Introduction: Several studies on late effects of childhood cancer have been conducted during the past decades. To ensure external validation of a study population, the participation rate must be high. This study investigated demographic data in late effect studies and potential factors impacting on participation rates such as cancer type, time since diagnosis and duration of clinical examinations. Procedure: By searching the databases PubMed, Embase and Web of Science and by contacting researchers and clinicians, we identified studies including an invitation to a clinical examination for late effects after childhood cancer. Studies conducted from January 2010 - March 2020 in the Nordic countries were included. Results: We found 80 published studies originating from 16 cohorts. The overall participation rates ranged between 27 and 100%. The majority of studies (eleven studies) were conducted more than ten years after the cancer diagnosis and primarily on hematologic malignancies (seven studies). The highest participation rates were seen in studies of survivors with solid tumors (92%) and the lowest in survivors with hematologic malignancies (67%) and central nervous system tumors (73%). Neither duration of the clinical examination nor time since diagnosis seemed to affect the participation rate. Conclusion: A trend of lower participation rates when recruiting survivors of hematologic malignancies and central nervous system tumors was found. We encourage future studies to describe the recruitment process more thouroughly to improve understanding of the factors influencing participation rates.

Invasive ants shape assemblages and interactions of native species, but their effect on fundamental ecological processes is poorly understood. In East Africa, Pheidole megacephala ants have invaded monodominant stands of the ant-tree Acacia drepanolobium, extirpating native ant defenders and rendering trees vulnerable to canopy damage by vertebrate herbivores. We used experiments and observations to quantify direct and interactive effects of invasive ants and large herbivores on A. drepanolobium photosynthesis over a 2-year period. Trees that had been invaded for ≥ 5 years exhibited 69% lower whole-tree photosynthesis during key growing seasons, resulting from interaction between invasive ants and vertebrate herbivores that caused leaf- and canopy-level photosynthesis declines. We also surveyed trees shortly before and after invasion, finding that recent invasion induced only minor changes in leaf physiology. Our results from individual trees likely scale up, highlighting the potential of invasive species to alter ecosystem-level carbon fixation and other biogeochemical cycles.

Purpose: It has been suggested, on a theoretical basis, that ultrasound screening of thyroid nodules in obese patients with additional risk factors (family history, thyroiditis or high thyrotropin) might be cost-effective for the early detection and treatment of thyroid cancer. The present study evaluates if this approach can be validated in a real clinical setting. Methods: Patients with obesity attended in hospital-based clinics were evaluated for risk factors of thyroid cancer and ultrasound screened for thyroid nodularity. Detected nodules were evaluated according to current guidelines. Results: A total of 429 patients were evaluated (70.2% women, mean age 49.1±11.0, mean body mass index 42.6±5.8 kg/m2). Risk factors were present in 129 (30.1%) patients. Thyroid nodules with indication for fine needle aspiration biopsy were detected in 69 (16.1%). We did not find differences in the risk of harbouring thyroid nodules according to the presence of risk factors (no risk factors 16.6%, risk factors 14.1%, p = 0.64). No single risk factor conferred an increased risk for thyroid nodules During the screening procedure 4 cases of thyroid cancer were detected, none of them with the evaluated risk factors. Conclusion: The present study, has been unable to demonstrate that the use of known risk factors for thyroid cancer is helpful to discriminate obese patients with higher risk of harbouring thyroid nodules.

The logarithmic representation of infinitesimal generators is generalized to the cases when the evolution operator is unbounded. The generalized result is applicable to the representation of infinitesimal generators of unbounded evolution operators, where unboundedness of evolution operator is an essential ingredient of nonlinear analysis. In conclusion a general framework for the identification between the infinitesimal generators with evolution operators is established. A mathematical framework for such an identification is indispensable to the rigorous treatment of nonlinear transforms: e.g., transforms appearing in the theory of integrable systems.

Background and Purpose: Azithromycin (AZM) is a macrolide antibiotic with well-described anti-inflammatory properties. This study aimed to substantiate its treatment potential in rheumatoid arthritis (RA). Experimental Approach: Gene expression profiles were collected by RNA-sequencing and the effects of AZM were assessed in functional assays. In vitro and vivo assays for examining the blockade of glucose-regulated protein 78 (GRP78) actions by AZM: assays for defining the anti-inflammatory activity of AZM using fibroblast-like synoviocytes (FLSs) from RA patients as well as collagen-induced arthritis (CIA) in DBA/1 mice. Identification and characterization of the binding of AZM to GRP78 using drug affability responsive target stability assay, proteomics and cellular thermal shift assay. Detect AZM inhibition of GRP78 and dependence of AZM’s anti-arthritis activity on GRP78. Key Results: AZM reduced pro-inflammatory factor production, cell migration, invasion and chemo-attractive potential, enhanced apoptosis, thereby reducing the deleterious inflammatory response of RA FLSs in vitro. AZM ameliorated the severity of CIA lesions. Transcriptional analyses implied that AZM treatment causes impairments in signaling cascades associated with cholesterol and lipid biosynthetic process. GRP78 was isolated as a novel target of AZM. AZM-mediated activation of unfolded protein response (UPR) via inhibiting GRP78 activity is required not only for inducing the expression of C/EBP-homologous protein (CHOP), but also for activation of sterol-regulatory element binding protein (SREBP) and its targeted genes involved in cholesterol and lipid biosynthetic process. Further, deletion of GRP78 abolished AZM’s anti-arthritis activity. Conclusion and Implications: These findings confirmed that AZM is an anti-arthritis therapeutic drug for RA treatment.

Background: Typical murine models of allergic inflammation are induced by the combination of ovalbumin and aluminum hydroxide. However, accumulating evidence indicates that, in models of asthma and atopic dermatitis, allergic inflammation can be generated in the absence of aluminum hydroxide. Moreover, co-administration of S. aureus enterotoxin B with ovalbumin can enhance inflammation. Objective: The objective of this study was to establish a rapid and mast cell-dependent murine model of allergic inflammation by inducing allergic peritonitis using ovalbumin and S. aureus enterotoxin B. Methods: Allergic peritonitis was induced in C57BL/6 mice by subcutaneous sensitization and intraperitoneal challenge with ovalbumin and S. aureus enterotoxin B. Disease characteristics were assessed by flow cytometry, ELISA, Trypan Blue exclusion and colorimetric assays. Results: Time course of the allergic peritonitis revealed a peak of peritoneal inflammation 48h after challenge, as assessed by total cells and eosinophil counts. Decrease of cell numbers started 96h post challenge with complete clearance within 168h. Moreover, significantly higher levels of tryptase and increased vascular permeability were found 30 min following challenge. Allergic inflammation induction by ovalbumin and S. aureus enterotoxin B was impaired in mast cells deficient mice and partially restored by mice reconstitution with bone marrow derived mast cells, indicating the mast cell role in this model. Conclusion: We present a novel model of allergic peritonitis that is mast cell-dependent, simple and robust. Moreover, the use of S. aureus enterotoxin B better resembles human allergic inflammation, which is known to be characterized by the colonization of Staphylococcus aureus.

Background and Purpose. Pseudomonas aeruginosa is a main cause of ventilator-associated pneumonia (VAP) with drug-resistant bacteria. Bacteriophage therapy has experienced resurgence to compensate for the limited development of novel antibiotics. However, phage therapy is limited to a compassionate use so far, resulting from lack of adequate studies in relevant pharmacological models. We used a pig model of VAP caused by P. aeruginosa that recapitulates essential features of human disease to study the antimicrobial efficacy of nebulized-phage therapy. Experimental Approach. (i) Lysis kinetic assays were performed to evaluate in vitro phage antibacterial efficacy against P. aeruginosa and select relevant combinations of lytic phages. (ii) The efficacy of the phage combinations was investigated in vivo (murine model of P. aeruginosa lung infection). (iii) We determined the optimal conditions to ensure efficient phage delivery by aerosol during mechanical ventilation. (iv) Lung antimicrobial efficacy of inhaled-phage therapy was evaluated in pigs, which were anesthetized, mechanically ventilated and infected with P. aeruginosa. Key Results. By selecting an active phage cocktail and optimizing aerosol delivery conditions, we were able to deliver high phage concentrations in the lungs, which resulted in a rapid and marked reduction in P. aeruginosa density (1.5 Log reduction, p<0.001). No phage was detected in the sera and urines throughout the experiment. Conclusion and Implications. Our findings demonstrated: (i) the feasibility of delivering large amounts of active phages by nebulization during mechanical ventilation, (ii) rapid control of in situ infection by inhaled bacteriophage in an experimental model of VAP with high translational value.

Article type: News and Views: Groundbreaking Discoveries in ImmunologyTitle: Uncovering the influence of diet and gut microbiota in human serum metabolomeAuthors: David Obeso1,2‡, Elisa Zubeldia-Varela1,2‡ and Alma Villaseñor11Instituto de Medicina Molecular Aplicada (IMMA), Departamento de Ciencias Médicas Básicas. Facultad de Medicina. Universidad San Pablo-CEU, CEU Universities, Madrid, España.2Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, España.‡: These Authors have equally contributedCorrespondence: Alma Villaseñor, Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, EspañaEmail address:[email protected]: Metabolomics, Diet, Microbiota, Allergy, Serum, MetabolomeAbbreviations: MS, mass spectrometry; LC, liquid chromatography; short chain fatty acids (SCFA)Acknowledgement: We would like to thank Anna Głobińska for her assistance in generating the graphical figure. AV Gratefully acknowledges the Martín-Carbajo family for supporting her scientific development through the X Mario Martín Velamazán award.Author contributions: D.O., E.Z-V. and A.V contributed to the writing of the manuscript and have given approval to the manuscript. A.V. supervised the final version.

We describe a case of isolated primary CNS lymphomatoid granulomatosis and a discordant low-grade B-cell lymphoma involving the bone marrow causing chronic immune thrombocytopenia. Clinical course was complicated with disseminated zoster and sub-massive pulmonary embolism. Our patient was successfully managed with a combination radioimmunotherapy strategy with rituximab and radiation therapy.

Endoscopic stone removal becomes challenging owing to a distal common bile duct stricture. A new dumbbell-shaped covered self-expanding metallic stent is efficient in removing the common bile duct stones with common bile duct strictures that occur due to chronic pancreatitis.

More accurate predictions of the biological properties of chemical compounds would guide the selection and design of new compounds in drug discovery and help to address the enormous cost and low success-rate of pharmaceutical R&D. However this domain presents a significant challenge for AI methods due to the sparsity of compound data and the noise inherent in results from biological experiments. In this paper, we demonstrate how data imputation using deep learning provides substantial improvements over quantitative structure-activity relationship (QSAR) machine learning models that are widely applied in drug discovery. We present the largest-to-date successful application of deep-learning imputation to datasets which are comparable in size to the corporate data repository of a pharmaceutical company (678,994 compounds by 1166 endpoints). We demonstrate this improvement for three areas of practical application linked to distinct use cases; i) target activity data compiled from a range of drug discovery projects, ii) a high value and heterogeneous dataset covering complex absorption, distribution, metabolism and elimination properties and, iii) high throughput screening data, testing the algorithm’s limits on early-stage noisy and very sparse data. Achieving median coefficients of determination, R2, of 0.69, 0.36 and 0.43 respectively across these applications, the deep learning imputation method offers an unambiguous improvement over random forest QSAR methods, which achieve median R2 values of 0.28, 0.19 and 0.23 respectively. We also demonstrate that robust estimates of the uncertainties in the predicted values correlate strongly with the accuracies in prediction, enabling greater confidence in decision-making based on the imputed values.

Background: The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Methods: Eight kindreds with familial AF and slow conduction, including a family affected by early onset AF, heart block and incompletely penetrant non-ischemic cardiomyopathy (NICM) underwent whole exome sequencing. Results: A known pathogenic mutation in the desmin (DES) gene resulting in S13F substitution at a PKC phosphorylation site was identified in all four members of the kindred with early-onset AF and heart block, while only two developed NICM. Higher penetrance of the mutation for AF and heart block prompted the screening for DES modifier(s). A second deleterious mutation in the phosphodiesterase 4D interacting-protein (PDE4DIP) gene resulting in A123T substitution segregated with early onset AF, heart block and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIPA123T in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the β2-adrenergic-receptor, and decreased PKA phosphorylation of Desmin in response to isoproterenol stimulation compared to wildtype PDE4DIP. Conclusion: Our findings identify an epistatic interaction between DES and PDE4DIP variants, increasing the penetrance for conduction disease and arrhythmia.

The hypercoagulable state observed in COVID-19 could be responsible for morbidity and mortality. In this retrospective study we investigated whether therapeutic anticoagulation prior to infection has a beneficial effect in hospitalized COVID-19 patients. 1154 COVID-19 patients admitted to 6 hospitals in the Netherlands between March and May 2020 were included. We applied 1:3 propensity score matching to evaluate the association between prior therapeutic anticoagulation use and clinical outcome, with in hospital mortality as primary endpoint. 190 (16%) patients used therapeutic anticoagulation prior to admission. In the propensity score matched analyses, we observed no associations between prior use of therapeutic anticoagulation and overall mortality (RR 1.02 (95% CI; 0.80-1.30) or length of hospital stay (7.0 [4-12] vs 7.0 {4-12] days, p=0.69), although we observed a lower risk of pulmonary embolism (RR 0.19 (95% CI; 0.05-0.80). This study shows that prior use of therapeutic anticoagulation is not associated with improved clinical outcome in hospitalized COVID-19 patients.

Background The long-term impact of childhood cancer treatment on dietary intake is likely to be complex and the length of time dietary behaviours are affected after childhood cancer treatment is unknown. Aim The aim of this study was to determine the diet quality in childhood cancer survivors recently off treatment and identify possible contributing factors that may affect diet quality in this population. Methods Participants were 65 parents and/or carers of childhood cancer survivors (CCS) (aged 2-18 years), recently off treatment and 81 age-matched controls. Methods Participants completed two self-administered dietary intake and eating behaviour questionnaires. Study data was explored to determine between group differences, bivariate analysis using Spearman’s correlations was used to determine the relationship between diet quality and identified variables, and hierarchical cluster analysis was completed to characterise specific variables into clusters. Results CCS had a significantly poorer diet quality score than the age-matched controls (t=-2.226, p=0.028). Childhood cancer survivors had significantly higher parent-reported rates of ‘picky eating’ behaviour than the control group (t=0.106 p=0.044). Factors such as picky eating, emotional overeating and Body Mass Index z-score appeared to drive diet quality in survivors. Conclusions A CCS with picky eating behaviours could avoid complete food groups, have strong food preferences/aversions and over- consume high energy foods to maintain their energy intake, possibly affecting diet quality. The outcomes highlighted the need for a tailored intervention aimed at improving healthy eating behaviours in CCS after treatment for cancer.

Abstract Continuous intravenous (IV) sildenafil may avoid the acute systemic vasodilatory effects of bolus dosing in infants with pulmonary hypertension (PH). We aimed to examine the tolerability of different methods of IV sildenafil administration. Methods: We retrospectively evaluated subjects less than 12 months old with PH, who had been started on IV sildenafil. Vital signs, oxygen requirement, and vasoactive-inotropic score (VIS) before and after sildenafil initiation were noted, as was the need for discontinuation due to side effects. Results: Forty-three subjects were identified (23 continuous, 20 intermittent dosing). There were no statistically significant differences between groups in gender or gestational age, but higher baseline inspired oxygen (FiO2) and VIS in the continuous group suggested a higher baseline severity of illness (p=0.012). After sildenafil initiation, there were no significant differences in the change in blood pressure, oxygen saturation, FiO2, or VIS between groups, and no difference in the number of subjects requiring discontinuation due to side effects (4 in the continuous group, 1 intermittent, p=0.35). Eight subjects (34.8%) in the continuous group and 3 (15%) in the intermittent group died (p=0.024). Conclusions: In this small cohort of infants with PH treated with continuous or intermittent IV sildenafil, there were no statistically significant differences between groups in the change in vital signs, VIS, and oxygen requirement, or the need for discontinuation of therapy due to side effects. A higher mortality rate in the continuous infusion group may be explained by higher baseline illness severity.

Over the past fifteen years, the number of papers focused on “eco-evo dynamics” has increased exponentially (Figure 1). This pattern suggests the rapid growth of a new, integrative discipline. We argue that this overstates the case. First, the terms “eco-evo dynamics” and “eco-evo interactions” are used too imprecisely. As a result, many studies that claim to describe eco-evo dynamics are actually describing basic ecological or evolutionary processes. Second, these terms are often used as if the study of how ecological and evolutionary processes are intertwined is novel when, in fact, it is not. The result is confusion over what the term “eco-evolution” and its derivatives describe, a loss of appreciation for the history of genuine eco-evolutionary studies, and a loss of appreciation for the novelty associated with the original rise of the term. We advocate a more precise definition of eco-evolution that is more useful in our effort to understand and characterize the diversity of ecological and evolutionary processes and that focuses attention on the subset of those processes that offer novel results.

Global influenza virus circulation declined and has been below traditional seasonal levels during the COVID-19 pandemic.1-3 We reviewed WHO influenza surveillance outputs from May 1-December 31, 2020 (epidemiologic weeks 18-53) from tropical Asian countries. For each country we report influenza surveillance specimens tested, and the percentage positive for influenza, by type and subtype. We compared current data to historical data from 2015-2019 in order to place the current season in historical context. Twelve included countries tested 17,407 surveillance specimens, with 592 (3.4%) testing positive for influenza viruses. From April 27-July 26, 2020 (epidemiologic weeks 18-30), specimens tested decreased from an average of 14,102 per year in 2015-2019 to 3,969 (71.9% decrease) and influenza positivity from 22% to <1%. During weeks 31-53, specimens tested decreased from an average of 24,782 per year in 2015-2019 to 13,438 (45.8% decrease) and influenza positivity from 18% to 4%. In six countries that maintained testing of surveillance specimens for >90% of weeks, influenza circulation was unseasonably low, or absent, during weeks 18-30, 2020. However, during weeks 31-53, the percentage of surveillance specimens testing positive for influenza approached or reached positivity rates of 2015-2019 in Bangladesh and Cambodia; and increased but remained lower than historical positivity in Lao PDR and Viet Nam. The data presented here are a reminder that the low levels of influenza circulation in the northern hemisphere in summer 2020 may not necessarily persist into the upcoming influenza season, and influenza surveillance and prevention strategies should continue as planned and not be delayed.

A document by Kefei Rao. Click on the document to view its contents.