack. We present Twizzler, an operating system redesign for this near-future. Twizzler removes the kernel from the I/O path, provides programs with memory-style access to persistent data using small (64 bit), object-relative cross-object pointers, and enables simple and efficient long-term sharing of data both between applications and between runs of an application. Twizzler provides a clean-slate programming model for persistent data, realizing the vision of
Unix
in a world of persistent RAM.

We show that Twizzler is simpler, more extensible, and more secure than existing I/O models and implementations by building software for Twizzler and evaluating it on NVM DIMMs. Most persistent pointer operations in Twizzler impose less than 0.5 ns added latency. Twizzler operations are up to

faster than
Unix
, and SQLite queries are up to

faster than on PMDK. YCSB workloads ran 1.1–

faster on Twizzler than on native and NVM-optimized SQLite backends.