Miracle-dz/UniFAR-FTUs huggingface dataset:
True First-Pass Effect.

Background and Purpose- It has been hypothesized that in stroke patients, complete reperfusion (modified Thrombolysis in Cerebral Infarction; mTICI 3) after a single thrombectomy pass is a predictor for favorable outcome (modified Rankin Scale score, 0-2), but a true first-pass effect defined as improved clinical outcome after complete reperfusion with one versus multiple passes has not yet been specifically addressed in the literature. Methods- We compared clinical outcome of 164 consecutive patients with occlusions in the anterior circulation and known symptom onset, in whom we achieved complete reperfusion (mTICI 3), depending on whether complete reperfusion was achieved after a single thrombectomy pass (n=62) or multiple thrombectomy passes (n=102). To adjust for confounding factors such as prolonged time spans between symptom onset and reperfusion, additional administration of intra-arterial thrombolysis, and clot localization, we also compared clinical outcome of our first-pass group with a matched cohort (n=54) and a superselective subgroup of first-pass patients (only M1 occlusions, no additional intra-arterial thrombolysis; n=46) with its matched cohort (n=24). Results- Multivariable analysis of our cohort of 164 nonmatched patients revealed that there was a significant association between first-pass complete reperfusion and favorable clinical outcome ( P=0.013). This was confirmed in our case-control analyses ( P=0.010 and P=0.042). In our matched cohorts, favorable clinical outcome was seen almost twice as often if complete reperfusion was achieved after one pass (62% and 67% versus 36% and 37%), and odds for favorable outcome were 2.4 to 3.2× higher (CIs, 1.1-4.8 and 1.0-9.9). Conclusions- First-pass complete reperfusion is an independent factor for favorable outcome and should be aimed for in mechanical thrombectomy.
Sub‐Micromolar Pulse Dipolar EPR Spectroscopy Reveals Increasing CuII‐labelling of Double‐Histidine Motifs with Lower Temperature

Abstract Electron paramagnetic resonance (EPR) distance measurements are making increasingly important contributions to the studies of biomolecules by providing highly accurate geometric constraints. Combining double‐histidine motifs with CuII spin labels can further increase the precision of distance measurements. It is also useful for proteins containing essential cysteines that can interfere with thiol‐specific labelling. However, the non‐covalent CuII coordination approach is vulnerable to low binding‐affinity. Herein, dissociation constants (K D) are investigated directly from the modulation depths of relaxation‐induced dipolar modulation enhancement (RIDME) EPR experiments. This reveals low‐ to sub‐μm CuII K Ds under EPR distance measurement conditions at cryogenic temperatures. We show the feasibility of exploiting the double‐histidine motif for EPR applications even at sub‐μm protein concentrations in orthogonally labelled CuII–nitroxide systems using a commercial Q‐band EPR instrument.
Conjunctival colonisation and antibiotic resistance of coagulase-negative Staphylococcus after cataract surgery: a 6-month longitudinal study at a medical centre in Taiwan

Objective To explored 6-month longitudinal changes in conjunctival colonisation and antibiotic resistance profiles of coagulase-negative Staphylococcus (CNS) after cataract surgery with 1 month tobramycin treatment. Design Prospective cohort study between 1 August 2012, and 31 July 2013. Setting A single medical centre in Taiwan. Participants A total of 128 Taiwanese patients with 46.9% of male participants. Interventions Samples from the conjunctival sacs of both operation (OP) and non-OP eyes were obtained separately before cataract surgery and at 1, 3 and 6 months after surgery. Tobramycin (0.3%) treatment was applied four times daily for 1 month postoperatively. Main outcome measure Identification of CNS isolates and their antibiotic susceptibility by using disk diffusion or E-test. Results CNS was detected in 24.2% of patients at baseline. During postoperative follow-up, the CNS colonisation rate did not decrease in either eye but showed an increasing trend in the OP eyes at 1 month (p=0.06). The colonisation rate showed no significant difference between the OP and non-OP eyes from baseline to a specific follow-up. We observed a significant increase (p<0.05) in resistance to tobramycin at 1 month and to ciprofloxacin at 3 months in the OP eyes and to trimethoprim/sulfamethoxazole at 1 month and 3 months and to oxacillin at 6 months in the non-OP eyes. Conclusions During the 6-month postoperative follow-up, 0.3% tobramycin administration failed to reduce CNS colonisation but increased resistance to several antibiotics. Postoperative antibiotic treatment may be replaced by other evidence-endorsed prophylactic routines.
INVESTIGATING OUTCOMES OF ADOLESCENTS AND YOUNG ADULTS (10-24 YEARS OF AGE) LOST TO FOLLOW-UP FROM TUBERCULOSIS TREATMENT IN GABORONE, BOTSWANA.

This retrospective study investigated outcomes among lost to follow-up (LTFU) adolescents and young adults (AYAs: 10-24 years of age) with tuberculosis (TB) registered from 2008 to 2014 in Gaborone, using surveillance data. Of 68 LTFU AYAs, 16 repeated treatment; 8 completed and 6 were again LTFU. Of 4 confirmed deaths, 3 had TB/HIV coinfection. Approaches to improve AYA retention in TB care are needed.
Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses

ABSTRACT Epigenetic mechanisms such as genomic imprinting have a fundamental role in embryo and fetal development. Hence, we here studied expression levels of epigenetic modifiers and imprinted genes in cases of ididopathic spontaneous abortion (SA). Thirty-five placental samples and 35 matched fetal tissues from second trimester SA were analysed; including 16 controls (placental and fetal infections as the known cause of spontaneous abortion) and 19 idiopathic SA cases. Transcript levels of epigenetic regulators and imprinted genes were measured by qRT-PCR and methylation at imprinted genes was studied by bisulfite genomic sequencing and MS-MLPA. Global DNA hydroxymethylation (5-hmC) levels were measured by an ELISA-based assay. We observed an upregulation of TET2 and TET3 in placental samples from idiopathic SA cases; however, no significant difference in global 5-hmC levels was observed. On the contrary, in fetal tissues, TET3 was markedly downregulated in idiopathic SA, showing an opposite trend to that observed in placental tissue. IGF2 and CDKN1C were upregulated and MEST downregulated in placentas from idiopathic SA cases; concordantly, IGF2 was also upregulated in fetal tissues from idiopathic SA cases. Although not reaching statistical significance, an increase in methylation levels of MEST, KvDMR1 and H19 DMRs was observed in idiopathic SA cases, concordantly with the observed changes in expression. Our study reveals, for the first time, deregulation of epigenetic modifiers and imprinted genes in both placental and fetal tissues from idiopathic SA cases in the second trimester of pregnancy, indicating a critical role during pregnancy.
Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes

Inhibition of tyrosine phosphatase PTP1B in mouse and human islets promotes islet revascularization and improves graft survival and function. Revascularizing eye-lets Pancreatic islet transplantation is a potentially promising therapy for type 1 diabetes, but poor revascularization hinders islet long-term viability. Figueiredo et al. studied the role of protein tyrosine phosphatase 1B (PTP1B) in regulating islet vascularization. Islets from PTP1B−/− mice retained more endothelial cells during in vitro culture and restored normoglycemia when transplanted into the anterior chamber of the eye in diabetic mice. Short hairpin RNA knockdown of PTP1B in human islets yielded similar effects. Deletion of PTP1B increased vascular endothelial growth factor A secretion by activating peroxisome proliferator–activated receptor γ coactivator 1α and estrogen-related receptor α signaling. Targeting PTP1B may improve islet transplantation. Deficient vascularization is a major driver of early islet graft loss and one of the primary reasons for the failure of islet transplantation as a viable treatment for type 1 diabetes. This study identifies the protein tyrosine phosphatase 1B (PTP1B) as a potential modulator of islet graft revascularization. We demonstrate that grafts of pancreatic islets lacking PTP1B exhibit increased revascularization, which is accompanied by improved graft survival and function, and recovery of normoglycemia and glucose tolerance in diabetic mice transplanted with PTP1B-deficient islets. Mechanistically, we show that the absence of PTP1B leads to activation of hypoxia-inducible factor 1α–independent peroxisome proliferator–activated receptor γ coactivator 1α/estrogen-related receptor α signaling and enhanced expression and production of vascular endothelial growth factor A (VEGF-A) by β cells. These observations were reproduced in human islets. Together, these findings reveal that PTP1B regulates islet VEGF-A production and suggest that this phosphatase could be targeted to improve islet transplantation outcomes.
Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma

Frequently observed DNA copy number gains of TCF4 in ABC-like DLBCL promote immunoglobulin expression and are targetable by BET inhibition. Lymphoma’s gain is its loss Activated B cell (ABC-like) diffuse large B cell lymphoma (DLBCL) can be curable, but therapies are needed for those who relapse or are refractory to current treatments. Jain et al. found that a percentage of ABC-like DLBCL patient tumors had copy gains on part of chromosome 18. The gains increased expression of transcription factor TCF4 (E2-2), which, in turn, activated immunoglobulin μ and MYC. Finding that tumors with this gain were dependent on TCF4 and that TCF4 was regulated by bromodomain protein BRD4, they tested bromodomain inhibition in xenograft models and reported reduced tumor growth and enhanced survival. This work suggests that targeting TCF4 may hold promise against ABC-like DLBCL. The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin μ (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative constructs was synthetically lethal to ABC-like DLBCL cell lines harboring TCF4 DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the TCF4 gene was one of the top BRD4-regulated genes in DLBCL cell lines. BET proteolysis-targeting chimera (PROTAC) ARV771 extinguished TCF4, MYC, and IgM expression and killed ABC-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. This work highlights a genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.
Reward-Related Attentional Capture Is Associated With Severity of Addictive and Obsessive–Compulsive Behaviors

A cue that signals reward can capture attention and elicit approach behaviors in people and animals. The current study examined whether attentional capture by reward-related cues is associated with severity of addiction-related and obsessive–compulsive behaviors. Participants were recruited via Mechanical Turk and included 143 adults (Mage = 34 years, SD = 8.5; 43% female) who had endorsed at least 1 addiction-related or obsessive–compulsive behavior in the past month. All assessment components were delivered via the Internet and included questionnaires to assess severity of compulsivity-related problems across addiction-related and obsessive–compulsive behaviors, as well as a visual search task to measure reward-related attentional capture. Reward-related attentional capture was associated with severity of compulsivity, transdiagnostically. These findings have implications for understanding the mechanisms that underlie compulsive behaviors and suggest that reward-related attentional capture is a promising transdiagnostic cognitive risk marker for compulsivity.
Oscillatory, Computational, and Behavioral Evidence for Impaired GABAergic Inhibition in Schizophrenia

Abstract The dysconnection hypothesis of schizophrenia (SZ) proposes that psychosis is best understood in terms of aberrant connectivity. Specifically, it suggests that dysconnectivity arises through aberrant synaptic modulation associated with deficits in GABAergic inhibition, excitation–inhibition balance and disturbances of high-frequency oscillations. Using a computational model combined with a graded-difficulty visual orientation discrimination paradigm, we demonstrate that, in SZ, perceptual performance is determined by the balance of excitation–inhibition in superficial cortical layers. Twenty-eight individuals with a DSM-IV diagnosis of SZ, and 30 age- and gender-matched healthy controls participated in a psychophysics orientation discrimination task, a visual grating magnetoencephalography (MEG) recording, and a magnetic resonance spectroscopy (MRS) scan for GABA. Using a neurophysiologically informed model, we quantified group differences in GABA, gamma measures, and the predictive validity of model parameters for orientation discrimination in the SZ group. MEG visual gamma frequency was reduced in SZ, with lower peak frequency associated with more severe negative symptoms. Orientation discrimination performance was impaired in SZ. Dynamic causal modeling of the MEG data showed that local synaptic connections were reduced in SZ and local inhibition correlated negatively with the severity of negative symptoms. The effective connectivity between inhibitory interneurons and superficial pyramidal cells predicted orientation discrimination performance within the SZ group; consistent with graded, behaviorally relevant, disease-related changes in local GABAergic connections. Occipital GABA levels were significantly reduced in SZ but did not predict behavioral performance or oscillatory measures. These findings endorse the importance, and behavioral relevance, of GABAergic synaptic disconnection in schizophrenia that underwrites excitation–inhibition balance.
The hitchhiker's guide to parasite dissemination

Toxoplasma gondii (T. gondii) is a parasitic protist that can infect nearly all nucleated cell types and tissues of warm‐blooded vertebrate hosts. T. gondii utilises a unique form of gliding motility to cross cellular barriers, enter tissues, and penetrate host cells, thus enhancing spread within an infected host. However, T. gondii also disseminates by hijacking the migratory abilities of infected leukocytes. Traditionally, this process has been viewed as a route to cross biological barriers such as the blood–brain barrier. Here, we review recent findings that challenge this view by showing that infection of monocytes downregulates the program of transendothelial migration. Instead, infection by T. gondii enhances Rho‐dependent interstitial migration of monocytes and macrophages, which enhances dissemination within tissues. Collectively, the available evidence indicates that T. gondii parasites use multiple means to disseminate within the host, including enhanced motility in tissues and translocation across biological barriers.
Opinions of Speech-Language Pathologists Regarding Speech Management for Children With Cleft Lip and Palate

Objective: The purpose of the present study was to examine practice patterns and opinions that speech-language pathologists (SLPs) have about speech-language intervention for children with cleft lip and palate. Methods: One hundred seven speech-language pathology members of the American Speech-Language-Hearing Association Special Interest Group 5: Craniofacial and Velopharyngeal Disorders Special Interest Group completed a 37-item online survey that examined common practices in early intervention as well as opinions about speech characteristics, assessment, and management strategies for children with cleft lip and palate. Results: The overwhelming majority of respondents (96%) agreed that speech-language pathologists (SLPs) should meet with parents before palatal surgery to discuss speech-language issues. Although 90% of the SLPs identified increasing consonant inventory as an early intervention goal, lack of consensus was evident regarding the type of consonant to stimulate. Respondents agreed that while blowing activities are not useful in strengthening labial, lingual, or velopharyngeal movements, they are useful in heightening awareness of oral airflow for children with cleft palate. A large degree of variability was evident in opinions regarding prevalence and treatment of compensatory articulations as well as the effectiveness of treatment strategies designed to reduce perceived hypernasality and audible nasal emission. Conclusions: The findings of this study indicate a large degree of variability in opinions of SLP respondents regarding assessment and treatment of children with cleft lip and palate.
Role of Chemotherapy, VEGFR Inhibitors, and mTOR Inhibitors in Advanced Perivascular Epithelioid Cell Tumors (PEComas)

Purpose: Perivascular epitheliod cell tumors (PEComas) are rare mesenchymal neoplasms for which the role of systemic treatments is not established as there are no published prospective clinical trials or sufficiently large retrospective case series. The aim of this study is to clarify the activity of conventional chemotherapy and biological agents in advanced/metastatic PEComas. Experimental Design: This was an observational, retrospective, international study that included patients with advanced/metastatic PEComa treated with systemic therapy at 5 European sarcoma reference centers and within the Italian Rare Cancer Network. Survival analyses were performed using the Kaplan–Meier method and the Cox hazards regression models. Results: A total of 53 patients were included. Cytotoxic chemotherapy regimens were active only in a small proportion of PEComas. Gemcitabine-based regimens [objective response rate (ORR): 20%, median progression-free survival (PFS): 3.4 months] seemed to have the same activity of anthracycline-based regimens (ORR: 13%, median PFS: 3.2 months). Antiangiogenic agents resulted in disease stabilization in some patients, with a number having density changes/tissue response on imaging, with an ORR of 8.3% and a median PFS of 5.4 months. mTOR inhibitors were the most active agents, with an ORR of 41% and a median PFS of 9 months. Conclusions: Our study provides data for the selection of systemic therapy in patients with advanced/metastatic PEComa: mTOR inhibitors are the most active agents. Antiangiogenics and chemotherapy with gemcitabine-based regimens or anthracycline-based regimens are options in further line, but with a lower response rate and PFS.
Higher-order encodings with constructors

As programming languages become more complex, there is a growing call in the research community for machine-checked proofs about programming languages. A key obstacle to this goal is in formalizing name binding, where a new name is created in a limited scope. Name binding is used in almost every programming language to refer to the formal arguments to a function. For example, the function f (x) = x * 2, which doubles its argument, binds the name x for its formal argument. Though this concept is intuitively straightforward, it is complex to define precisely because of the intended properties of name binding. For example, the above function is considered "syntactically equivalent" to f (y) = y * 2. It is the goal of this dissertation to posit a new technique for encoding name binding, called Higher-Order Encodings with Constructors or HOEC. HOEC encodes name binding with a construct called the ν-abstraction, which binds new constructors in a limited scope. These constructors can then be used to encode names. ν-abstractions already have the required properties of name bindings, so name binding need only be formalized once, in the definition of the ν-abstraction. The user thus then gets name binding "for free" and need not define it explicitly. To demonstrate the usefulness of HOEC, this dissertation gives a language, CPTT, with ν-abstractions. CPTT is a form of Intensional Constructive Type Theory, a formalism which is both a programming language and a logical theory whose proofs can be checked by machine. The key novelty that enables CPTT is the constructor predicates, which limits the constructors that may appear in a term, allowing pattern-matching to be defined. The consistency proof for CPTT also has independent interest, as it demonstrates how a simpler form of name binding can be added to a wide variety of theories.
Use and Effect of Declarative Information in User Instructions

Introduction 1 Using instructive texts: Literature review 2 The use of different types of declarative information and their effect on task performances 3 The effects of declarative information on task performance, cognitive load, confidence and the appreciation of instructions and devices 4 The effects of system information on the transfer of knowledge 5 Conclusions and discussion References
Overexpression of long noncoding RNA Malat1 ameliorates traumatic brain injury induced brain edema by inhibiting AQP4 and the NF‐κB/IL‐6 pathway

Brain edema is a major traumatic brain injury (TBI)‐related neurological complication. In the initiation stage of TBI, brain edema is characterized by astrocyte swelling (cytotoxic edema). We studied the impact of a long noncoding RNA, Malat1, on the TBI‐induced astrocyte swelling and brain edema. Our results showed that Malat1 was downregulated in both the TBI rat model and the astrocyte fluid percussion injury (FPI) model, which concurred with brain edema and astrocyte swelling. Overexpression of Malat1 significantly inhibited rat brain edema, meanwhile reducing interleukin‐6 (IL‐6), nuclear factor‐κB (NF‐κB), and aquaporin 4 (AQP4) expression after TBI. In addition, overexpression of Malat1 ameliorated FPI‐induced astrocyte swelling and reduced IL‐6 release. Quantitative real‐time polymerase chain reaction and Western blot analysis also corroborated the inhibitory effects of Malat1 on NF‐κB and AQP4 expression after FPI. Our results highlighted the protective effects of Malat1 on the TBI‐induced brain edema, which were mediated through regulating IL‐6, NF‐κB, and AQP4 expression. Our study could provide a novel approach for TBI treatment.
A sixth-order continuous-time quadrature bandpass sigma-delta modulator for UMTS low-IF receivers and a study of the inherent excess loop delay effect

The first continuous-time (CT) quadrature bandpass /spl Sigma//spl Delta/ modulator with a sixth-order architecture is presented. It provides a signal bandwidth of 3.84 MHz (according to the universal mobile telecommunication system (UMTS) standard), centered at a low-IF of 4 MHz, and achieves a simulated peak signal-to-noise-distortion ratio (SNDR) of 78.3 dB and a dynamic range (DR) of 78.6 dB at a clock frequency of 96 MHz. Furthermore, the excess loop delay effect is studied. This effect is one of the main problems in CT /spl Sigma//spl Delta/ modulators. Previously presented papers investigate this effect for CT lowpass and bandpass /spl Sigma//spl Delta/ modulators and for a second-order CT quadrature bandpass /spl Sigma//spl Delta/ modulator. This paper, however, analytically describes and simulates the excess loop delay effect for the high-order CT quadrature bandpass /spl Sigma//spl Delta/ modulator with a sixth-order architecture.