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Summary: In an attempt to unravel functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we show that USP7 and TRIM27 are integral components of PRC1.1. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H2AK119ub marks are also lost at PRC1 loci. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients.

Aim: To provide insight in the primary health care (PHC) case management of febrile children under-five in Dar es Salaam, and to identify areas for improving quality of care.Methods: We used data from the routine care arm of the ePOCT trial, including children aged 2–59 months who presented with an acute febrile illness to two health centers in Dar es Salaam (2014–2016). The presenting complaint, anthropometrics, vital signs, test results, final diagnosis, and treatment were prospectively collected in all children. We used descriptive statistics to analyze the frequencies of diagnoses, adherence to diagnostics, and prescribed treatments.Results: We included 547 children (47% male, median age 14 months). Most diagnoses were viral: upper respiratory tract infection (60%) and/or gastro-enteritis (18%). Vital signs and anthropometric measurements taken by research staff and urinary testing failed to influence treatment decisions. In total, 518/547 (95%) children received antibiotics, while 119/547 (22%) had an indication for antibiotics based on local guidelines. Antibiotic dosing was frequently out of range. Non-recommended treatments were common (29%), most often cough syrup and vitamins.Conclusion: Our study points to challenges in using diagnostic test results, concerns regarding quality of antibiotic prescriptions, and frequent use of non-evidence-based complementary medicines in PHC in Tanzania. Larger studies on diagnostic and treatments processes in PHC in Tanzania are needed to inform effective solutions to support PHC workers in case management of children.

Background: Coronavirus disease of 2019 (COVID-19) is associated with a prothrombotic state and a high incidence of thrombotic event(s) (TE).Objectives: To study platelet reactivity in hospitalized COVID-19 patients and determine a possible association with the clinical outcomes thrombosis and all-cause mortality.Methods: Seventy nine hospitalized COVID-19 patients were enrolled in this retrospective cohort study and provided blood samples in which platelet reactivity in response to stimulation with ADP and TRAP-6 was determined using flow cytometry. Clinical outcomes included thrombotic events, and all-cause mortality.Results: The incidence of TE in this study was 28% and all-cause mortality 16%. Patients that developed a TE were younger than patients that did not develop a TE [median age of 55 vs. 70 years; adjusted odds ratio (AOR) = 0.96 per 1 year of age, 95% confidence interval (CI) 0.92–1.00; p = 0.041]. Furthermore, patients using preexisting thromboprophylaxis were less likely to develop a thrombotic complication than patients that were not (18 vs. 54%; AOR = 0.19, 95% CI 0.04–0.84; p = 0.029). Conversely, having asthma strongly increased the risk on TE development (AOR = 6.2, 95% CI 1.15–33.7; p = 0.034). No significant differences in baseline P-selectin expression or platelet reactivity were observed between the COVID-19 positive patients (n = 79) and COVID-19 negative hospitalized control patients (n = 21), nor between COVID-19 positive survivors or non-survivors. However, patients showed decreased platelet reactivity in response to TRAP-6 following TE development.Conclusion: We observed an association between the use of preexisting thromboprophylaxis and a decreased risk of TE during COVID-19. This suggests that these therapies are beneficial for coping with COVID-19 associated hypercoagulability. This highlights the importance of patient therapy adherence. We observed lowered platelet reactivity after the development of TE, which might be attributed to platelet desensitization during thromboinflammation.

Introduction: The role of surgery for early stage malignant pleural mesothelioma (MPM) remains controversial. Current expert opinion is only to treat patients surgically as part of multimodality therapy. It is still challenging to identify patients who will not benefit from surgery. We specifically evaluated tumor-related parameters in combination with clinical parameters to identify prognostic markers for survival. Methods: Clinical data of 27 consecutive patients with MPM treated with extended pleurectomy and decortication within a multimodality approach were collected and analyzed. Several tumor (immuno-)histopathologic characteristics were determined on resected tumor material, among which MTAP and Ki67 (MIB-1). Univariable and multivariable analyses served to correlate clinical and tumor-related parameters to overall survival (OS) and progression-free survival (PFS). Results: The median PFS (mPFS) was 15.3, and the median OS (mOS) was 26.5 months. Patients with a Ki67 score greater than 10% had a significantly shorter PFS (mPFS = 8.81 versus 25.35 mo, p = 0.001) and OS (mOS 19.7 versus 44.5 mo, p = 0.002) than those with a Ki67 score less than or equal to 10. Receiver operating characteristic curve analysis for Ki67 revealed an area under the curve of 0.756 with a sensitivity of 90% and specificity of 71% for a cutoff of 10% for Ki67. Patients with loss of MTAP had a significantly shorter mPFS (9 versus 21.1 mo, p = 0.014) and mOS (19.7 versus 42.6 mo, p = 0.047) than those without MTAP loss. Conclusions: In our study, Ki67 was prognostic for OS and PFS in patients with MPM treated with extended pleurectomy/decortication in a multimodality approach. Determination of Ki67 before surgery combined with specific clinical parameters could assist in clinical decision making by identifying patients, with high Ki67, who are unlikely to benefit from surgery.

Von Willebrand factor (VWF) multimer analysis is important in the classification of von Willebrand disease (VWD). Current visual VWF multimer analysis is time consuming and inaccurate in detecting subtle changes in multimer patterns. Although VWF multimer densitometric analysis may be useful, the accuracy needs further investigation before it can be widely applied. In this study we aimed to validate VWF multimer densitometric analysis in a large cohort of VWD patients and to identify patient characteristics associated with densitometric outcomes. Patients were included from the Willebrand in the Netherlands (WiN) study, in which a bleeding score (BS) was obtained, and blood was drawn. For multimer analysis, citrated blood was separated on an agarose gel and visualized by Western blotting. IMAGEJ was used to generate densitometric images and medium-large VWF multimer index was calculated. We included 560 VWD patients: 328 type 1, 211 type 2, and 21 type 3 patients. Medium-large VWF multimer index performed excellent in distinguishing visually classified normal VWF multimers from reduced high-molecular-weight (HMW) multimers (area under the curve [AUC]: 0.96 [0.94-0.98], P < 0.001), normal multimers from absence of HMW multimers (AUC 1.00 [1.00-1.00], P < 0.001), and type 2A and 2B from type 2M and 2N (AUC: 0.96 [0.94-0.99], P < 0.001). Additionally, higher medium-large VWF multimer index was associated with lower BS in type 1 VWD: β = -7.6 (-13.0 to -2.1), P = 0.007, adjusted for confounders. Densitometric analysis of VWF multimers had an excellent accuracy compared with visual multimer analysis and may contribute to a better understanding of the clinical features such as the bleeding phenotype of VWD patients.

Summary: Background: During the COVID-19 pandemic, the scarcity of resources has necessitated triage of critical care for patients with the disease. In patients aged 65 years and older, triage decisions are regularly based on degree of frailty measured by the Clinical Frailty Scale (CFS). However, the CFS could also be useful in patients younger than 65 years. We aimed to examine the association between CFS score and hospital mortality and between CFS score and admission to intensive care in adult patients of all ages with COVID-19 across Europe. Methods: This analysis was part of the COVID Medication (COMET) study, an international, multicentre, retrospective observational cohort study in 63 hospitals in 11 countries in Europe. Eligible patients were aged 18 years and older, had been admitted to hospital, and either tested positive by PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or were judged to have a high clinical likelihood of having SARS-CoV-2 infection by the local COVID-19 expert team. CFS was used to assess level of frailty: fit (CFS1–3), mildly frail (CFS4–5), or frail (CFS6–9). The primary outcome was hospital mortality. The secondary outcome was admission to intensive care. Data were analysed using a multivariable binary logistic regression model adjusted for covariates (age, sex, number of drugs prescribed, and type of drug class as a proxy for comorbidities). Findings: Between March 30 and July 15, 2020, 2434 patients (median age 68 years [IQR 55–77]; 1480 [61%] men, 954 [30%] women) had CFS scores available and were included in the analyses. In the total sample and in patients aged 65 years and older, frail patients and mildly frail patients had a significantly higher risk of hospital mortality than fit patients (total sample: CFS6–9 vs CFS1–3 odds ratio [OR] 2·71 [95% CI 2·04–3·60], p

Serine proteases drive important physiological processes such as coagulation, fibrinolysis, inflammation and angiogenesis. These proteases are controlled by serine protease inhibitors (SERPINs) that neutralize their activity. Currently, over 1,500 SERPINs are known in nature, but only 37 SERPINs are found in humans. Thirty of these are functional protease inhibitors. The inhibitory potential of SERPINs is in perfect balance with the proteolytic activities of its targets to enable physiological protease activity. Hence, SERPIN deficiency (either qualitative or quantitative) can lead to disease. Several SERPIN resupplementation strategies have been developed to treat SERPIN deficiencies, including concentrates derived from plasma and recombinant SERPINs. SERPINs usually inhibit multiple proteases, but only in their active state. Over the past decades, considerable insights have been acquired in the identification of SERPIN biological functions, their inhibitory mechanisms and specificity determinants. This paves the way for the development of therapeutic SERPINs. Through rational design, the inhibitory properties (selectivity and inhibitory potential) of SERPINs can be reformed and optimized. This review explores the current state of SERPIN engineering with a focus on reactive center loop modifications and backbone stabilization. We will discuss the lessons learned from these recombinant SERPINs and explore novel techniques and strategies that will be essential for the creation and application of the future generation of therapeutic SERPINs.

Objective To explore how parents judge disease severity of their febrile child and to identify symptoms they associate with serious illness, minor illness or health.Design Semistructured interviews were conducted. Interviews were audio taped, transcribed verbatim and analysed thematically.Participants Parents of children aged 0–5 years with a febrile illness.Setting Participants were recruited at the paediatric ward and the emergency department.Results Twenty-six interviews were conducted, in which 37 parents participated. Parents described disease severity of their child mainly in terms of changes in their child’s normal characteristics (behaviour and physical features). They found it harder to describe specific disease symptoms such as dyspnoea or dehydration. Their child being active, eating and drinking well, and smiling were perceived as reassuring, whereas high fever, moving very little and uncertainty about the type of infections were mentioned as alarming symptoms. Previous experience with febrile illnesses in their children was of great influence on the number and accuracy of symptoms they reported.Conclusion Parents used the normal behaviour and physical features of their child as a reference frame for judging disease severity. With a larger deviation from the child’s normal characteristics, parents considered the illness more serious. They were less able to describe specific symptoms of disease such as dyspnoea or dehydration. This knowledge is important for clinicians in their communication with parents of children with febrile illness.

IntroductionNeutrophils contribute to host defense through different mechanisms, including the formation of neutrophil extracellular traps (NETs). The genetic background and underlying mechanisms contributing to NET formation remain unclear.Materials and MethodsWe performed a genome-wide association study (GWAS) and exome-sequencing analysis to identify common and rare genetic variants associated with plasma myeloperoxidase (MPO)-DNA complex levels, a biomarker for NETs, in the population-based Rotterdam Study cohort. GWAS was performed using haplotype reference consortium(HRC)-imputed genotypes of common variants in 3,514 individuals from the first and 2,076 individuals from the second cohort of the Rotterdam Study. We additionally performed exome-sequencing analysis in 960 individuals to investigate rare variants in candidate genes.ResultsThe GWAS yielded suggestive associations (p-value < 5.0 × 10−6) of SNPs annotated to four genes. In the exome-sequencing analysis, a variant in TMPRSS13 gene was significantly associated with MPO-DNA complex levels (p-value < 3.06×10−8). Moreover, gene-based analysis showed ten genes (OR10H1, RP11-461L13.5, RP11-24B19.4, RP11-461L13.3, KHDRBS1, ZNF200, RP11-395I6.1, RP11-696P8.2, RGPD1, AC007036.5) to be associated with MPO-DNA complex levels (p-value between 4.48 × 10−9 and 1.05 × 10−6). Pathway analysis of the identified genes showed their involvement in cellular development, molecular transport, RNA trafficking, cell-to-cell signaling and interaction, cellular growth and proliferation. Cancer was the top disease linked to the NET-associated genes.ConclusionIn this first GWAS and exome-sequencing analysis of NETs levels, we found several genes that were associated with NETs. The precise mechanism of how these genes may contribute to neutrophil function or the formation of NETs remains unclear and should be further investigated in experimental studies.

Introduction Neutrophil extracellular traps (NETs) are DNA scaffolds enriched with antimicrobial proteins. NETs have been implicated in the development of various diseases, such as cardiovascular disease. Here, we investigate the association of demographic and cardiovascular (CVD) risk factors with NETs in the general population. Material and methods Citrated plasma was collected from 6449 participants, aged ≥55 years, as part of the prospective population-based Rotterdam Study. NETs were quantified by measuring MPO-DNA complex using an ELISA. We used linear regression to determine the associations between MPO-DNA complex and age, sex, cardio-metabolic risk factors, and plasma markers of inflammation and coagulation. Results MPO-DNA complex levels were weakly associated with age (log difference per 10 year increase: -0.04 mAU/mL, 95% confidence interval [CI] -0.06;-0.02), a history of coronary heart disease (yes versus no: -0.10 mAU/mL, 95% CI -0.17;-0.03), the use of lipid-lowering drugs (yes versus no: -0.06 mAU/mL, 95% CI -0.12;-0.01), and HDL-cholesterol (per mmol/l increase: -0.07 mAU/mL/, 95% CI -0.12;-0.03). Conclusions Older age, a history of coronary heart disease, the use of lipid-lowering drugs and higher HDL-cholesterol are weakly correlated with lower plasma levels of NETs. These findings show that the effect of CVD risk factors on NETs levels in a general population is only small and may not be of clinical relevance. This supports that NETs may play a more important role in an acute phase of disease than in a steady state situation.

ObjectiveTo describe clinical characteristics, disease course and outcomes in a large and well-documented cohort of hospitalized COVID-19 patients in the Netherlands.MethodsWe conducted a multicentre retrospective cohort study in The Netherlands including 952 of 1183 consecutively hospitalized patients that were admitted to participating hospitals between March 2nd, 2020, and May 22nd, 2020. Clinical characteristics and laboratory parameters upon admission and during hospitalization were collected until July 1st.ResultsThe median age was 69 years (IQR 58-77 years) and 605 (63.6%) were male. Cardiovascular disease was present in 558 (58.6%) patients. The median time of onset of symptoms prior to hospitalization was 7 days (IQR 5-10). A non ICU admission policy was applicable in 312 (32.8%) patients and in 165 (56.3%) of the severely ill patients admitted to the ward. At admission and during hospitalization, severely ill patients had higher values of CRP, LDH, ferritin and D-dimer with higher neutrophil counts and lower lymphocyte counts. Overall in-hospital mortality was 25.1% and 183 (19.1%) patients were admitted to ICU, of whom 56 (30.6%) died. Patients aged ≥70 years had high mortality, both at the ward (52.4%) and ICU (47.4%). The median length of ICU stay was 8 days longer in patients aged ≥70 years compared to patients aged ≤60 years.ConclusionHospitalized COVID-19 patients aged ≥70 years had high mortality and longer ICU stay compared to patients aged ≤60 years. These findings in combination with the patient burden of an ICU admission and possible long term complications after discharge should encourage us to further investigate the benefit of ICU admission in elderly and fragile COVID-19-patients.

BackgroundTo date, survival data on risk factors for COVID-19 mortality in western Europe is limited, and none of the published survival studies have used a competing risk approach. This study aims to identify risk factors for in-hospital mortality in COVID-19 patients in the Netherlands, considering recovery as a competing risk.MethodsIn this observational multicenter cohort study we included adults with PCR-confirmed SARS-CoV-2 infection that were admitted to one of five hospitals in the Netherlands (March to May 2020). We performed a competing risk survival analysis, presenting cause-specific hazard ratios (HRCS) for the effect of preselected factors on the absolute risk of death and recovery.Results1,006 patients were included (63.9% male; median age 69 years, IQR: 58-77). Patients were hospitalized for a median duration of 6 days (IQR: 3-13); 243 (24.6%) of them died, 689 (69.9%) recovered, and 74 (7.4%) were censored. Patients with higher age (HRCS 1.10, 95% CI 1.08-1.12), immunocompromised state (HRCS 1.46, 95% CI 1.08-1.98), who used anticoagulants or antiplatelet medication (HRCS 1.38, 95% CI 1.01-1.88), with higher modified early warning score (MEWS) (HRCS 1.09, 95% CI 1.01-1.18), and higher blood LDH at time of admission (HRCS 6.68, 95% CI 1.95-22.8) had increased risk of death, whereas fever (HRCS 0.70, 95% CI 0.52-0.95) decreased risk of death. We found no increased mortality risk in male patients, high BMI or diabetes.ConclusionOur competing risk survival analysis confirms specific risk factors for COVID-19 mortality in a the Netherlands, which can be used for prediction research, more intense in-hospital monitoring or prioritizing particular patients for new treatments or vaccination.

Social animals flexibly use a variety of vocalizations to communicate in complex and dynamic environments. However, it remains unknown whether the auditory perception of different vocalizations changes according to the ecological context. By using miniature wireless devices to synchronously record vocal interactions and local neural activity in freely-behaving zebra finches in combination with playback experiments, we investigate whether the auditory processing of vocalizations changes across life-history stages. We show that during breeding, females (but not males) increase their estrogen levels and reply faster to their mates when interacting vocally. These changes are associated with an increase in the amplitude of the female’s neural auditory responses. Furthermore, the changes in auditory response are not general, but specific to a subset of functionally distinct vocalizations and dependent on the emitter’s identity. These results provide novel insights into auditory plasticity of communication systems, showing that the perception of specific signals can shift according to ecologically-determined physiological states.

BackgroundAutism and schizophrenia spectrum disorders both represent severely disabling neurodevelopmental disorders with marked impairments in social functioning. Despite an increased incidence of psychosis in autism, and substantial overlap in symptoms and cognitive markers, it is unclear whether such phenotypes are specifically related to risk for psychosis or perhaps reflect more general, idiosyncratic autism traits. The attenuated psychosis syndrome (APS) is primarily defined by the presence of attenuated psychotic symptoms, which currently constitute the best and most-replicated clinical predictors of psychosis, and are common in clinical youth with and without autism. The aims of this study were to test the hypothesis that facial affect processing is impaired in adolescents with APS and to explore whether such deficits are more indicative of psychotic or autistic phenotypes on a categorical and dimensional level.Materials and MethodFifty-three adolescents with APS and 81 typically developing controls (aged 12–18) were included. The APS group consisted of adolescents with (n = 21) and without (n = 32) a diagnosis of autism spectrum disorder. Facial affect recognition was assessed with the Amsterdam Neuropsychological Tasks using a cascade model of cognitive processing, in which disturbances in “lower-level” cognitive abilities (pattern recognition), affect “higher-level” cognitive processes (face recognition and facial affect recognition). For associations with schizotypal and autistic-like traits the Schizotypal Personality Questionnaire and Social Communication Questionnaire were used in a confirmatory item factor analysis framework.ResultsContrary to expectation, APS in adolescents was not associated with impairments in pattern, face, or facial affect recognition. However, the APS group with autism spectrum disorder showed a general latency in response time to social and non-social stimuli. Dimensionally assessed schizotypal and autistic-like traits did not predict the accuracy or the speed of face or facial affect recognition.ConclusionFacial affect processing performance was not associated with APS in adolescence and represents an unlikely early vulnerability marker for psychosis. APS individuals with a more autistic-like profile were characterized by slower responses to social- and non-social stimuli, suggesting that the combined effect of APS and autism spectrum disorder on cognition is larger than for APS alone.

This paper presents the Subterranean 2.0 cipher suite that can be used for hashing, MAC computation, stream encryption and several types of authenticated encryption schemes. At its core it has a duplex object with a 257-bit state and a lightweight single-round permutation. This makes Subterranean 2.0 very well suited for low-area and low-energy implementations in dedicated hardware.

Attention problems hinder many children in their cognitive and social emotional development. Children at risk for developmental problems, like preterm born infants, are specifically known for attention difficulties. Early identification of attention difficulties is important for application of appropriate stimulation in trying to reduce further problems. Specifically designed instruments with good psychometric characteristics are needed to show difficulties in attention, that may contribute to early identification. The Utrecht Tasks of Attention in Toddlers using Eye tracking (UTATE) is an instrument to measure orienting, alerting and executive attention capacities in young children. Reliability and validity of the UTATE are specifically addressed in three studies, reported in this paper. A sample of 95 term born children assessed at 18 months of age was used that provided data for both the second and third study reported here. In addition, three other small samples were used, of which the first consisted of 12 children at 18 months with test-retest data available that are reported in the first study. Two other samples that were used in the third study, consisted of 14 children measured at 12 months, and 15 children examined at 24 months. The UTATE resulted in reliable information on eye movements and some first support for construct and predictive validity was found. Low scores on the UTATE at 18 months were found to be related to slower cognitive development as measured with the Bayley-III-NL at 24 months. Furthermore, a first indication that the UTATE is able to detect some age differences in attention was found. It is concluded that the UTATE can be used to study attention capacities in toddlers that underlie cognitive functioning and development, but further research is necessary.

C1-inhibitor (C1-INH) is an important regulator of the complement, coagulation, fibrinolytic and contact systems. The quantity of protease/C1-INH complexes in the blood is proportional to the level of the in vivo activation of these four cascade-like plasma enzyme systems. Parallel determination of C1-INH-containing activation complexes could be important to understand the regulatory role of C1-INH in diseases such as hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE). We developed in-house ELISAs to measure the concentration of complexes of C1-INH formed with active proteases: C1r, C1s, MASP-1, MASP-2, plasma kallikrein, factor XIIa, factor XIa, and thrombin, as well as to determine total and functionally active C1-INH. We measured the concentration of the complexes in EDTA plasma from 6 healthy controls, from 5 with type I and 5 with type II C1-INH-HAE patients during symptom-free periods and from five patients during HAE attacks. We also assessed the concentration of these complexes in blood samples taken from one C1-INH-HAE patient during the kinetic follow-up of a HAE attack. The overall pattern of complexed C1-INH was similar in controls and C1-INH-HAE patients. C1-INH formed the highest concentration complexes with C1r and C1s. We observed higher plasma kallikrein/C1-INH complex concentration in both type I and type II C1-INH-HAE, and higher concentration of MASP-1/C1-INH, and MASP-2/C1-INH complexes in type II C1-INH-HAE patients compared to healthy controls and type I patients. Interestingly, none of the C1-INH complex concentrations changed significantly during HAE attacks. During the kinetic follow-up of an HAE attack, the concentration of plasma kallikrein/C1-INH complex was elevated at the onset of the attack. In parallel, C1r, FXIIa and FXIa complexes of C1-INH also tended to be elevated, and the changes in the concentrations of the complexes followed rather rapid kinetics. Our results suggest that the complement classical pathway plays a critical role in the metabolism of C1-INH, however, in C1-INH-HAE, contact system activation is the most significant in this respect. Due to the fast changes in the concentration of complexes, high resolution kinetic follow-up studies are needed to clarify the precise molecular background of C1-INH-HAE pathogenesis.

The incidence of adenocarcinoma at the gastrooesophageal junction increased over the last years. Curative treatment for patients with upper gastrointestinal (UGI) malignancies, such as oesophageal and gastric tumours, is challenging and requires a multidisciplinary approach. Radical surgical resection with complete lymphadenectomy is the cornerstone of UGI cancer treatment. Combined with peri-operative treatment (i.e. by applying CROSS, EOX or FLOT regimen), the survival is even better than with surgery alone. However, peri-operative treatment is not effective in all patients, and the most effective strategy is a topic of active debate, as is reflected by varying treatment guidelines between countries. UGI cancers are (epi)genetically highly heterogeneous. It is thus not likely that a uniform treatment will benefit all patients equally well. Over recent years, patient-derived organoids (PDOs) gained more and more interest as an in vitro prediction model that may assist as a diagnostic tool in the future to select and eventually optimize the best peri-operative treatments for each patient. PDOs can be derived from endoscopic tumour biopsies, which maintain heterogeneity in culture. They can be rapidly established and expanded in a relatively short time for in vitro drug screening experiments. This review summarizes the clinical and molecular aspects of oesophageal and gastric tumours, as well as the current progress and remaining challenges in the use of PDOs for drug and radiation screens.

Extra virgin Olive oil is extracted from fruit that can be used as anti-inflammatory agent. This research aimed to test the potential of extra virgin olive oil in reducing edema volume and TNF-α plasma in carrageenan-induced rats. This research was purely experimental research with the post test control group design. A total of twenty eight Wistar rats were divided randomly into four treatment groups. Group I was a control negative group, while the group II, III, and IV were orally administered with extra virgin Olive oil at the dose of 0.9 ; 1.8 ; 2.7 mL/day, respectively. Paw edema was measured one hour before the rats was induced to carrageenan and every hour until four hours after it was induced to carrageenan. TNF-α plasma was measured at four hours. Analysis of the data was done by calculating the presentation of edema inhibition in every group, then the data was statistically analyzed by Anova, Repeated Anova, LSD and Kruskal Wallis test with 95% confidence interval. The result showed that extra virgin olive oil has an anti-inflammatory effect. The highest decrease in edema volume percentage was in group III (14.21%). There was a significant difference in the edema volume of all treatment groups at each time of the experiment with TNF-α value (p < 0.05). In conclusion, the administration of extra virgin olive oil can lower the volume of carrageenan-induced edema in rats depend on the dose. Also, the administration of extra virgin olive oil can be dose-dependent in reducing the levels of TNF-α in carrageenan-induced edema in rats.

We present efficient and compact hardware/software co-design implementations of the Supersingular Isogeny Key Encapsulation (SIKE) protocol on field-programmable gate arrays (FPGAs). In order to be better equipped for different post-quantum scenarios, our architectures were designed to feature high-flexibility by covering all the currently available parameter sets and with support for primes up to 1016 bits. In particular, any of the current SIKE parameters equivalent to the post-quantum security of AES-128/192/256 and SHA3-256 can be selected and run on-the-fly. This security scalability property, together with the small footprint and efficiency of our architectures, makes them ideal for embedded applications in a post-quantum world. In addition, the proposed implementations exhibit regular, constant-time execution, which provides protection against timing and simple sidechannel attacks. Our results demonstrate that supersingular isogeny-based primitives such as SIDH and SIKE can indeed be deployed for embedded applications featuring competitive performance. For example, our smallest architecture based on a 128-bit MAC unit takes only 3415 slices, 21 BRAMs and 57 DSPs on a Virtex 7 690T and can perform key generation, encapsulation and decapsulation in 14.4, 24.4 and 26.0 milliseconds for SIKEp434 and in 52.3, 86.4 and 93.2 milliseconds for SIKEp751, respectively.

BACKGROUND:Optimising the use of antibiotics is a key component of antibiotic stewardship. Respiratory tract infections (RTIs) are the most common reason for antibiotic prescription in children, even though most of these infections in children under 5 years are viral. This study aims to safely reduce antibiotic prescriptions in children under 5 years with suspected lower RTI at the emergency department (ED), by implementing a clinical decision rule. METHODS AND FINDINGS:In a stepped-wedge cluster randomised trial, we included children aged 1-60 months presenting with fever and cough or dyspnoea to 8 EDs in The Netherlands. The EDs were of varying sizes, from diverse geographic and demographic regions, and of different hospital types (tertiary versus general). In the pre-intervention phase, children received usual care, according to the Dutch and NICE guidelines for febrile children. During the intervention phase, a validated clinical prediction model (Feverkidstool) including clinical characteristics and C-reactive protein (CRP) was implemented as a decision rule guiding antibiotic prescription. The intervention was that antibiotics were withheld in children with a low or intermediate predicted risk of bacterial pneumonia (≤10%, based on Feverkidstool). Co-primary outcomes were antibiotic prescription rate and strategy failure. Strategy failure was defined as secondary antibiotic prescriptions or hospitalisations, persistence of fever or oxygen dependency up to day 7, or complications. Hospitals were randomly allocated to 1 sequence of treatment each, using computer randomisation. The trial could not be blinded. We used multilevel logistic regression to estimate the effect of the intervention, clustered by hospital and adjusted for time period, age, sex, season, ill appearance, and fever duration; predicted risk was included in exploratory analysis. We included 999 children (61% male, median age 17 months [IQR 9 to 30]) between 1 January 2016 and 30 September 2018: 597 during the pre-intervention phase and 402 during the intervention phase. Most children (77%) were referred by a general practitioner, and half of children were hospitalised. Intention-to-treat analyses showed that overall antibiotic prescription was not reduced (30% to 25%, adjusted odds ratio [aOR] 1.07 [95% CI 0.57 to 2.01, p = 0.75]); strategy failure reduced from 23% to 16% (aOR 0.53 [95% CI 0.32 to 0.88, p = 0.01]). Exploratory analyses showed that the intervention influenced risk groups differently (p < 0.01), resulting in a reduction in antibiotic prescriptions in low/intermediate-risk children (17% to 6%; aOR 0.31 [95% CI 0.12 to 0.81, p = 0.02]) and a non-significant increase in the high-risk group (47% to 59%; aOR 2.28 [95% CI 0.84 to 6.17, p = 0.09]). Two complications occurred during the trial: 1 admission to the intensive care unit during follow-up and 1 pleural empyema at day 10 (both unrelated to the study intervention). Main limitations of the study were missing CRP values in the pre-intervention phase and a prolonged baseline period due to logistical issues, potentially affecting the power of our study. CONCLUSIONS:In this multicentre ED study, we observed that a clinical decision rule for childhood pneumonia did not reduce overall antibiotic prescription, but that it was non-inferior to usual care. Exploratory analyses showed fewer strategy failures and that fewer antibiotics were prescribed in low/intermediate-risk children, suggesting improved targeting of antibiotics by the decision rule. TRIAL REGISTRATION:Netherlands Trial Register NTR5326.

At the height of the Ebola epidemic in Sierra Leone in November 2014, a new decentralized approach to ending infection chains was adopted. This approach was based on building local, small-scale Community Care Centres (CCC) intended to serve as triage units for safe handling of patients waiting for test results, with subsequent transfer to Ebola Treatment Centers (ETC) for those who tested positive for Ebola. This paper deals with local response to the CCC, and explains, through qualitative analysis of focus group data sets, why this development was seen in a positive light. The responses of 562 focus group participants in seven villages with CCC and seven neighbouring referral villages without CCC are assessed. These data confirm that CCC are compatible with community values concerning access to, and family care for, the sick. Mixed reactions are reported in the case of "safe burial", a process that directly challenged ritual activity seen as vital to maintaining good relations between socially-enclaved rural families. Land acquisitions to build CCC prompted divided responses. This reflects problems about land ownership unresolved since colonial times between communities and government. The study provides insights into how gaps in understanding between international Ebola responders and local communities can be bridged.

Staphylococcus argenteus has been reported worldwide in humans, while reported non-human cases are sparse. Its complete epidemiology, alongside its infectivity and pathogenicity in humans and non-humans, remain to be clarified. Here, we describe the first reported canine Staphylococcus argenteus, causing a deep wound infection in a Labrador retriever after orthopedic surgery. The closed genome is reported, with phylogenic and genetic analyses, as well as extensive phenotypic antimicrobial susceptibility testing for human and veterinary antibiotics. No genetic explanation could be found for its interaction with a canine host, underscoring the intrinsic multispecies pathogenicity and potential (anthropo-)zoonotic spread of Staphylococcus argenteus.

This article investigates the connection between performance, group, and society. The argument is that group formation around particular farm operations and the details of the activities they engage in are an expression of the preferred way of technology implementation. The argument is developed using Paul Richards' notion of agriculture as performance. Two cases are presented. The first is the composition of a spraying team for weed control in smallholder oil palm production in Sumatra, connected to a global agreement on sustainable oil palm production, known as the Roundtable on Sustainable Palm Oil (RSPO). The second case is about a team of women transplanting young rice seedlings on prepared paddy fields in a village in Uttarakhand, India. A new way of rice transplanting was introduced by a local non-governmental organization, known as the System of Rice Intensification (SRI). The analysis shows that group performances provide essential information about how introduced plans, regulations and material designs are reworked and turned into meaningful and effective changes to agricultural practices. The article concludes that these activities are not merely technical adjustments but in themselves express arguments about the preferred way of organising farming, farm labor, and payments. Performing groups thus exert a form of bargaining power against development actors. Keywords: Group performance, smallholder farming, technology transfer, political acts

Alongside the trans-Atlantic slave trade, plant species travelled from Africa to the Americas and back. This article examines the emerging rice gene pool in Suriname due to the global circulation of people, plants and goods. We distinguish three phases of circulation, marked by two major transitions. Rice was brought to the Americas by European colonizers, mostly as food on board of slave ships. In Suriname rice started off as a crop grown only by Maroon communities in the forests of the Suriname interior. For these runaway slaves cultivating several types of rice for diverse purposes played an important role in restoring some of their African culture. Rice was an anti-commodity that acted as a signal of protest against the slave-based plantation economy. After the end of slavery, contract labourers recruited from British India and the Dutch Indies also brought rice to Suriname. These groups grew rice as a commodity for internal and global markets. This formed the basis of a second transition, turning rice into an object of scientific research. The last phase of science-driven circulation of rice connected the late-colonial period with the global Green Revolution.

Abstract Background Patients with comorbid depression and personality disorders suffer from a heavy disease burden while tailored treatment options are limited, accounting for a high psychological and economic burden. Little is known about the effect of treatment dosage and type of psychotherapy for this specific co-morbid patient population, in terms of treatment-effect and cost-effectiveness. This study aims to compare treatment outcome of 25 versus 50 individual therapy sessions in a year. We expect the 50-session condition to be more effective in treating depression and maintaining the effect. Secondary objectives will be addressed in order to find therapy-specific and non-specific mechanisms of change. Methods In a mono-center pragmatic randomized controlled trial with a 2 × 2 factorial design, 200 patients with a depressive disorder and personality disorder(s) will be included. Patients will be recruited from a Dutch mental health care institute for personality disorders. They will be randomized over therapy dosage (25 vs 50 sessions in a year) and type of therapy (schema therapy vs short-term psychodynamic supportive psychotherapy). The primary clinical outcome measure will be depression severity and remission. Changes in personality functioning and quality of life will be investigated as secondary outcomes. A priori postulated effect moderators and mediators will be collected as well. All patients are assessed at baseline and at 1, 2, 3, 6, 9–12 months (end of therapy) and at follow up (6 and 12 months after end of treatment). Alongside the trial, an economic evaluation will be conducted. Costs will be collected from a societal perspective. Discussion This trial will be the first to compare two psychotherapy dosages in patients with both depression and personality disorders. Insight in the effect of treatment dosage for this patient group will contribute to both higher treatment effectiveness and lower costs. In addition, this study will contribute to the limited evidence base on treating patients with both depression and personality disorders. Understanding the processes that account for the therapeutic changes could help to gain insight in what works for whom. Trial registration This trial has been registered on July 20th 2016, Netherlands Trial Register, part of the Dutch Cochrane Centre (NTR5941).

Abstract Background In the Netherlands, a substantial proportion of newly diagnosed HIV patients present late for care, therefore, we investigated the effectiveness of a blended educational programme for trainers of GPs designed to stimulate proactive HIV testing. Methods GP trainers at the Academic Medical Center in Amsterdam were invited to participate in a two days training programme incorporating evidence-based practice guidelines and multiple teaching strategies, including interactive lectures, discussion groups, e-learning and quality improvement targets. The GP trainers completed questionnaires before and after the programme to evaluate the effect of the programme. We also used six-monthly cumulative laboratory data from 2010 to 2015 to compare the participating GPs’ HIV tests to the general trend in testing among non-participating GPs. Results 150 GP trainers attended the first session, and 74 completed the questionnaires for both sessions. GPs median score on achieving their quality improvement targets was high and the quality of the programme highly appreciated. Between 2010 and 2013, the mean annual number of laboratory-documented HIV tests decreased by 9.1% in the 624 GPs in the control group, and by 13.0% for 11 GPs in the intervention group. After the programme, the annual decreases were 2.3% and 1.8%, respectively. Before the programme, the GPs in the intervention group had 50% more laboratory-documented HIV tests than GPs in the control group. After the programme, GPs in the intervention group had twice as many laboratory-documented HIV tests as the controls. Conclusions We provided a detailed description of a programme based on educational and clinical evidence. We could not retrieve laboratory-documented HIV testing data for the majority of GPs in both the intervention and control groups. Therefore, the limited results should be interpreted with caution as our findings may not be representative of all participants. The blended educational programme appears to have stabilized – at a higher level – the initially stronger downward trend in testing for 11 GPs undergoing the intervention, indicating that the programme may have had an impact on their HIV testing behaviour.

Abstract Background The objective of this study is to investigate the role and experience of early stage non-small cell lung cancer (NSCLC) patient in decision making process concerning treatment selection in the current clinical practice. Methods Stage I-II NSCLC patients (surgery 55 patients, SBRT 29 patients, median age 68) were included in this prospective study and completed a questionnaire that explored: (1) perceived patient knowledge of the advantages and disadvantages of the treatment options, (2) experience with current clinical decision making, and (3) the information that the patient reported to have received from their treating physician. This was assessed by multiple-choice, 1–5 Likert Scale, and open questions. The Decisional Conflict Scale was used to assess the decisional conflict. Health related quality of life (HRQoL) was measured with SF-36 questionnaire. Results In 19% of patients, there was self-reported perceived lack of knowledge about the advantages and disadvantages of the treatment options. Seventy-four percent of patients felt that they were sufficiently involved in decision-making by their physician, and 81% found it important to be involved in decision making. Forty percent experienced decisional conflict, and one-in-five patients to such an extent that it made them feel unsure about the decision. Subscores with regard to feeling uninformed and on uncertainty, contributed the most to decisional conflict, as 36% felt uninformed and 17% of patients were not satisfied with their decision. HRQoL was not influenced by patient experience with decision-making or patient preferences for shared decision making. Conclusions Dutch early-stage NSCLC patients find it important to be involved in treatment decision making. Yet a substantial proportion experiences decisional conflict and feels uninformed. Better patient information and/or involvement in treatment-decision-making is needed in order to improve patient knowledge and hopefully reduce decisional conflict.

Student engagement is a multidimensional construct that predicts learning performance. However, student engagement receives limited attention, especially in mathematics. Thus, this study conducts a survey to determine the influence of student engagement on mathematical achievement. Stratified random sampling was employed to select secondary school students (n = 1000). Questionnaires and end-of-year examination grades were collected as data on student engagement and respective mathematics achievement. The findings indicate that there is a significant relationship between cognitive engagement, affective engagement, behavioural engagement, and mathematical achievement. The results of multiple linear regression analysis show that affective engagement is the largest predictor of mathematical achievement (β = 0.743, p < 0.001), followed by behavioural engagement (β = 0.585, p < 0.001), and cognitive engagement (β = −0.375, p < 0.01). This suggests that policymakers should formulate a curriculum that enables the improvement of affective and behavioural engagement. Furthermore, this study recommends that school administrators and teachers plan and implement activities that stimulate such engagement.

Scanning Electron Microscopy (SEM) is a powerful, high-resolution imaging technique widely used to analyze the structure of fibrin networks. Currently, structural features, such as fiber diameter, length, density, and porosity, are mostly analyzed manually, which is tedious and may introduce user bias. A reliable, automated structural image analysis method would mitigate these drawbacks. We evaluated the performance of DiameterJ (an ImageJ plug-in) for analyzing fibrin fiber diameter by comparing automated DiameterJ outputs with manual diameter measurements in four SEM data sets with different imaging parameters. We also investigated correlations between biophysical fibrin clot properties and diameter, and between clot permeability and DiameterJ-determined clot porosity. Several of the 24 DiameterJ algorithms returned diameter values that highly correlated with and closely matched the values of the manual measurements. However, optimal performance was dependent on the pixel size of the images—best results were obtained for images with a pixel size of 8–10 nm (13–16 pixels/fiber). Larger or smaller pixels resulted in an over- or underestimation of diameter values, respectively. The correlation between clot permeability and DiameterJ-determined clot porosity was modest, likely because it is difficult to establish the correct image depth of field in this analysis. In conclusion, several DiameterJ algorithms (M6, M5, T3) perform well for diameter determination from SEM images, given the appropriate imaging conditions (13–16 pixels/fiber). Determining fibrin clot porosity via DiameterJ is challenging.

The interconnectedness between climate change and development has generated an increasing interest amongst development organisations to integrate adaptation into government rural development plans in a way that effectively increases resilience at a local level. However, the nature of climate change resilience is widely debated in the literature, and there is a knowledge gap regarding the best way to address adaptation at the interface with development objectives as part of mainstreaming. This paper aims to address this knowledge gap via a case study of a community-based, Climate-Smart Agriculture (CSA) project in Vietnam. A case study approach was applied with fieldwork at one project site, complemented by semi-structured interviews with government stakeholders, key experts, and project leaders of related projects. The analysis identifies five key factors that enhance rural resilience in a smallholder agricultural context: (i) engaging local governments as partners, (ii) considering broader landscape issues such as markets, (iii) providing farmers with support to facilitate adoption of CSA practices, (iv) fostering community capacity building, and (v) promoting adaptive management and scenario planning to deal with uncertainty. The paper concludes that resilience is multidimensional and not solely in line with any one of the approaches dominant in the literature.

Using x-ray magnetic circular dichroism, we have detected the very interfacial spins that are responsible for the horizontal loop shift in three different exchange bias sandwiches, chosen because of their potential for device applications. The "pinned" uncompensated interfacial spins constitute only a fraction of a monolayer and do not rotate in an external magnetic field since they are tightly locked to the antiferromagnetic lattice. A simple extension of the Meiklejohn and Bean model is proposed to account quantitatively for the exchange bias fields in the three studied systems from the experimentally determined number of pinned moments and their sizes.

Lower respiratory tract infections (LRTIs) in children are common and, although often mild, a major cause of mortality and hospitalization. Recently, the respiratory microbiome has been associated with both susceptibility and severity of LRTI. In this current study, we combined respiratory microbiome, viral, and clinical data to find associations with the severity of LRTI. Nasopharyngeal aspirates of children aged one month to five years included in the STRAP study (Study to Reduce Antibiotic prescription in childhood Pneumonia), who presented at the emergency department (ED) with fever and cough or dyspnea, were sequenced with nanopore 16S-rRNA gene sequencing and subsequently analyzed with hierarchical clustering to identify respiratory microbiome profiles. Samples were also tested using a panel of 15 respiratory viruses and Mycoplasma pneumoniae, which were analyzed in two groups, according to their reported virulence. The primary outcome was hospitalization, as measure of disease severity. Nasopharyngeal samples were isolated from a total of 167 children. After quality filtering, microbiome results were available for 54 children and virology panels for 158 children. Six distinct genus-dominant microbiome profiles were identified, with Haemophilus-, Moraxella-, and Streptococcus-dominant profiles being the most prevalent. However, these profiles were not found to be significantly associated with hospitalization. At least one virus was detected in 139 (88%) children, of whom 32.4% had co-infections with multiple viruses. Viral co-infections were common for adenovirus, bocavirus, and enterovirus, and uncommon for human metapneumovirus (hMPV) and influenza A virus. The detection of enteroviruses was negatively associated with hospitalization. Virulence groups were not significantly associated with hospitalization. Our data underlines high detection rates and co-infection of viruses in children with respiratory symptoms and confirms the predominant presence of Haemophilus-, Streptococcus-, and Moraxella-dominant profiles in a symptomatic pediatric population at the ED. However, we could not assess significant associations between microbiome profiles and disease severity measures.