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The immunopathophysiological mechanisms underlying chronic inflammatory demyelinating polyneuropathy (CIDP) in an individual patient are largely unknown. Better understanding of these mechanisms may aid development of biomarkers and targeted therapies. Both B- and T-cell dominant mechanisms have been implicated. We therefore investigated whether B-cell and T-cell receptor (BCR/TCR) repertoires might function as immunological biomarkers in CIDP. In this prospective cohort study, we longitudinally sampled peripheral blood of CIDP patients in three different phases of CIDP: starting induction treatment (IT), starting withdrawal from IVIg maintenance treatment (MT), and patients in remission (R). BCR and TCR repertoires were analyzed using RNA based high throughput sequencing. In baseline samples, the number of total clones, the number of dominant BCR and TCR clones and their impact on the repertoire was similar for patients in the IT, MT, and remission groups compared with healthy controls. Baseline samples in the IT or MT did not predict treatment response or potential relapse at follow-up. Treatment responders in the IT group showed a potential IVIg-induced increase in the number of dominant BCR clones and their impact at follow-up (baseline1.0 [IQR 1.0-2.8] vs. 6 m 3.5 [0.3-6.8]; P

Extra-organismal DNA (eoDNA) from material left behind by organisms (noninvasive DNA, e.g., feces, hair) or from environmental samples (eDNA, e.g., water, soil) is a valuable source of genetic information. However, the relatively low quality and quantity of eoDNA, which can be further degraded by environmental factors, results in reduced amplification and sequencing success. This is often compensated for through cost- and time-intensive replications of genotyping/sequencing procedures. Therefore, system- and site-specific quantifications of environmental degradation are needed to maximize sampling efficiency (e.g., fewer replicates, shorter sampling durations), and to improve species detection and abundance estimates. Using 10 environmentally diverse bat roosts as a case study, we developed a robust modeling pipeline to quantify the environmental factors degrading eoDNA, predict eoDNA quality, and estimate sampling-site-specific ideal exposure duration. Maximum humidity was the strongest eoDNA-degrading factor, followed by exposure duration and then maximum temperature. We also found a positive effect when hottest days occurred later. The strength of this effect fell between the strength of the effects of exposure duration and maximum temperature. With those predictors and information on sampling period (before or after offspring were born), we reliably predicted mean eoDNA quality per sampling visit at new sites with a mean squared error of 0.0349. Site-specific simulations revealed that reducing exposure duration to 2–8 days could substantially improve eoDNA quality for future sampling. Our pipeline identified high humidity and temperature as strong drivers of eoDNA degradation even in the absence of rain and direct sunlight. Furthermore, we outline the pipeline's utility for other systems and study goals, such as estimating sample age, improving eDNA-based species detection, and increasing the accuracy of abundance estimates.

On 8–9 November 2022, the European Society of Pharmacogenomics and Personalised Therapy organized its sixth biennial congress, in Belgrade, Serbia (congress website: www.sspt.rs ). The congress aimed to address the current status and future perspectives of pharmacogenomics, share latest knowledge in the field of precision medicine and showcase the implementation of clinical applications in pharmacogenomics/pharmacogenetics. The 2 day congress consisted of 17 lectures given by key-opinion leaders and included a poster session plus discussions. The meeting was a great success by generating an informal environment and enabling the exchange of information between 162 participants from 16 different countries.

Background Major depression is a highly prevalent disorder causing severe personal distress, and high societal costs. Patients with depression often have comorbid insomnia disorder (ID) leading to even worse personal distress and worse treatment outcomes. Recent results from a non-randomised pilot study with internet-delivered Cognitive Behavioural Therapy (CBTi) for Insomnia (I-Sleep) added to regular depression care were promising regarding feasibility and initial effects on insomnia complaints and depression. However, no randomised controlled trial (RCT) has been performed yet to access the (cost-) effectiveness of I-Sleep for depression. Therefore, this protocol article presents the design of an RCT aimed to assess the (cost-) effectiveness of I-Sleep in addition to usual care for depression compared to usual care alone in depressed patients with a comorbid Insomnia Disorder (ID) treated at outpatient clinics for mood disorders. Methods /design This is a multi-centre RCT with measurements at baseline and at 3, 6, 9, and 12 months of follow-up. Patients with depression and an ID are randomised to either I-Sleep treatment followed by regular depression care or to regular depression care alone. Our aim is to recruit one hundred and seventy-five patients from multiple outpatient clinics for mood disorders. The primary outcome is the change in depressive symptoms over 12 months of follow-up measured with the Patient Health Questionnaire (PHQ-9). Secondary outcomes are recovery from depression (PHQ-9), insomnia severity (Insomnia Severity Index, ISI), daily functioning (Work and Social Adjustment Scale, WSAS), general quality of life (EuroQol 5-level version, EQ-5D-5L), and societal costs (Adapted versions of the iMTA Productivity Cost Questionnaire, iPCQ and iMTA Medical Cost Questionnaire, iMCQ). Discussion We hypothesize that the addition of I-Sleep to usual care will result in a significant improvement in depression treatment outcomes and quality of life as well as a decrease in healthcare and societal costs compared to usual care alone. This study is the first pragmatic RCT evaluating the effectiveness and cost-effectiveness of adding CBTi to usual care for depression. Trial registration Netherlands Trial Register (NL8955). Registered on October 6th2020. https://trialsearch.who.int/Trial2.aspx?TrialID=NL8955

Infectious bronchitis virus (IBV) is an avian pathogen from the Coronavirus family causing major health issues in poultry flocks worldwide. Because of its negative impact on health, performance, and bird welfare, commercial poultry are routinely vaccinated by administering live attenuated virus. However, field strains are capable of rapid adaptation and may evade vaccine-induced immunity. We set out to describe dynamics within and between lineages and assess potential escape from vaccine-induced immunity. We investigated a large nucleotide sequence database of over 1700 partial sequences of the S1 spike protein gene collected from clinical samples of Dutch chickens submitted to the laboratory of Royal GD between 2011 and 2020. Relative frequencies of the two major lineages GI-13 (793B) and GI-19 (QX) did not change in the investigated period, but we found a succession of distinct GI-19 sublineages. Analysis of dN/dS ratio over all sequences demonstrated episodic diversifying selection acting on multiple sites, some of which overlap predicted N-glycosylation motifs. We assessed several measures that would indicate divergence from vaccine strains, both in the overall database and in the two major lineages. However, the frequency of vaccine-homologous lineages did not decrease, no increase in genetic variation with time was detected, and the sequences did not grow more divergent from vaccine sequences in the examined time window. Concluding, our results show sublineage turnover within the GI-19 lineage and we demonstrate episodic diversifying selection acting on the partial sequence, but we cannot confirm nor rule out escape from vaccine-induced immunity. RESEARCH HIGHLIGHTS Succession of GI-19 IBV variants in broiler populations. IBV lineages overrepresented in either broiler, or layer production chickens. Ongoing episodic selection at the IBV S1 spike protein gene sequence. Several positively selected codons coincident with N-glycosylation motifs.

Dispersal has been suggested to be challenging, especially for species that heavily rely on social learning for knowledge acquisition. One of the obstacles that migrants face is learning how to cope with an unfamiliar, new habitat, which may involve learning from resident individuals. So far, only very few studies have looked at social learning in migrants after dispersal. Here we examine how migrant male orangutans use a behavior called “peering” (an indicator of observational social learning), to learn from local individuals. In total, we analyzed 4,009 daily dyadic associations with and without peering events of 77 males of the highly sociable Sumatran orangutans (Pongo abelii) at the Suaq population and 75 males of the less sociable Bornean orangutans (Pongo pygmaeus wurmbii) at the Tuanan population, covering a combined study time of 30 years. Analysis using generalized linear mixed models supported our prediction that migrant males in Suaq preferentially peered at the local adult females. However, in Tuanan, migrants peered mostly at other adult males and local immatures. Migrants’ peering rates were highest shortly after their arrival, and significantly decreased with increasing time spent in the area. Migrants in both sites peered significantly more at peering targets’ feeding on food items that are rarely eaten within the locals’ diet, than at commonly eaten ones and peered significantly more at skill-intense food items than easy-to-process ones. Further, migrants interacted significantly more with the peered-at food item after the peering event, than before, suggesting that they practice the observed behavior. Our results therefore suggest that migrant males use peering to learn new ecological knowledge after dispersal (e.g., where and what to feed on), and continue to learn complex skills even within adulthood, (e.g., how to feed on skill-intense food items). To do so, migrants selectively attend to the most knowledgeable and/or available individuals, practice the new skill afterwards and even flexibly adjust their learning, e.g., when confronted with intolerant locals or when the need for learning decreases. Together, our study provides important evidence that social learning in great apes expands towards adulthood, an ability which critically impacted also human evolution.

The true prevalence of dairy cattle herds with M. bovis infections in the Netherlands is unknown. Previous attempts to estimate prevalences were hampered by the absence of a diagnostic serological test that was validated under field conditions. This study estimated sensitivity and specificity of two commercial serum ELISAs and the true M. bovis herd prevalence using different Bayesian latent class models. A total of 7305 serum samples from 415 randomly chosen dairy herds were collected in fall/winter 2019 and investigated for presence of antibodies against M. bovis using the BIO-K-260 ELISA from Bio-X. Serum samples from 100 of these herds were also tested with a second ELISA, from IDvet. A Bayesian latent class model using the paired test results estimated a sensitivity of 14.1% (95% Bayesian probability interval (BPI): 11.6–16.7%) for the Bio-X ELISA and a specificity of 97.2% (95% BPI: 95.9–98.4%). Sensitivity and specificity for the IDvet ELISA were estimated at 92.5% (95% BPI: 88.3–96.5%) and 99.3% (95% BPI: 98.7–99.8%), respectively. Also, Bio-X ELISA sensitivity was considerably higher with data from calves only and with data from a selection of herds with a clinical outbreak, whereas the IDvet ELISA sensitivity was fairly constant under these conditions. These differences in test sensitivity is expected to be related to an effect of time since infection. A second Bayesian model, applied on test results of all 415 herds, estimated a true herd prevalence of 69.9% (95% BPI: 62.7–77.6%), suggesting M. bovis in endemic amongst dairy cattle herds in the Netherlands. To what extent seropositive herds have experienced a clinical outbreak needs further investigation.

Objectives In this study we describe the development and validation of a liquid chromatography mass spectrometry method (LC-MS/MS) to quantify five tryptophan (TRP) metabolites within the kynurenine– and serotonin pathway and apply the method to serum samples of women in the first trimester of pregnancy. A secondary aim was to investigate the correlation between body mass index (BMI) and the five analytes. Methods A LC-MS/MS was developed for the analysis of TRP, kynurenine (KYN), 5-hydroxytryptophan (5-HTP), hydroxytryptamine (5-HT), and 5-hydroxyindole acetic acid (5-HIAA). Serum samples (n=374) were analyzed of pregnant women (median gestational age: 8 ± 2 weeks) participating in a subcohort of the Rotterdam Periconceptional Cohort (Predict study). Results The LC-MS/MS method provided satisfactory separation of the five analytes (7 min run). For all analytes R2 was >0.995. Within- and between-run accuracies were 72–97% and 79–104%, and the precisions were all Conclusions The LC-MS/MS method is able to accurately quantify kynurenine– and serotonin pathway metabolites in pregnant women, providing an opportunity to investigate the role of the TRP metabolism in the (patho)physiology of pregnancy.

Purpose: This study aims to systematically review and critically appraise the content validity of the adult versions of the Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF) item bank and its derivative measures in any adult population. Methods: MEDLINE and EMBASE were searched in October 2021 for studies on measurement properties of PROMIS-PF measures in an adult population. Studies were included if the study described the development of a PROMIS-PF measure or investigated its relevance, comprehensiveness, or comprehensibility. Assessment of the methodological quality of eligible studies, rating of results, and summarizing evidence was performed following the COnsensus‐based Standards for the selection of health Measurement INstruments (COSMIN) methodology for assessing content validity. A modified GRADE approach was used to determine the level of evidence. Results: Three development studies and eight studies on the content validity of one or more of the PROMIS-PF measures were identified. The methodological quality of most studies was rated doubtful. There was low to high level evidence for sufficient relevance, comprehensiveness, and comprehensibility of most PROMIS-PF measures for healthy seniors and various disease populations. We found low to moderate level evidence for insufficient relevance of PROMIS-PF measures for patients with conditions that affected only one body part, and insufficient comprehensibility of the PROMIS-PF measures for minority elderly. Conclusion: Most PROMIS-PF measures demonstrate sufficient content validity in healthy seniors and various disease populations. However, the quality of this evidence is generally low to moderate, due to limitations in the methodological quality of the studies.

We sought to assess if a state-wide lockdown implemented due to COVID-19 was associated with increased odds of being a potentially avoidable transfer (PAT).We conducted a retrospective observational analysis using hospital administrative data of interfacility ED-to-ED transfers to a single, quaternary care adult ED after "Safer at Home" orders were issued March 23rd, 2020 in [Blinded for submission]. Using the PAT classification to identify transfers rapidly discharged from the ED or hospital and may not require in-person care, we used a multivariable logistic regression model to examine the association of the lockdown order with odds of a transfer being a PAT. We compared the period January 1, 2018 to March 23, 2020 with March 24, 2020 to September 30, 2020, adjusting for seasonality, patient, and situational factors.There were 20,978 ED-to-ED transfers from during this period that were eligible and 4806 (23%) that met PAT criteria. While the first month post-lockdown saw a decrease in PATs (28%), this was not sustained. In the multivariable model there was a significant seasonal effect; May through September had the highest number of transfers as well as PATs. After adjusting for seasonality, the lockdown was not associated with PATs (adjusted odds ratio [aOR] 0.99, 95% CI 0.2, 5.2) and PATs decreased over time.We did not find an effect of the COVID-19 lockdown on PATs though there was a considerable seasonal effect and an overall downward trend in PATs over time.

Contains fulltext : 290620.pdf (Publisher’s version ) (Open Access) BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor and is registered for the treatment of ulcerative colitis (UC). The effectiveness of tofacitinib has been evaluated up to 12 months of treatment. AIM: The aim of this study was to assess the effectiveness and safety of 24 months of tofacitinib use in UC patients in the Netherlands. METHODS: Patients initiating tofacitinib treatment were included in the ICC Registry, a nationwide, observational registry. Patients were prospectively evaluated for up to 24 months. The primary outcome was corticosteroid-free clinical remission (CSFR, Simple Clinical Colitis Activity Index [SCCAI] ≤2) at week 104. Secondary outcomes included biochemical remission (C-reactive protein (CRP) ≤5 mg/L and faecal calprotectin (FC) ≤250 μg/g), safety, and discontinuation rate. RESULTS: We included 110 patients of whom 104 (94.5%) were anti-TNF experienced. After 104 weeks of tofacitinib, 31.8% (34/107) were in CSFR, 23.4% (25/107) in biochemical remission and 18.7% (20/107) in combined clinical and biochemical remission. Of the patients in CSFR at week 52, 76.5% (26/34) remained so after 104 weeks of treatment. Sixty-one patients (55.5%) discontinued tofacitinib after a median duration of 13 weeks (IQR 7-34). The main reasons for discontinuation were non-response (59%), loss of response (14.8%), and adverse events (18%). There were 33.9 possible tofacitinib-related adverse events per 100 patient-years during follow-up. Adverse events most probably related to tofacitinib were skin reactions and headaches. There were 6.4 herpes zoster infections per 100 patient-years. CONCLUSION: Tofacitinib was effective in 31.8% of patients after 24 months of treatment. 01 januari 2023

Objective: We evaluate nationwide perioperative outcomes of complex EVAR and assess the volume-outcome association of complex EVAR. Summary of Background Data: Endovascular treatment with fenestrated (FEVAR) or branched (BEVAR) endografts is progressively used for excluding complex aortic aneurysms (complex AAs). It is unclear if a volumeoutcome association exists in endovascular treatment of complex AAs (complex EVAR). Methods: All patients prospectively registered in the Dutch Surgical Aneurysm Audit who underwent complex EVAR (FEVAR or BEVAR) between January 2016 and January 2020 were included. The effect of annual hospital volume on perioperative mortality was examined using multivariable logistic regression analyses. Patients were stratified into quartiles based on annual hospital volume to determine hospital volume categories. Results: We included 694 patients (539 FEVAR patients, 155 BEVAR patients). Perioperative mortality following FEVAR was 4.5% and 5.2% following BEVAR. Postoperative complication rates were 30.1% and 48.7%, respectively. The first quartile hospitals performed

Item does not contain fulltext STUDY DESIGN: Consensus study. OBJECTIVES: The purpose of this study is to define a standardized (network) outcomes set for traumatic spinal cord injury (t-SCI), covering the patient journey from acute to chronic rehabilitation phase, including patient-relevant outcomes, adequate measurement instruments, as well as case-mix and risk factors. SETTING: Acute Spinal Cord Injury (ASCI) Unit Nijmegen, the Netherlands. METHODS: A modified Delphi method was performed, including a multidisciplinary panel of 19 health-care professionals with experience in t-SCI management. Formal consensus was reached after two web-based surveys, a face-to-face meeting, and a final confirmation round (threshold consensus: 70%). RESULTS: In the first two Delphi rounds, 18/19 invited panelists (94.7%) responded and 10 panelists participated in the final meeting. The prefinal set was confirmed by all panelists. The standard set encompasses the three-tiered outcome hierarchy and consists of patient-reported and clinician-reported outcome domains and measurement instruments. Consensus was reached to include survival, degree of health or recovery, time to recovery, and return to normal activities, disutility of care or treatment process, sustainability of health and nature of recurrences, and long-term consequences of therapy. A measurement schedule was defined as well as for proposed casemix and risk factors, including demographics, clinical status, and treatment process. CONCLUSION: A standard set of network outcomes is developed that could be implemented in hospitals and rehabilitation centers involved in the treatment of t-SCI. Using this standard set, comparison of the quality of care is possible and prognostic prediction of outcomes of treatment is feasible, so that each patient receives the right care at the right time in the right place. 01 september 2022

Central to this article are two maps by Floris Balthasarsz van Berckenrode, both on the siege of Grave (1602) by Maurice of Orange during the Dutch Revolt. The first map was in 1602 produced as a news map about the events, the second was a re-edition, published eight years later as a book illustration for Jan Jansz Orlers, Den Nassauschen Lauren-Crans (Leiden 1610). In this article, principles for a new method are introduced to analyse and compare these ‘story maps’ with particular attention to the narrative impact of the map. Using this method in combi-nation with (book) historical research, it argues that the 1610 map should be considered as a ‘memorial map’ that reframes the collective memory of the Dutch Revolt. It emphasizes the dynamic relationship between news, map and book publishing and pleads for a more prominent position of story maps and book illustrations in Early Modern memory landscapes.

Background and Objective: The tacrolimus concentration within peripheral blood mononuclear cells may correlate better with clinical outcomes after transplantation compared to concentrations measured in whole blood. However, intracellular tacrolimus measurements are not easily implemented in clinical practice. The prediction of intracellular concentrations based on whole-blood concentrations would be a solution for this. Therefore, the aim of this study was to describe the relationship between intracellular and whole-blood tacrolimus concentrations in a population pharmacokinetic (popPK) model. Methods: Pharmacokinetic analysis was performed using non-linear mixed effects modelling software (NONMEM). The final model was evaluated using goodness-of-fit plots, visual predictive checks, and a bootstrap analysis. Results: A total of 590 tacrolimus concentrations from 184 kidney transplant recipients were included in the study. All tacrolimus concentrations were measured in the first three months after transplantation. The intracellular tacrolimus concentrations (n = 184) were best described with an effect compartment. The distribution into the effect compartment was described by the steady-state whole-blood to intracellular ratio (RWB:IC) and the intracellular distribution rate constant between the whole-blood and intracellular compartments. Lean body weight was negatively correlated [delta objective function value (ΔOFV) −8.395] and haematocrit was positively correlated (ΔOFV = − 6.752) with RWB:IC, and both lean body weight and haematocrit were included in the final model. Conclusion: We were able to accurately describe intracellular tacrolimus concentrations using whole-blood concentrations, lean body weight, and haematocrit values in a popPK model. This model may be used in the future to more accurately predict clinical outcomes after transplantation and to identify patients at risk for under- and overexposure.

Background Efficient recovery of circulating tumor DNA (ctDNA) depends on the quantity and quality of circulating cell-free DNA (ccfDNA). Here, we evaluated whether various ccfDNA extraction methods routinely applied in Dutch laboratories affect ccfDNA yield, ccfDNA integrity, and mutant ctDNA detection, using identical lung cancer patient–derived plasma samples. Methods Aliquots of 4 high-volume diagnostic leukapheresis plasma samples and one artificial reference plasma sample with predetermined tumor-derived mutations were distributed among 14 Dutch laboratories. Extractions of ccfDNA were performed according to local routine standard operating procedures and were analyzed at a central reference laboratory for mutant detection and assessment of ccfDNA quantity and integrity. Results Mutant molecule levels in extracted ccfDNA samples varied considerably between laboratories, but there was no indication of consistent above or below average performance. Compared to silica membrane–based methods, samples extracted with magnetic beads–based kits revealed an overall lower total ccfDNA yield (−29%; P Conclusions In the Netherlands, we encountered diversity in preanalytical workflows with potential consequences on mutant ctDNA detection in clinical practice. Silica membrane–based methodologies resulted in the highest total ccfDNA yield and are therefore preferred to detect low copy numbers of relevant mutations. Harmonization of the extraction workflow for accurate quantification and sensitive detection is required to prevent introduction of technical divergence in the preanalytical phase and reduce interlaboratory discrepancies.

INTRODUCTION: A genetic variant explaining a part of the exposure of many kinase inhibitors (KIs) is the single nucleotide polymorphism (SNP) CYP3A4*22, resulting in less CYP3A4 enzyme activity. The primary aim of this study was to investigate if the systemic exposure is non-inferior after a dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to patients without this SNP (i.e., wildtype patients) receiving the standard dose. METHODS: In this multicenter, prospective, non-inferiority study, patients were screened for the presence of CYP3A4*22. Patients with the CYP3A4*22 SNP received a 20-33% dose reduction. At steady state, a pharmacokinetic (PK) analysis was performed and compared to the PK results from wildtype patients treated with the registered dose using a two-stage individual patient data meta-analysis approach. RESULTS: In total, 207 patients were included in the final analysis. The CYP3A4*22 SNP was found in 16% of the patients in the final analysis (n = 34). Most of the included patients received imatinib (37%) or pazopanib (22%) treatment. The overall geometric mean ratio (GMR) comparing the exposure of the CYP3A4*22 carriers to the exposure of the wildtype CYP3A4 patients was 0.89 (90% confidence interval: 0.77-1.03). CONCLUSION: Non-inferiority could not be proven for dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to the registered dose in wildtype patients. Therefore, an up-front dose reduction based upon the CYP3A4*22 SNP for all KIs does not seem an eligible new way of personalized therapy. TRIAL REGISTRATION: International Clinical Trials Registry Platform Search Portal; number NL7514; registered 11/02/2019.

The crosstalk between prostate cancer (PCa) cells and the tumor microenvironment plays a pivotal role in disease progression and metastasis and could provide novel opportunities for patient treatment. Macrophages are the most abundant immune cells in the prostate tumor microenvironment (TME) and are capable of killing tumor cells. To identify genes in the tumor cells that are critical for macrophage-mediated killing, we performed a genome-wide co-culture CRISPR screen and identified AR, PRKCD, and multiple components of the NF-κB pathway as hits, whose expression in the tumor cell are essential for being targeted and killed by macrophages. These data position AR signaling as an immunomodulator, and confirmed by androgen-deprivation experiments, that rendered hormone-deprived tumor cells resistant to macrophage-mediated killing. Proteomic analyses showed a downregulation of oxidative phosphorylation in the PRKCD- and IKBKG-KO cells compared to the control, suggesting impaired mitochondrial function, which was confirmed by electron microscopy analyses. Furthermore, phosphoproteomic analyses revealed that all hits impaired ferroptosis signaling, which was validated transcriptionally using samples from a neoadjuvant clinical trial with the AR-inhibitor enzalutamide. Collectively, our data demonstrate that AR functions together with the PRKCD and the NF-κB pathway to evade macrophage-mediated killing. As hormonal intervention represents the mainstay therapy for treatment of prostate cancer patients, our findings may have direct implications and provide a plausible explanation for the clinically observed persistence of tumor cells despite androgen deprivation therapy.

Background The general aim of this study was to investigate the effectiveness of blended Cognitive Behavioral Therapy (bCBT) as compared to Treatment as Usual (TAU) for depression in specialized routine mental healthcare in the Netherlands. We further explored a range of secondary outcome variables, including quality of life, clinical response, remission and reliable improvement, as well as clinical deterioration and potential negative effects of treatment. Methods n = 103 patients with Major Depressive Disorder were recruited as part of the E-COMPARED project, and randomly allocated to bCBT (n = 53) or TAU (n = 50). Measurements took place at baseline, 3-, 6- and 12-months follow-up. Treatment effects were analyzed using linear mixed-effects models for repeated measures. Results Depressive symptoms significantly declined and quality of life significantly improved over time in both bCBT and TAU during 12-months follow-up. No significant interaction effects between treatment group and assessment point were found. Likewise, there were no significant differences between the two treatment groups on secondary outcomes. Patients following bCBT went from severe to mild symptom severity, along with large within-group effects. Conclusion Applying bCBT in routine specialized mental health care seems promising, but is a relatively new form of treatment that is still under development and more research is needed. Clinical Trial Registration Netherlands Trials Register NTR4962. Registered on 5 January 2015.

In young calves on dairy farms the animal prevalence of extended-spectrum and AmpC β-lactamase-producing Escherichia coli (ESBL/AmpC-EC) is significantly higher compared with the animal prevalence in young stock and dairy cows. Hitherto it was unknown at what age antimicrobial resistant bacteria appear for the first time in the gut of calves on dairy farms, and how long these infections persist. The aim of this study was to examine the prevalence of ESBL/AmpC-EC, the number of excreted ESBL/AmpC-EC (in cfu/g of feces), as well as the ESBL/AmpC genotypes in young dairy calves (0–21 d of age) and the variation of these parameters between calves of different ages. Next to this, the course of shedding ESBL/AmpC-EC during the first year in dairy calves was studied. In a cross-sectional study, fecal samples from 748 calves, from 0 to 88 d of age, on 188 Dutch dairy farms were collected. The prevalence of calves testing positive for ESBL/AmpC-EC in a phenotypic assay was determined for different age categories (per 2 d of age). Positive samples were subjected to a semiquantitative test to determine the numbers of ESBL/AmpC-EC per gram of feces and for a selection of ESBL/AmpC-EC isolates the ESBL/AmpC genotype was determined. Ten of the 188 farms were selected for a longitudinal study based on the presence of at least 1 female calf with ESBL/Amp-EC in the cross-sectional study. These farms were additionally visited 3 times with a 4-mo interval. All calves that were sampled in the cross-sectional study were, if still present, resampled during the follow-up visits. Results show that from the day of birth ESBL/AmpC-EC can be present in the gut of calves. The phenotypic prevalence of ESBL/AmpC-EC was 33.3% in 0- to 21-d-old calves and 28.4% in 22- to 88-d-old calves. The prevalence of ESBL/AmpC-EC positive calves varied per age category among calves up to 21 d of age: significant increases and decreases at an early age were shown. Results of the longitudinal study show that after 4, 8, and 12 mo the prevalence of ESBL/AmpC-EC positive calves dropped to 3.8% (2/53), 5.8% (3/52), and 2.0% (1/49), respectively. This indicates that early gut colonization in young calves with ESBL/AmpC-EC is transient and does not lead to long-term shedding of these bacteria.

Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the delivery and immunosuppressive nature of tumors in the brain. To address this challenge, we first established PTEN-deficient melanoma brain metastasis mouse models and characterized them to be more immunosuppressive compared with primary melanoma, mimicking the clinical settings. Next, we developed an allogeneic twin stem cell (TSC) system composed of two tumor-targeting stem cell (SC) populations. One SC was loaded with oncolytic herpes simplex virus (oHSV), and the other SC was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1 KO ) to acquire resistance to oHSV and release immunomodulators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Using mouse models of brain metastatic BRAF V600E /PTEN −/− and BRAF V600E/wt /PTEN −/− mutant melanomas, we show that locoregional delivery of TSCs releasing oHSV and GM-CSF (TSC-G) activated dendritic cell– and T cell–mediated immune responses. In addition, our strategy exhibited greater therapeutic efficacy when compared with the existing oncolytic viral therapeutic approaches. Moreover, the TSCs composed of SC-oHSV and SC N1KO –releasing GM-CSF and single-chain variable fragment anti–PD-1 (TSC-G/P) had therapeutic efficacy in both syngeneic and patient-derived humanized mouse models of leptomeningeal metastasis. Our findings provide a promising allogeneic SC-based immunotherapeutic strategy against melanomas in the CNS and a road map toward clinical translation.

Background Haemosporidian parasites of the genus Polychromophilus infect bats worldwide. They are vectored by obligate ectoparasitic bat flies of the family Nycteribiidae. Despite their global distribution, only five Polychromophilus morphospecies have been described to date. The two predominant species, Polychromophilus melanipherus and Polychromophilus murinus, are broadly distributed and mainly infect miniopterid and vespertilionid bats, respectively. In areas where species from different bat families aggregate together, the infection dynamics and ability of either Polychromophilus species to infect other host families is poorly characterized. Methods We collected 215 bat flies from two bat species, Miniopterus schreibersii and Rhinolophus ferrumequinum, which sometimes form mixed clusters in Serbia. Miniopterus schreibersii is known to be frequently infected with P. melanipherus, whereas R. ferrumequinum has been observed to be incidentally infected with both Polychromophilus species. All flies were screened for Polychromophilus infections using a PCR targeting the haemosporidian cytb gene. Positive samples were subsequently sequenced for 579 bp of cytochrome b (cytb) and 945 bp of cytochrome oxidase subunit 1 (cox1). Results Polychromophilus melanipherus DNA was detected at six out of nine sampling locations and in all three examined bat fly species collected from M. schreibersii (Nycteribia schmidlii, n = 21; Penicillidia conspicua, n = 8; Penicillidia dufourii, n = 3). Four and five haplotypes were found for cytb and cox1, respectively. Evidence for multiple Polychromophilus haplotypes was found in 15 individual flies. These results point to a high diversity of P. melanipherus parasites in Miniopterus hosts and efficient transmission throughout the study area. A single Phthiridium biarticulatum bat fly collected from R. ferrumequinum screened positive for P. melanipherus, but only yielded a partial cox1 sequence fragment. Nevertheless, this result suggests that secondary hosts (both bat and fly species) are regularly confronted with this parasite. Conclusions The results of this study provide new insights into the prevalence and distribution of Polychromophilus parasites in European bats and their nycteribiid vectors. The use of bat flies for the non-invasive investigation of Polychromophilus infections in bat populations has proven to be efficient and thus represents an alternative for large-scale studies of infections in bat populations without the need to invasively collect blood from bats. Graphical Abstract

Platformarbeid is een relatief nieuw fenomeen. Hierbij worden ZZP-ers ingezet die op basis van feiten en omstandigheden niet zelden als werknemer aan te merken zijn. In Nederland geldt dat deze arbeidsrelaties beoordeeld worden op basis van de reguliere criteria voor de kwalificatie van de arbeidsrelatie uit het BW. De invulling van deze criteria is in beweging, enerzijds vanuit jurisprudentie en anderzijds vanuit plannen voor nieuwe wetgeving. Specifiek over platformarbeid zijn er inmiddels 3 uitspraken van de Hoge Raad, waarin in twee zaken (Deliveroo en Uber) werd geoordeeld dat de platformwerkers geen ZZP-er was, maar werknemer en 1w zaak (Helpling) waarin de platformwerker geen ZZP-er was, maar uitzendkracht. In de EU wordt momenteel gewerkt aan een richtlijn voor de verbetering van de arbeidsvoorwaarden bij platformwerk. Deze richtlijn is nog niet in werking getreden. Het doel van de richtlijn is om aan de hand van criteria vast te kunnen stellen of een dienstverband tussen de platformwerker en het platform moet worden aangenomen. Dit zou de positie van de platformwerker moeten verbeteren. De criteria die bepalen of er sprake is van een dienstverband zijn gedurende het wetgevingsproces uitgebreid ten opzichte van het initiële voorstel voor de conceptrichtlijn. Deze scriptie tracht antwoord te geven op de vraag hoe de Nederlandse situatie zich verhoudt tot de nieuwe conceptrichtlijn.

Background: Antidepressant medication and running therapy are both effective treatments for patients with depressive and anxiety disorders. However, they may work through different pathophysiological mechanisms and could differ in their impact on physical health. This study examined effects of antidepressants versus running therapy on both mental and physical health. Methods: According to a partially randomized patient preference design, 141 patients with depression and/or anxiety disorder were randomized or offered preferred 16-week treatment: antidepressant medication (escitalopram or sertraline) or group-based running therapy ≥2 per week. Baseline (T0) and post-treatment assessment at week 16 (T16) included mental (diagnosis status and symptom severity) and physical health indicators (metabolic and immune indicators, heart rate (variability), weight, lung function, hand grip strength, fitness). Results: Of the 141 participants (mean age 38.2 years; 58.2 % female), 45 participants received antidepressant medication and 96 underwent running therapy. Intention-to-treat analyses showed that remission rates at T16 were comparable (antidepressants: 44.8 %; running: 43.3 %; p = .881). However, the groups differed significantly on various changes in physical health: weight (d = 0.57; p = .001), waist circumference (d = 0.44; p = .011), systolic (d = 0.45; p = .011) and diastolic (d = 0.53; p = .002) blood pressure, heart rate (d = 0.36; p = .033) and heart rate variability (d = 0.48; p = .006). Limitations: A minority of the participants was willing to be randomized; the running therapy was larger due to greater preference for this intervention. Conclusions: While the interventions had comparable effects on mental health, running therapy outperformed antidepressants on physical health, due to both larger improvements in the running therapy group as well as larger deterioration in the antidepressant group. Trial registration: Trialregister.nl Number of identification: NTR3460.

Soil health is defined as the capacity of a soil to function as vital living ecosystem. No-tillage is a non-inversion practice that has been highlighted as a practice for improving soil health, and thereby improving soil ecosystem delivery. However, evidence on soil health and farming practices that improve soil health is limited in Norway. We present results on effects of long-term farming practices on soil health in Southeast (SE) Norway on similar soil and topographic characteristics. Physical, chemical, and biological soil indicators were measured on two neighbouring farms, one with no-till and cover crops (NT+CC) and one with conventional harrowing and ploughing (CP), on loam soil in SE Norway. Soil samples were collected to compare soil health indicator between farming practices. We established two systematic sampling grids (~ 0.4 ha) with grid intersection points every 15 m x 15 m to produce a total of 33 sampling points and 17 and 20 cells in the CP and NT+CC field, respectively. We used a combined approach of transect-, point- and cell sampling, depending on the spatial variations of the soil indicators. Soil health indicators included bulk density, cohesion, aggregate stability, saturated hydraulic conductivity (Ksat), total organic carbon, total nitrogen, pH, permanganate-oxidizable carbon and earthworm count. Preliminary results indicate significantly different (p

Predicting the spatiotemporal variability of soil moisture dynamics at different scales is a major challenge. Moreover, multimodal soil hydraulic properties resulting from complex soil structures, such as the exhibited by volcanic soils, still lack realistic and dynamic parameterisation. This work aimed to shed light on the spatiotemporal heterogeneity of subsurface water flows and soil water distribution during wet and dry conditions in volcanic ash-derived soil. The volumetric moisture content (VMC) at 10, 20, and 60 cm depth was measured with a set of eight TDR sensors from September 2019 to January 2022 with a 10-minute resolution. These VMC time series were separated into wet (WP) and dry (DP) periods based on the mean VMC. Subsequently, the spatiotemporal variability in moisture content within the soil profile was analysed using spectral analyses. The propagation of periodicities from Prate to the three topsoil VMC time series as well as the time scales in the correlation of the VMC between sensors were described. Finally, the time dependency of wetting slopes (St) on Prate was assessed by the cross-correlation function (CCF). The VMC dynamics vary between WP and DP, related to the water-filled pore space and pore size distribution. The CWT showed that Prate periodicities propagate to VMC, except for periodicities of 3 to 6 months scales. The WC showed that increases in VMC result in an exponential decrease in the minimum time scale of correlation between moisture contents measured within the topsoil. The CCF described a moderate temporal correlation between Prate and St. The soil wetting response to precipitation was notably faster during wet periods, while the cross-correlation lag and the response heterogeneity increased during dry conditions. The heterogeneity of subsurface water flows resulting from complex soil structure dynamics were described by the spatiotemporal variability of soil moisture in volcanic ash- derived soil. VMC response to Prate is faster during wetter conditions than in dry periods. Temporal periodicities within the topsoil suggest that hydraulic properties experience a dynamic shift from a heterogeneous to a homogeneous system. Changes in the temporal correlation of the soil moisture measured within the topsoil, along with an accurate description of the time dependency of St on Prate, can be valuable for further understanding the hysteresis of soil moisture variations in a soil profile.

Background Healthcare professionals in palliative care are found to be confronted with moral challenges on a frequent basis. CURA is a low-threshold instrument for dialogical ethical reflection that was developed to deal with these challenges. A previous study identified the need of healthcare professionals to be trained to introduce CURA in their organization, initiate and facilitate reflections with CURA, and contribute to the implementation of CURA. The aim of this study was to develop and evaluate a training for professionals to become ‘CURA-ambassadors’.Methods The training was developed in a participatory way in two cycles. We trained 72 healthcare professionals. The training was evaluated by means of a questionnaire and six semi-structured interviews.Results The study resulted in a blended learning training combining training sessions with an e-module and with practicing with organizing and facilitating CURA in daily healthcare practice. The main objectives of the training are to enable CURA-ambassadors to introduce CURA within their organization, initiate and facilitate ethical reflections using CURA, and contribute to the implementation of CURA. Participants were generally positive about the training program and the trainers. Technical difficulties related to the e-module were mentioned as main point of improvement.Discussion The training program can generate ownership, responsibility, and competency among CURA-ambassadors, which are essential foundations for implementing complex interventions in healthcare practice. The training program received positive evaluations shortly after completing the program. This study adds to our understanding of what is needed for healthcare professionals to use CURA, in order to support them in dealing with moral challenges and to foster their moral resilience. Further research is needed to assess whether participants experience the training as sufficient and effective when using and implementing CURA structurally in their organizations over a longer period of time.

Most neuropsychiatric symptoms (NPS) common in frontotemporal dementia (FTD) are currently not part of the Neuropsychiatric Inventory (NPI). We piloted an FTD Module that included eight extra items to be used in conjunction with the NPI. Caregivers of patients with behavioural variant FTD (n = 49), primary progressive aphasia (PPA; n = 52), Alzheimer’s dementia (AD; n = 41), psychiatric disorders (n = 18), presymptomatic mutation carriers (n = 58) and controls (n = 58) completed the NPI and FTD Module. We investigated (concurrent and construct) validity, factor structure and internal consistency of the NPI and FTD Module. We performed group comparisons on item prevalence, mean item and total NPI and NPI with FTD Module scores, and multinomial logistic regression to determine its classification abilities. We extracted four components, together explaining 64.1% of the total variance, of which the largest indicated the underlying dimension ‘frontal-behavioural symptoms’. Whilst apathy (original NPI) occurred most frequently in AD, logopenic and non-fluent variant PPA, the most common NPS in behavioural variant FTD and semantic variant PPA were loss of sympathy/empathy and poor response to social/emotional cues (part of FTD Module). Patients with primary psychiatric disorders and behavioural variant FTD showed the most severe behavioural problems on both the NPI as well as the NPI with FTD Module. The NPI with FTD Module correctly classified more FTD patients than the NPI alone. By quantifying common NPS in FTD the NPI with FTD Module has large diagnostic potential. Future studies should investigate whether it can also prove a useful addition to the NPI in therapeutic trials.

Background: Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated (EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+ NSCLC patients. Methods: Patients who started treatment with osimertinib for EGFRm+ NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. Findings: From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11–0.73; p = 0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p = 0.010). Interpretation: ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. Funding: No funding was received for this trial.

In the Surveillance Tool for Outcome-based Comparison of FREEdom from infection (STOC free) project (https://www.stocfree.eu), a data collection tool was constructed to facilitate standardised collection of input data, and a model was developed to allow a standardised and harmonised comparison of the outputs of different control programmes (CPs) for cattle diseases. The STOC free model can be used to evaluate the probability of freedom from infection for herds in CPs and to determine whether these CPs comply with the European Union's pre-defined output-based standards. Bovine viral diarrhoea virus (BVDV) was chosen as the case disease for this project because of the diversity in CPs in the six participating countries. Detailed BVDV CP and risk factor information was collected using the data collection tool. For inclusion of the data in the STOC free model, key aspects and default values were quantified. A Bayesian hidden Markov model was deemed appropriate, and a model was developed for BVDV CPs. The model was tested and validated using real BVDV CP data from partner countries, and corresponding computer code was made publicly available. The STOC free model focuses on herd-level data, although that animal-level data can be included after aggregation to herd level. The STOC free model is applicable to diseases that are endemic, given that it needs the presence of some infection to estimate parameters and enable convergence. In countries where infection-free status has been achieved, a scenario tree model could be a better suited tool. Further work is recommended to generalise the STOC free model to other diseases.

ObjectivesTo investigate an outbreak ofEnterococcus faeciumin a hospital haematology ward and uncover the mechanism of a vancomycin resistance phenotype-genotype disparity in an isolate from this outbreak.MethodsWhole genome shotgun sequencing was used for the phylogenetic analysis ofE. faeciumisolates (n = 39) and to identify the carriage of antibiotic resistance genes. A long-read sequencing approach was adopted to identify structural variations in the vancomycin resistance region of a vancomycin-variableE. faecium(VVE) and to uncover the resistance reversion mechanism in this isolate. RT-qPCR and RT-PCR were used to determine differences in the expression ofvanRSandvanHAXamong strains.ResultsTheE. faeciumstrains isolated in the hospital haematology ward were extensively drug resistant and highly diverse. The notable expansion of ST262 among patients was the likely driver of a VRE outbreak. A VVE isolate was identified that could rapidly revert to a vancomycin-resistant state in the presence of vancomycin. Disruption of thevanRgene in this isolate by an IS6-family element impaired its response to vancomycin. However, when the isolate was evolved to vancomycin resistance, it could constitutively express thevanHAXgenes at levels up to 36,000-fold greater than the parent isolate via co-transcription with a ribosomal RNA operon.ConclusionIn this study, we report a VVE isolate that was isolated during a VRE outbreak. This strain was capable of rapidly reverting to a resistant phenotype through a novel mechanism involving integration ofvanHAXdownstream of a ribosomal RNA operon. During VRE outbreaks, attention should be paid to contemporaneous vancomycin-susceptible strains as these may carry silent vancomycin resistance genes that can be activated through genomic rearrangements upon exposure to vancomycin.

The long non-coding RNAs (lncRNAs) are evolutionarily conserved classes of non-coding regulatory transcripts of > 200 nucleotides in length. They modulate several transcriptional and post-transcriptional events in the organism. Depending on their cellular localization and interactions, they regulate chromatin function and assembly; and alter the stability and translation of cytoplasmic mRNAs. Although their proposed range of functionality remains controversial, there is increasing research evidence that lncRNAs play a regulatory role in the activation, differentiation and development of immune signaling cascades; microbiome development; and in diseases such as neuronal and cardiovascular disorders; cancer; and pathogenic infections. This review discusses the functional roles of different lncRNAs in regulation of host immune responses, signaling pathways during host-microbe interaction and infection caused by obligate intracellular bacterial pathogens. The study of lncRNAs is assuming significance as it could be exploited for development of alternative therapeutic strategies for the treatment of severe and chronic pathogenic infections caused by Mycobacterium, Chlamydia and Rickettsia infections, as well as commensal colonization. Finally, this review summarizes the translational potential of lncRNA research in development of diagnostic and prognostic tools for human diseases.

Background The prediction of bacteriophage sequences in metagenomic datasets has become a topic of considerable interest, leading to the development of many novel bioinformatic tools. A comparative analysis of ten state-of-the-art phage identification tools was performed to inform their usage in microbiome research. Methods Artificial contigs generated from complete RefSeq genomes representing phages, plasmids, and chromosomes, and a previously sequenced mock community containing four phage species, were used to evaluate the precision, recall, and F1 scores of the tools. We also generated a dataset of randomly shuffled sequences to quantify false-positive calls. In addition, a set of previously simulated viromes was used to assess diversity bias in each tool’s output. Results VIBRANT and VirSorter2 achieved the highest F1 scores (0.93) in the RefSeq artificial contigs dataset, with several other tools also performing well. Kraken2 had the highest F1 score (0.86) in the mock community benchmark by a large margin (0.3 higher than DeepVirFinder in second place), mainly due to its high precision (0.96). Generally, k-mer-based tools performed better than reference similarity tools and gene-based methods. Several tools, most notably PPR-Meta, called a high number of false positives in the randomly shuffled sequences. When analysing the diversity of the genomes that each tool predicted from a virome set, most tools produced a viral genome set that had similar alpha- and beta-diversity patterns to the original population, with Seeker being a notable exception. Conclusions This study provides key metrics used to assess performance of phage detection tools, offers a framework for further comparison of additional viral discovery tools, and discusses optimal strategies for using these tools. We highlight that the choice of tool for identification of phages in metagenomic datasets, as well as their parameters, can bias the results and provide pointers for different use case scenarios. We have also made our benchmarking dataset available for download in order to facilitate future comparisons of phage identification tools.

This paper presents a reconfigurable digital implementation of an event-based binaural cochlear system on a Field Programmable Gate Array (FPGA). It consists of a pair of the Cascade of Asymmetric Resonators with Fast Acting Compression (CAR FAC) cochlea models and leaky integrate and fire (LIF) neurons. Additionally, we propose an event-driven SpectroTemporal Receptive Field (STRF) Feature Extraction using Adaptive Selection Thresholds (FEAST). It is tested on the TIDIGTIS benchmark and compared with current event-based auditory signal processing approaches and neural networks., 12 pages, 8 figures

The field of neuromorphic computing holds great promise in terms of advancing computing efficiency and capabilities by following brain-inspired principles. However, the rich diversity of techniques employed in neuromorphic research has resulted in a lack of clear standards for benchmarking, hindering effective evaluation of the advantages and strengths of neuromorphic methods compared to traditional deep-learning-based methods. This paper presents a collaborative effort, bringing together members from academia and the industry, to define benchmarks for neuromorphic computing: NeuroBench. The goals of NeuroBench are to be a collaborative, fair, and representative benchmark suite developed by the community, for the community. In this paper, we discuss the challenges associated with benchmarking neuromorphic solutions, and outline the key features of NeuroBench. We believe that NeuroBench will be a significant step towards defining standards that can unify the goals of neuromorphic computing and drive its technological progress. Please visit neurobench.ai for the latest updates on the benchmark tasks and metrics.

Limited data significantly hinders our capability of biothreat assessment of novel bacterial strains. Integration of data from additional sources that can provide context about the strain can address this challenge. Datasets from different sources, however, are generated with a specific objective and which makes integration challenging. Here, we developed a deep learning-based approach called the neural network embedding model (NNEM) that integrates data from conventional assays designed to classify species with new assays that interrogate hallmarks of pathogenicity for biothreat assessment. We used a dataset of metabolic characteristics from a de-identified set of known bacterial strains that the Special Bacteriology Reference Laboratory (SBRL) of the Centers for Disease Control and Prevention (CDC) has curated for use in species identification. The NNEM transformed results from SBRL assays into vectors to supplement unrelated pathogenicity assays from de-identified microbes. The enrichment resulted in a significant improvement in accuracy of 9% for biothreat. Importantly, the dataset used in our analysis is large, but noisy. Therefore, the performance of our system is expected to improve as additional types of pathogenicity assays are developed and deployed. The proposed NNEM strategy thus provides a generalizable framework for enrichment of datasets with previously collected assays indicative of species.

ESBL resistance significantly impacts clinical management of E. coli infections in hospitals globally. It is important to understand the structures of ESBL-EC populations carried by hospital patients and staff, their capacity to persist in hospital environments, and the dynamics of mobile genes that drive the spread of ESBL resistance.