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We present our anytime MaxSAT solver TT-Open-WBO-Inc, focusing on its evolution since the initial version that won both of the weighted incomplete tracks of MaxSAT Evaluation 2019 (MSE19). The solver’s MSE20 version claimed victory in these tracks at MSE20 and secured second place in both unweighted incomplete tracks. The major innovation in the MSE20 version was the integration of SAT-based local search. The contributions of this paper include: (1) Introducing a previously unpublished variant of the SAT-based local search algorithm Polosat, Polosat-OBV, applied by default already in the MSE20 version, and showing its superiority for weighted solving; (2) Describing and analyzing TT-Open-WBO-Inc’s unweighted component, not studied in previous work; (3) Demonstrating that integrating the local search algorithm SATLikeinto TT-Open-WBO-Incas a preprocessor enables it to outperform the winners of MSE20 in all four incomplete tracks.

MR imaging is currently the main imaging modality used for the diagnosis and post therapeutic assessment of glioblastomas. Recently, several innovative PET radioactive tracers have been investigated for the evaluation of glioblastomas (GBM). These radiotracers target several biochemical and pathophysiological processes seen in tumors. These include glucose metabolism, DNA synthesis and cell proliferation, amino acid transport, cell membrane biosynthesis, specific membrane antigens such as prostatic specific membrane antigens, fibroblast activation protein inhibitor, translocator protein and hypoxia sensing agents, and antibodies targeting specific cell receptor antigen. This review aims to discuss the clinical value of these PET radiopharmaceuticals in the evaluation and treatment of GBMs.

Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection.

Sepsis is a leading cause of global mortality in children, yet definitions for pediatric sepsis are outdated and lack global applicability and validity. In adults, the Sepsis-3 Definition Taskforce queried databases from high-income countries to develop and validate the criteria. The merit of this definition has been widely acknowledged; however, important considerations about less-resourced and more diverse settings pose challenges to its use globally. To improve applicability and relevance globally, the Pediatric Sepsis Definition Taskforce sought to develop a conceptual framework and rationale of the critical aspects and context-specific factors that must be considered for the optimal operationalization of future pediatric sepsis definitions. It is important to address challenges in developing a set of pediatric sepsis criteria which capture manifestations of illnesses with vastly different etiologies and underlying mechanisms. Ideal criteria need to be unambiguous, and capable of adapting to the different contexts in which children with suspected infections are present around the globe. Additionally, criteria need to facilitate early recognition and timely escalation of treatment to prevent progression and limit life-threatening organ dysfunction. To address these challenges, locally adaptable solutions are required, which permit individualized care based on available resources and the pretest probability of sepsis. This should facilitate affordable diagnostics which support risk stratification and prediction of likely treatment responses, and solutions for locally relevant outcome measures. For this purpose, global collaborative databases need to be established, using minimum variable datasets from routinely collected data. In summary, a “Think globally, act locally” approach is required.

Background In patients with tetralogy of Fallot and major aortopulmonary collaterals (MAPCAs), pulmonary blood supply is highly variable. Our approach to this condition emphasizes complete unifocalization of the pulmonary circulation, incorporating all lung segments and addressing stenoses out to the segmental level. Post-repair, we recommend serial lung perfusion scintigraphy (LPS) to assess short-term changes in pulmonary blood flow distribution.Methods We reviewed post-discharge and follow-up LPS performed through three years post-repair and analyzed serial changes in perfusion, risk factors for change, and the relationship between LPS parameters and pulmonary artery reintervention.Results Of 543 patients who had postoperative LPS results in our system, 317 (58%) had only a predischarge LPS available for review, while 226 had 1 (20%) or more (22%) follow-up scans within three years. Overall, pulmonary flow distribution prior to discharge was balanced, and there was minimal change over time; however, there was considerable patient-to-patient variation in both metrics. On multivariable mixed modeling, time after repair (P= .025), initial anatomy consisting of a ductus arteriosus to one lung (P< .001), and age at repair (P= .014) were associated with changes on serial LPS. Patients who had follow-up LPS were more likely to undergo pulmonary artery reintervention, but within that cohort, LPS parameters were not associated with reintervention risk.Conclusion Serial LPS during the first year after MAPCAs repair is a noninvasive method of screening for significant post-repair pulmonary artery stenosis that occurs in a small but important minority of patients. In patients who received follow-up LPS beyond the perioperative period, there was minimal change over time in the population overall, but large changes in some patients and considerable variability. There was no statistical association between LPS findings and pulmonary artery reintervention.

The Epipalaeolithic Natufian Culture (latest Pleistocene Levant, ca. 15,000–11,500 cal bp) represents relatively sedentary and complex foraging societies, but the plant communities near their most intensively occupied hamlets (in the Mediterranean region of the southern Levant) are not well known. Here we present the charcoal and seed assemblages, and direct radiocarbon dating of select specimens, from el-Wad Terrace, Mount Carmel, Israel, a thick and multi-layered Early to Late Natufian sequence. Wood remains indicate an East Mediterranean oak forest/maquis, with varying ratios of evergreen and deciduous oak types as primary components of the local environment, as well as almond and buckthorn. The highest density of remains is in the architectural phase of the Early Natufian, when the site was very intensively inhabited (15,000–13,800 cal bp). In this phase, wood and seed remains are distributed all over the residential area, conforming to patterns of other finds that show primary discard and no rigid partitioning of space. Comparison of the seed assemblages to Kebara Cave, a Middle Palaeolithic site in the same geographic setting, points to an elevated use of cereals in the Natufian. Our data provide insights into several chronological, spatial and behavioural patterns, which emerge along the Natufian sequence at the site.

•We studied experimentally a sequence of three typical breakage agents of bladelets.•Experiments produced diagnostic breakage patterns associated with each agent.•The history of damage on bladelets underwent multiple processes can be identified.•We characterized new types of breakage which have been given little attention.•Experiments created fractures similar to projectile diagnostic impact fractures.

With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

Electrophysiological methods were used to test the visual sensitivity of European grapevine moth, Lobesia botrana(Lepidoptera: Tortricidae) to wavelengths ranging from 300 to 700 nm. For male and females tested, a main, peak response occurred in the 460–540 nm range (blue-green wavelengths) with females having a generally lower response to wavelengths in that range. A second smaller peak was observed for both sexes at the 340–420 nm range. A general linear model indicated that males, virgin females, and mated females did not react differently to changes in wavelength. No moths showed any obvious sensitivity to wavelengths between 580 and 700 nm. Based on our retinal recording data we suggest that UV light traps (≤480 nm) could be utilized alongside pheromone traps when monitoring L. botranain high risk areas.

abstract:This article explores the sources and application of Philip Roth’s understanding of Russian writing and culture to his fiction. It examines Russian texts he owned, the influence of select authors, and the translations of Roth’s work in Russia. It also considers Roth’s reaction to the Cold War and offers an alternate triangle of influence: not Franz Kafka/Bruno Schulz/Primo Levi but Anton Chekhov/Fyodor Dostoevsky/Isaac Babel.

The ontogeny of human haematopoietic stem cells (HSCs) is poorly defined owing to the inability to identify HSCs as they emerge and mature at different haematopoietic sites1. Here we created a single-cell transcriptome map of human haematopoietic tissues from the first trimester to birth and found that the HSC signature RUNX1+HOXA9+MLLT3+MECOM+HLF+SPINK2+distinguishes HSCs from progenitors throughout gestation. In addition to the aorta–gonad–mesonephros region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks. A comparison of HSCs at different maturation stages revealed the establishment of HSC transcription factor machinery after the emergence of HSCs, whereas their surface phenotype evolved throughout development. The HSC transition to the liver marked a molecular shift evidenced by suppression of surface antigens reflecting nascent HSC identity, and acquisition of the HSC maturity markers CD133 (encoded by PROM1) and HLA-DR. HSC origin was tracked to ALDH1A1+KCNK17+haemogenic endothelial cells, which arose from an IL33+ALDH1A1+arterial endothelial subset termed pre-haemogenic endothelial cells. Using spatial transcriptomics and immunofluorescence, we visualized this process in ventrally located intra-aortic haematopoietic clusters. The in vivo map of human HSC ontogeny validated the generation of aorta–gonad–mesonephros-like definitive haematopoietic stem and progenitor cells from human pluripotent stem cells, and serves as a guide to improve their maturation to functional HSCs.

Effective antitumour immunity depends on the orchestration of potent T cell responses against malignancies1. Regression of human cancers has been induced by immune checkpoint inhibitors, T cell engagers or chimeric antigen receptor T cell therapies2–4. Although CD8 T cells function as key effectors of these responses, the role of CD4 T cells beyond their helper function has not been defined. Here we demonstrate that a trispecific antibody to HER2, CD3 and CD28 stimulates regression of breast cancers in a humanized mouse model through a mechanism involving CD4-dependent inhibition of tumour cell cycle progression. Although CD8 T cells directly mediated tumour lysis in vitro, CD4 T cells exerted antiproliferative effects by blocking cancer cell cycle progression at G1/S. Furthermore, when T cell subsets were adoptively transferred into a humanized breast cancer tumour mouse model, CD4 T cells alone inhibited HER2+breast cancer growth in vivo. RNA microarray analysis revealed that CD4 T cells markedly decreased tumour cell cycle progression and proliferation, and also increased pro-inflammatory signalling pathways. Collectively, the trispecific antibody to HER2 induced T cell-dependent tumour regression through direct antitumour and indirect pro-inflammatory/immune effects driven by CD4 T cells.

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Use of extracorporeal membrane oxygenation (ECMO) in children receiving haematopoietic cell transplantation (HCT) and immune effector cell therapy is controversial and evidence-based guidelines have not been established. Remarkable advancements in HCT and immune effector cell therapies have changed expectations around reversibility of organ dysfunction and survival for affected patients. Herein, members of the Extracorporeal Life Support Organization (ELSO), Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network (HCT and cancer immunotherapy subgroup), the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation (EBMT), the supportive care committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC), and the Pediatric Intensive Care Oncology Kids in Europe Research (POKER) group of the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) provide consensus recommendations on the use of ECMO in children receiving HCT and immune effector cell therapy. These are the first international, multidisciplinary consensus-based recommendations on the use of ECMO in this patient population. This Review provides a clinical decision support tool for paediatric haematologists, oncologists, and critical care physicians during the difficult decision-making process of ECMO candidacy and management. These recommendations can represent a base for future research studies focused on ECMO selection criteria and bedside management.

The Society of Nuclear Medicine and Molecular Imaging (SNMMI), founded in 1954, is an international scientific and professional organization with a purpose to promote the science, technology, and practical application of nuclear medicine. The European Association of Nuclear Medicine (EANM), founded in 1985, is a nonprofit professional medical association with a purpose to facilitate international communication among individuals in nuclear medicine pursuing clinical and academic excellence. Members of the SNMMI and EANM are physicians, technologists, and scientists who specialize in the research and practice of nuclear medicine. The SNMMI and EANM will periodically publish new guidelines for nuclear medicine practice to further advance the science of nuclear medicine and improve patient care. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate. Each standard/guideline, representing a policy statement by the SNMMI/EANM, has undergone a thorough review, and represents an expert consensus. The SNMMI and EANM recognize that the safe and effective use of diagnostic nuclear medicine imaging requires specific training and skills, as described in each document. These standards/guidelines are educational resources designed to assist practitioners in providing appropriate nuclear medicine care for patients. They are consensus documents, and are not mandatory provisions or requirements of practice. They are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the SNMMI and the EANM cautions against the use of these standards/guidelines in litigation procedures that call into question the clinical decisions of a practitioner. The ultimate judgment regarding the appropriateness and propriety of any specific procedure or course of action must be made by medical professionals, taking into account the unique context of each case. Thus, there is no implication that action differing from what is detailed in these standards/guidelines, on its own, is below the standard of care. On the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, based on the reasonable judgment of the practitioner, such course of action is warranted based on the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the standards/guidelines. Practicing medicine involves not only the science, but also the art of dealing with the prevention, detection, diagnosis, and treatment of disease. The variety and complexity of human conditions make it impossible for general guidelines to consistently allow for an accurate diagnosis to be reached or a specific treatment response to be predicted. Therefore, it should be recognized that adhering to these standards/guidelines does not ensure a successful outcome. All that should be expected is that a practitioner follows a reasonable course of action based on their level of training, the current landscape of knowledge, the resources at their disposal, and the needs/context of the particular patient being treated. The purpose of this document is to provide nuclear medicine physicians, radiologists, and other clinicians with guidelines for the recommendation, performance and interpretation of 99mTc-dimercaptosuccinic acid renal cortical scintigraphy ([99mTc] Tc-DMSA scintigraphy) in pediatric patients. These recommendations represent the expert opinions of experienced leaders in this field, and these recommendations are not all supported by a high level of evidence. Further studies are required to have evidence-based recommendations for the application of [99mTc] Tc-DMSA renal cortical scintigraphy in pediatrics. This guideline summarizes the views of the SNMMI Renal Cortical Scintigraphy in Children Working Group and the EANM Pediatrics Committee. It reflects recommendations for which the SNMMI and EANM cannot be held responsible. The recommendations should be taken into context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions.

Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms of schizophrenia. These observations and the fact that increasing brain-wide dopamine improves cognition have fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms. However, this idea has never been explicitly tested with DS-pathway specificity. To determine if excess DS dopamine is involved in cognitive and negative symptoms, we selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of Trpv1knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively activate these neurons, validated this approach with fiber photometry, and assessed its effects on social interaction and working memory, behavioral constructs related to negative and cognitive symptoms. We combined this manipulation with antipsychotic treatment (haloperidol) and compared it to brain-wide dopamine release via amphetamine treatment. We found that selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired social interaction and working memory. Haloperidol normalized locomotion, but only partially rescued working memory and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. These results suggest that excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Future therapies should address this disregarded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis.

Diet optimization is an important process to increase the efficiency of rearing insects and can be used to develop high-quality insects with specific fitness and life-history traits. Galleria mellonella(L.), the greater wax moth, is widely used in research, microbiology assays, as pet food, and host for biological control agents. Although artificial diets for G. mellonellahave been researched and optimized for decades, preliminary tests indicated that the predominantly utilized G. mellonelladiet could be improved to yield larger larvae with a short development time. We used a design of experiments (DOE) approach that incorporated multiple full factorial designs and a final mixture design to test the qualitative and quantitative effects of ingredients and their interactions on larval mass and survival. Analysis of 17 ingredient variations in 35 diet formulations yielded an optimized diet that supported high survival and 2.4-fold greater larval body mass than the standard rearing diet. This study demonstrates the importance and efficiency of statistical DOE in guiding the optimization of insect diets to improve traits that represent the quality and fitness of the reared insects.

The article discusses that the Phellodendron Supports Healthy Dopamine Levels. Topics discussed include the activity of an enzyme called monoamine oxidase B (MAO-B) increases; and MAO-B breaks down dopamine, reducing vital dopamine levels; and Increased MAO-B activity also has neurotoxic effects, contributing to age-related loss of brain function and risk for neurodegenerative diseases.

BackgroundAlthough intracranial aneurysms (IA) and abdominal aortic aneurysms (AAA) share similar risk factors, little is known about the relationship between them. Previous studies have shown an increased incidence of IA in patients with AAA, though the rate of subarachnoid hemorrhage (SAH) in patients with AAA has not been described.ObjectiveTo use claims data with longitudinal follow-up, to evaluate the incidence of aneurysmal SAH in patients diagnosed with AAA.MethodsWe examined longitudinally linked medical claims data from a large private insurer to determine rates of aneurysmal SAH (aSAH) and secured aSAH (saSAH) in 2004–2014 among patients with previously diagnosed AAA.ResultsWe identified 62 910 patients diagnosed with AAA and compared them 5:1 with age- and sex-matched controls. Both populations were predominantly male (70.9%), with an average age of 70.8 years. Rates of hypertension (69.7% vs 50.6%) and smoking (12.8% vs 4.1%) were higher in the AAA group (p<0.0001) than in controls. Fifty admissions for aSAH were identified in patients with AAA (26/100 000 patient-years, 95% CI 19 to 44) and 115 admissions for aSAH in controls (7/100 000 years, 95% CI 6 to 9), giving an incidence rate ratio (IRR) of 3.6 (95% CI 2.6 to 5.0, p<0.0001) and a comorbidity-adjusted incidence rate ratio (IRR) of 2.8 (95% CI 1.9 to 3.9) for patients with AAA. The incidence of secured aneurysmal SAH was proportionally even higher in patients with AAA, 7 vs 2/100 000 years, IRR 4.5 (95% CI 3.2 to 6.3, p<0.0001).ConclusionSAH rate was elevated in patients with AAA, even after adjustment for comorbidities. Among risk factors evaluated, AAA was the strongest predictor for SAH. The relative contributions of common genetic and environmental risk factors to both diseases should be investigated.

Follicular lymphoma (FL) is an indolent yet challenging disease. Despite a generally favorable response to immunochemotherapy regimens, a fraction of patients does not respond or relapses early with unfavorable prognosis. For the vast majority of those who initially respond, relapses will repeatedly occur with increasing refractoriness to available treatments. Addressing the clinical challenges in FL warrants deep understanding of the nature of treatment-resistant FL cells seeding relapses, and of the biological basis of early disease progression. Great progress has been made in the last decade in the description and interrogation of the (epi)genomic landscape of FL cells, of their major dependency to the tumor microenvironment (TME), and of the stepwise lymphomagenesis process, from healthy to subclinical disease and to overt FL. A new picture is emerging, in which an ever-evolving tumor-TME duo sparks a complex and multilayered clonal and functional heterogeneity, blurring the discovery of prognostic biomarkers, patient stratification and reliable designs of risk-adapted treatments. Novel technological approaches allowing to decipher both tumor and TME heterogeneity at the single-cell level are beginning to unravel unsuspected cell dynamics and plasticity of FL cells. The upcoming drawing of a comprehensive functional picture of FL within its ecosystem holds great promise to address the unmet medical needs of this complex lymphoma.