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Despite the relatively uncontested importance of promoting school attendance in the policy arena, little evidence exists on the causal effect of school absence on long-run outcomes. We address this question by combining historical and administrative records for cohorts of Swedish individuals born in the 1930s. We find that elementary school absence significantly reduces contemporaneous academic performance, final educational attainment and labour income throughout the life cycle. The findings are consistent with a dynamic model of human capital formation, whereby absence causes small immediate learning losses, which cumulate to larger human capital losses over time and lead to worse labour market performance.

We investigated the co-occurrence of the nine of the most relevant canine vector-borne pathogens (CVBP) using conventional and real-time PCR and evaluated risk factors and potential non-apparent haematological alterations associated with co-infection in 111 rural, owned, free-ranging dogs in the Metropolitan Region of Chile.At least one pathogen was detected in 75% of the dogs. DNA of Anaplasma platys (Ap; 36%), Candidatus Mycoplasma haematoparvum (CMhp; 31%), Mycoplasma haemocanis (Mhc; 28%), Trypanosoma cruzi (17%), Leishmania spp. (4.5%), and Acanthocheilonema reconditum (1%) was detected. All dogs were negative for Ehrlichia spp., Rickettsia spp., Bartonella spp., Piroplasmida, and Hepatozoon spp. Thirty-eight dogs (34%) were coinfected. CMhp was involved in 71%, Mhc in 58%, and Ap in 50% of the co-infections. The most common co-infection pattern was CMhp–Mhc (37% of the cases). The prevalence of Ap was higher in juvenile than in adult dogs, whereas the opposite was found for CMhp and Mhc. Adult dogs were four times more likely of being co-infected than juveniles. Co-infected animals showed higher white blood cell count, segmented neutrophil count, and GGT levels than non-co-infected dogs. Clinically healthy but infected dogs may act as reservoirs of CVBP, and their free-ranging behavior would facilitate the spread of these pathogens to other dogs as well as human beings or wild carnivores.

Children's experiences during early childhood are critical for their cognitive and socioemotional development, two key dimensions of human capital. However, children from low-income backgrounds often grow up lacking stimulation and basic investments, which leads to developmental deficits that are difficult, if not impossible, to reverse later in life without intervention. The existence of these deficits is a key driver of inequality and contributes to the intergenerational transmission of poverty. In this article, we discuss the framework used in economics to model parental investments and early childhood development and use it as an organizing tool to review some of the empirical evidence on early childhood research. We then present results from various important early childhood interventions, with an emphasis on developing countries. Bringing these elements together, we draw conclusions on what we have learned and provide some directions for future research.

Il est peu dire que Thérèse Saint-Julien a profondément marqué nos vies, et si elle n’avait que peu d’attrait pour les hommages et les cérémonies, ces quelques lignes témoigneront de la place qu’elle a occupée dans le champ de la géographie urbaine, théorique et quantitative, d’une manière de faire, d’être à l’université et surtout de l’impression durable qu’elle laisse parmi plusieurs générations d’étudiants. Thérèse Saint-Julien était exigeante et bienveillante. À la manière de son propre p...

ObjectiveT cells are major effectors of the antitumoural immune response. Their activation by tumour-associated antigens can unleash their proliferation and cytotoxic functions, leading to tumour cell elimination. However, tumour-related immunosuppressive mechanisms including the overexpression of immune checkpoints like programmed cell death protein-1 (PD-1), are also engaged, promoting immune escape. Current immunotherapies targeting these pathways have demonstrated weak efficacy in colorectal cancer (CRC). It is thus crucial to find new targets for immunotherapy in this cancer type.DesignIn a prospective cohort of patients with CRC, we investigated the phenotype of tumour-related and non-tumour related intestinal T cells (n=44), particularly the adenosinergic pathway, correlating with clinical phenotype. An autologous coculture model was developed between patient-derived primary tumour spheroids and their autologous tumour-associated lymphocytes. We used this relevant model to assess the effects of CD39 blockade on the antitumour T cell response.ResultsWe show the increased expression of CD39, and its co-expression with PD-1, on tumour infiltrating T cells compared with mucosal lymphocytes. CD39 expression was higher in the right colon and early-stage tumours, thus defining a subset of patients potentially responsive to CD39 blockade. Finally, we demonstrate in autologous conditions that CD39 blockade triggers T cell infiltration and tumour spheroid destruction in cocultures.ConclusionIn CRC, CD39 is strongly expressed on tumour infiltrating lymphocytes and its inhibition represents a promising therapeutic strategy for treating patients.

Predictors of the efficacy of endoscopic dilation for caustic esophageal stricture have been poorly studied.All patients undergoing an endoscopic dilation for an esophageal caustic stricture between 1990 and 2015 in a French national reference center were included. Success of dilation was defined by self-food autonomy without the need for reconstructive esophageal surgery.During the study period, 894 patients were admitted after caustic ingestion. Among them, 101 patients developed esophageal stricture and 92 patients were eligible for analysis (missing data in 8 cases, 1 patient died before endoscopic dilation). In this cohort (median age 42 years, women 53%, strong alkali 74%, suicide attempt 77%, hydrostatic balloon use 93%), the overall success rate of dilation was 57% with a median number of 3 dilation sessions (274 sessions, range 1-17). Factors predicting the success of the procedure were: non-inflammatory stricture or non-inflammatory intercalated mucosa between stricture (88% vs 47%, p = 0.001), a single stricture versus 2 or more strictures (69% vs 47% vs 33%, respectively, p = 0.04), a stricture of less than 5 cm (70% vs 27%, p 0.001) and the existence of mild/ moderately tight or very tight stricture (70% vs 21% of success, p 0.001). Perforation rate was 6.5% (18/274) requiring emergency surgery in 2 cases.Several characteristics of caustic esophageal strictures are significantly associated with the success rate of endoscopic dilation. Our data may be useful for customizing treatment strategies in patients with a caustic stricture.

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Trifluridine/tipiracil (FTD/TPI) is a new antimetabolite agent used to treat chemorefractory metastatic colorectal cancer. FTD/TPI induced immunogenic cell death (ICD) in vitro in the microsatellite-stable (MSS) CT26 mouse colon carcinoma cell line, as well as in various human MSS colorectal cancer cell lines (SW620, Caco-2, and Colo-320). The combination of FTD/TPI with oxaliplatin synergized to promote ICD. In vivo, the combination was able to induce ICD, but not the single agents, although all treatment groups showed T-cell dependency. In addition, FTD/TPI and oxaliplatin did not affect regulatory T cells or myeloid-derived suppressor cells but eliminated type-2 tumor-associated macrophages (TAM2), resulting in higher cytotoxic CD8+ T-cell infiltration and activation. This effect was concomitantly associated with PD-L1 expression on tumor cells and PD-1 induction on CD8+ T cells, leading to secondary T-cell exhaustion. Finally, although anti–PD-1 was unable to synergize with FTD/TPI or oxaliplatin monotherapy, concomitant administration of anti–PD-1 to FTD/TPI and oxaliplatin enhanced the antitumor efficacy of the double chemotherapy. Our study showed a novel immunomodulatory role of FTD/TPI and oxaliplatin in depleting TAM2. The combination of oxaliplatin and FTD/TPI induced ICD in vivo, providing a rationale for the use of these drugs to eliminate immunosuppressive cells and boost checkpoint efficacy in patients with metastatic colorectal cancer.

Supplementary Table 2

Late effect of S49076 treatment

Pharmacokinetic parameters of S49076 administered orally to female balb/c nu/nu mice

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749–62. ©2013 AACR.

In vivo activity of S49076 and ionizing radiation combination

S49076 in vitro activity

In vitro activity of S49076 and ionizing radiation combination

Western blot detection of total and phosphorylated MET, AXL, FGFR1/2/3 and phosphorylated FRS2 in cell lines and tumor xenografts used in the study

Tumor growth delays of subcutaneous tumors

Supplementary materials and methods and supplementary Figure and Table legends

Supplementary Figure Legends

S49076 tumor concentration

Kinase interaction map for S49076 at 100 nM

Supplementary Table from Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial

Supplementary Data from Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial

Supplementary Figure from Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial

Purpose:KEYNOTE-224 cohort 1 demonstrated that pembrolizumab was efficacious and tolerable in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. We report results from KEYNOTE-224 (NCT02702414) cohort 2, which enrolled patients with advanced HCC and no prior systemic therapy.Patients and Methods:KEYNOTE-224 was an open-label, multicountry phase II trial. Eligible patients in cohort 2 had advanced HCC not amenable or refractory to locoregional therapy and not previously treated with systemic therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤2 years. Primary endpoint was objective response rate (ORR) by central imaging review per RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety/tolerability.Results:Between September 4, 2018, and February 20, 2019, 51 patients were allocated in cohort 2. The median time from the first dose to data cutoff (January 19, 2021) was 27 months (range, 23–29). ORR was 16% [95% confidence interval (CI), 7–29] and was similar across key subgroups. Median DOR was 16 months (range, 3–24+), and DCR was 57%. The median PFS was 4 months (95% CI, 2–8), and median TTP was 4 months (95% CI, 3–9). Median OS was 17 months (95% CI, 8–23). Grade ≥3 treatment-related adverse events occurred in 16% of patients.Conclusions:In patients with advanced HCC with no prior systemic therapy, pembrolizumab provided durable antitumor activity, promising OS, and had a safety profile consistent with previous observations. These findings support further evaluation of pembrolizumab-based regimens for HCC.

Quantum computing is a promising technology for machine learning, in terms of computational costs and outcomes. In this work, we intend to provide a framework that facilitates the use of quantum machine learning in the domain of brain-computer interfaces – where biomedical signals, such as brain waves, are processed. To this end, we integrated Qiskit, a well-known quantum library, with pyRiemann, a framework for the analysis of biomedical signals using Riemannian Geometry. In this paper, we describe our approach, the main elements of our implementation and our research directions. A key result is the creation of a standardised pipeline (QuantumClassifierWithDefaultRiemannianPipeline) for the binary classification of brain waves. The git repository reported in this paper also contains a complete test suite and examples to guide practitioners. We believe that this software will enable further research on the joint field of brain-computer interfaces and quantum computing.

Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) or progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported. Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed by blinded independent central review (BICR) per RECIST v1.1. Secondary endpoints included objective response rate (ORR), assessed by BICR per RECIST v1.1, and safety. Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7–48.8) months for pembrolizumab and 39.8 (31.7–47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4–22.5%) for pembrolizumab and 11.7% (6.8–17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3–13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0–23.4%) for pembrolizumab and 4.4% (1.6–9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported. Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC.

The past decade has witnessed a growth in the use of knowledge graph technologies for advanced data search, data integration, and query-answering applications. The leading example of a public, general-purpose open knowledge network (aka knowledge graph) is Wikidata, which has demonstrated remarkable advances in quality and coverage over this time. Proprietary knowledge graphs drive some of the leading applications of the day including, for example, Google Search, Alexa, Siri, and Cortana. Open Knowledge Networks are exciting: they promise the power of structured database-like queries with the potential for the wide coverage that is today only provided by the Web. With the current state of the art, building, using, and scaling large knowledge networks can still be frustratingly slow. This article describes a National Science Foundation Convergence Accelerator project to build a set of Knowledge Network Programming Infrastructure systems to address this issue.

Cylindrospermopsis raciborskii is a central bloom-forming cyanobacteria. However, despite its ecological significance, little is known of its interactions with the phages that infect it. Currently, only a single sequenced genome of a Cylindrospermopsis-infecting phage is publicly available. Here we describe the isolation and characterization of Cr-LKS3, a second phage infecting Cylindrospermopsis. Cr-LKS3 is a siphovirus with a higher genome similarity to prophages within heterotrophic bacteria genomes than to any other cyanophage/cyano-prophage, suggesting that it represents a novel cyanophage group. The function, order and orientation of the 72 genes in the Cr-LKS3 genome are highly similar to those of Escherichia virus Lambda (hereafter Lambda), despite the very low sequence similarity between these phages, showing high evolutionary convergence despite the substantial difference in host characteristics. Similarly to Lambda, the genome of Cr-LKS3 contains various genes that are known to be central to lysogeny, suggesting it can enter a lysogenic cycle. Cr-LKS3 has a unique ability to infect a host with a dramatically different GC content, without carrying any tRNA genes to compensate for this difference. This ability, together with its potential lysogenic lifestyle shed light on the complex interactions between C. raciborskii and its phages.

Purpose To compare the analgesic effects of pregabalin to those of single-shot interscalene brachial plexus block (ISBPB) in adults having arthroscopic rotator cuff (RC) repair, as well as ISBPB’s effect on postoperative opioid consumption, patient satisfaction, and opioid-related adverse effects. Methods In this randomized trial, 79 adults having arthroscopic RC repair were randomized to receive perioperative oral pregabalin (Lyrica, twice daily starting the evening before surgery, for a total of 4 doses) or single-shot ISBPB (20 ml of bupivacaine 0.25%). Intra- and postoperative management was standardized. The primary outcome was median self-reported pain score (on a visual analog scale of 0 to 100) at rest during the initial 10 postoperative days. Other outcomes included pain during activity, postoperative opioid consumption, opioid-related adverse effects, quality of recovery, and pain satisfaction score. Results Of 71 eligible patients, 59 were analyzed, of whom 29 received pregabalin and 30 received ISBPB. Groups were similar regarding demographic, baseline, and intraoperative variables. Median pain score at rest over the 10 postoperative days was 51 (interquartile range 26, 76) in the pregabalin group and 52 (22, 74) in the ISBPB group (difference 0.5 points; 95% confidence interval [CI] –3.2 to 6.3; P = .53). Opioid consumption during the initial 10 postoperative days was also similar (difference in median 90 mg of morphine equivalents; 95% CI –32 to 177.5; P = .12). No differences were found in any other outcome. Conclusions Perioperative use of pregabalin in adults undergoing arthroscopic RC repair provided analgesia comparable to that of ISBPB for 10 days after surgery. Level of Evidence II, randomized controlled trial (high dropout rate)

The COVID-19 pandemic, caused by SARS-CoV-2 infection, has become the most devastating zoonotic event in recent times, with negative impacts on both human and animal welfare as well as on the global economy. Although SARS-CoV-2 is considered a human virus, it likely emerged from animals, and it can infect both domestic and wild animals. This constitutes a risk for human and animal health including wildlife with evidence of SARS-CoV-2 horizontal transmission back and forth between humans and wild animals.Molecular surveillance in different wildlife rehabilitation centers and wildlife associated institutions in Chile, which are critical points of animal-human interaction and wildlife conservation, especially since the aim of wildlife rehabilitation centers is to reintroduce animals to their original habitat.The survey was conducted in six WRCs and three wildlife associated institutions. A total of 185 samples were obtained from 83 individuals belonging to 15 different species, including vulnerable and endangered species. Each specimen was sampled with two different swabs: one oropharyngeal or nasopharyngeal according to the nostril diameter, and/or a second rectal sample. RNA was extracted from the samples and two different molecular assays were performed: first, a conventional RT-PCR with pan-coronavirus primers and a second SARS-CoV-2 qPCR targeting the N and S genes.All 185 samples were negative for SARS-CoV-2.

Machine translation (MT) requires a wide range of linguistic capabilities, which current end-to-end models are expected to learn implicitly by observing aligned sentences in bilingual corpora. In this work, we ask: \emph{How well do MT models learn coreference resolution from implicit signal?} To answer this question, we develop an evaluation methodology that derives coreference clusters from MT output and evaluates them without requiring annotations in the target language. We further evaluate several prominent open-source and commercial MT systems, translating from English to six target languages, and compare them to state-of-the-art coreference resolvers on three challenging benchmarks. Our results show that the monolingual resolvers greatly outperform MT models. Motivated by this result, we experiment with different methods for incorporating the output of coreference resolution models in MT, showing improvement over strong baselines., Comment: EACL paper