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Abstract Background Obtaining a properly fitting non-invasive ventilation (NIV) mask to treat acute respiratory failure is a major challenge, especially in young children and patients with craniofacial abnormalities. Personalization of NIV masks holds promise to improve pediatric NIV efficiency. As current customization methods are relatively time consuming, this study aimed to test the air leak and surface pressure performance of personalized oronasal face masks using 3D printed soft materials. Personalized masks of three different biocompatible materials (silicone and photopolymer resin) were developed and tested on three head models of young children with abnormal facial features during preclinical bench simulation of pediatric NIV. Air leak percentages and facial surface pressures were measured and compared for each mask. Results Personalized NIV masks could be successfully produced in under 12 h in a semi-automated 3D production process. During NIV simulation, overall air leak performance and applied surface pressures were acceptable, with leak percentages under 30% and average surface pressure values mostly remaining under normal capillary pressure. There was a small advantage of the masks produced with soft photopolymer resin material. Conclusion This first, proof-of-concept bench study simulating NIV in children with abnormal facial features, showed that it is possible to obtain biocompatible, personalized oronasal masks with acceptable air leak and facial surface pressure performance using a relatively short, and semi-automated production process. Further research into the clinical value and possibilities for application of personalized NIV masks in critically ill children is needed.

Foot-and-mouth disease (FMD) outbreaks affecting Asiatic black bears (Ursus thibetanus) and a Malayan sun bear (Helarctos malayanus) were previously reported in 2011 in two housing facilities at a Vietnamese bear rescue centre. In this study, demographic data of all animals housed in the centre at the time of the outbreaks (n = 79) were collected. Blood samples drawn from 23 bears at different timepoints were tested for FMDV-specific antibodies targeting using a non-structural protein (NSP) ELISA and by virus neutralisation test (VNT). The relationship between seroconversion and clinical signs was explored and epidemic curves and transmission diagrams were generated for each outbreak, where FMD cases were defined as animals showing FMD clinical signs. Outbreak-specific attack rates were 18.75 and 77.77%, with corresponding basic reproduction numbers of 1.11 and 1.92, for the first and second outbreaks, respectively. Analyses of risk factors showed that after adjusting for sex there was strong evidence for a decrease in odds of showing clinical signs per year of age. All samples collected from bears before the outbreak tested negative to NSP and VNT. All cases tested positive to VNT following onset of clinical signs and remained positive during the rest of the follow up period, while only 6 out of 17 cases tested positive to NSP after developing clinical signs. Six animals without clinical signs were tested post outbreaks; five seroconverted using VNT and three animals were seropositive using NSP ELISA. This study provides initial epidemiological parameters of FMD in captive bears, showing that FMDV is easily spread between bears in close proximity and can cause clinical and subclinical disease, both of which appear to induce rapid and long-lasting immunity.

Abstract Background Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account. Methods We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients’ outcomes were compared using Cox regression and competing risk models. Results Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18–3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78–0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9–100%). Conversely, among the 61 patients with gBRCA1m and

Abstract Understanding the variability of the Atlantic Meridional Overturning Circulation is essential for better predictions of our changing climate. Here we present an updated time series (August 2014 to June 2020) from the Overturning in the Subpolar North Atlantic Program. The 6-year time series allows us to observe the seasonality of the subpolar overturning and meridional heat and freshwater transports. The overturning peaks in late spring and reaches a minimum in early winter, with a peak-to-trough range of 9.0 Sv. The overturning seasonal timing can be explained by winter transformation and the export of dense water, modulated by a seasonally varying Ekman transport. Furthermore, over 55% of the total meridional freshwater transport variability can be explained by its seasonality, largely owing to overturning dynamics. Our results provide the first observational analysis of seasonality in the subpolar North Atlantic overturning and highlight its important contribution to the total overturning variability observed to date.

Abstract Background High-dose chemotherapy with autologous stem cell rescue (HDCT) is a promising treatment for patients with stage III, HER2-negative, homologous recombination deficient (HRD) breast cancer. Clinical effectiveness and cost-effectiveness are currently under investigation in an international multicenter randomized controlled trial. To increase the chance of successful introduction of HDCT into daily clinical practice, we aimed to identify relevant factors for smooth implementation using an early comprehensive assessment framework. Methods This is a qualitative, multi-stakeholder, exploratory research using semi-structured interviews guided by the Constructive Technology Assessment model, which evaluates the quality of a novel health technology by clinical, economic, patient-related, and organizational factors. Stakeholders were recruited by purposeful stratified sampling and interviewed until sufficient content saturation was reached. Two researchers independently created themes, categories, and subcategories by following inductive coding steps, these were verified by a third researcher. Results We interviewed 28 stakeholders between June 2019 and April 2021. In total, five overarching themes and seventeen categories were identified. Important findings for optimal implementation included the structural identification and referral of all eligible patients, early integration of supportive care, multidisciplinary collaboration between- and within hospitals, (de)centralization of treatment aspects, the provision of information for patients and healthcare professionals, and compliance to new regulation for the BRCA1-like test. Conclusions In anticipation of a positive reimbursement decision, we recommend to take the highlighted implementation factors into consideration. This might expedite and guide high-quality equitable access to HDCT for patients with stage III, HER2-negative, HRD breast cancer in the Netherlands.

Abstract Breast cancer tumor grade is strongly associated with patient survival. In current clinical practice, pathologists assign tumor grade after visual analysis of tissue specimens. However, different studies show significant inter-observer variation in breast cancer grading. Computer-based breast cancer grading methods have been proposed but only work on specifically selected tissue areas and/or require labor-intensive annotations to be applied to new datasets. In this study, we trained and evaluated a deep learning-based breast cancer grading model that works on whole-slide histopathology images. The model was developed using whole-slide images from 706 young (

Rift Valley fever virus (RVFV) is a mosquito-borne pathogen that has caused epidemics involving people and animals across Africa and the Arabian Peninsula. A number of studies have found evidence for the circulation of RVFV among livestock between these epidemics but the population-level incidence of infection during this inter-epidemic period (IEP) is rarely reported. General force of infection (FOI) models were applied to age-adjusted cross-sectional serological data to reconstruct the annual FOI and population-level incidence of RVFV infection among cattle, goats, and sheep in northern Tanzania from 2009 through 2015, a period without reported Rift Valley fever (RVF) cases in people or animals. To evaluate the potential for zoonotic RVFV spillover during this period, the relationship between village-level livestock RVFV FOI and human RVFV seropositivity was quantified using multi-level logistic regression. The predicted average annual incidence was 72 (95% Credible Interval [CrI] 63, 81) RVFV infections per 10,000 animals and 96 (95% CrI 81, 113), 79 (95% CrI 62, 98), and 39 (95% CrI 28, 52) per 10,000 cattle, sheep, and goats, respectively. There was variation in transmission intensity between study villages, with the highest estimated village-level FOI 2.49% (95% CrI 1.89, 3.23) and the lowest 0.12% (95% CrI 0.02, 0.43). The human RVFV seroprevalence was 8.2% (95% Confidence Interval 6.2, 10.9). Human seropositivity was strongly associated with the village-level FOI in livestock, with the odds of seropositivity in an individual person increasing by around 1.2 times (95% CrI 1.1, 1.3) for each additional annual RVFV seroconversion per 1,000 animals. A history of raw milk consumption was also positively associated with human seropositivity. RVFV has circulated at apparently low levels among livestock in northern Tanzania in the period since the last reported epidemic. Although our data do not allow us to confirm human RVFV infections during the IEP, a strong association between human seropositivity and the FOI in cattle, goats, and sheep supports the hypothesis that RVFV circulation among livestock during the IEP poses a risk for undetected zoonotic spillover in northern Tanzania. We provide further evidence for the likely role of raw milk consumption in RVFV transmission from animals to people.

Abstract Background Diagnosing urinary tract infections (UTI) in nursing home residents is complex, due to frequent non-specific symptomatology and asymptomatic bacteriuria. The objective of this study was to explore health care professionals’ perceptions of the proposed use of inflammatory marker Point-Of-Care Testing (POCT) in this respect. Methods We conducted a qualitative inquiry (2018–2019) alongside the multicenter PROGRESS study (NL6293), which assessed the sensitivity of C-reactive protein and procalcitonin POCT in UTI. We used semi-structured face-to-face interviews. The participants were physicians (n = 12) and nurses (n = 6) from 13 nursing homes in the Netherlands. Most respondents were not familiar with inflammatory marker POCT, while some used POCT for respiratory tract infections. Both the interview guide and the analysis of the interview transcripts were based on the Consolidated Framework for Implementation Research. Results All respondents acknowledged that sufficiently sensitive POCT could decrease diagnostic uncertainty to some extent in residents presenting with non-specific symptoms. They primarily thought that negative test results would rule out UTI and justify withholding antibiotic treatment. Secondly, they described how positive test results could rule in UTI and justify antimicrobial treatment. However, most respondents also expected new diagnostic uncertainties to arise. Firstly, in case of negative test results, they were not sure how to deal with residents’ persisting non-specific symptoms. Secondly, in case of positive test results, they feared overlooking infections other than UTI. These new uncertainties could lead to inappropriate antibiotics use. Therefore, POCT was thought to create a false sense of confidence. Conclusions Our study suggests that inflammatory marker POCT will only improve UTI management in nursing homes to some extent. To realize the expected added value, any implementation of POCT requires thorough guidance to ensure appropriate use. Developing UTI markers with high negative and positive predictive values may offer greater potential to improve UTI management in nursing homes.

Open burning of agricultural crop residues is widespread across eastern China, and during certain post-harvest periods this activity is believed to significantly influence air quality. However, the exact contribution of crop residue burning to major air quality exceedances and air quality episodes has proven difficult to quantify. Whilst highly successful in many regions, in areas dominated by agricultural burning, MODIS-based (MODIS: Moderate Resolution Imaging Spectroradiometer) fire emissions inventories such as the Global Fire Assimilation System (GFAS) and Global Fire Emissions Database (GFED) are suspected of significantly underestimating the magnitude of biomass burning emissions due to the typically very small, but highly numerous, fires involved that are quite easily missed by coarser-spatial-resolution remote sensing observations. To address this issue, we use twice-daily fire radiative power (FRP) observations from the “small-fire-optimised” VIIRS-IM FRP product and combine them with fire diurnal cycle information taken from the geostationary Himawari-8 satellite. Using this we generate a unique high-spatio-temporal-resolution agricultural burning inventory for eastern China for the years 2012–2015, designed to fully take into account small fires well below the MODIS burned area or active fire detection limit, focusing on dry matter burned (DMB) and emissions of CO2, CO, PM2.5, and black carbon. We calculate DMB totals 100 % to 400 % higher than reported by the GFAS and GFED4.1s, and we quantify interesting spatial and temporal patterns previously un-noted. Wheat residue burning, primarily occurring in May–June, is responsible for more than half of the annual crop residue burning emissions of all species, whilst a secondary peak in autumn (September–October) is associated with rice and corn residue burning. We further identify a new winter (November–December) burning season, hypothesised to be caused by delays in burning driven by the stronger implementation of residue burning bans during the autumn post-harvest season. Whilst our emissions estimates are far higher than those of other satellite-based emissions inventories for the region, they are lower than estimates made using traditional “crop-yield-based approaches” (CYBAs) by a factor of between 2 and 5. We believe that this is at least in part caused by outdated and overly high burning ratios being used in the CYBA, leading to the overestimation of DMB. Therefore, we conclude that satellite remote sensing approaches which adequately detect the presence of agricultural fires are a far better approach to agricultural fire emission estimation.

Introduction Causal methods have been adopted and adapted across health disciplines, particularly for the analysis of single studies. However, the sample sizes necessary to best inform decision-making are often not attainable with single studies, making pooled individual-level data analysis invaluable for public health efforts. Researchers commonly implement causal methods prevailing in their home disciplines, and how these are selected, evaluated, implemented and reported may vary widely. To our knowledge, no article has yet evaluated trends in the implementation and reporting of causal methods in studies leveraging individual-level data pooled from several studies. We undertake this review to uncover patterns in the implementation and reporting of causal methods used across disciplines in research focused on health outcomes. We will investigate variations in methods to infer causality used across disciplines, time and geography and identify gaps in reporting of methods to inform the development of reporting standards and the conversation required to effect change.Methods and analysis We will search four databases (EBSCO, Embase, PubMed, Web of Science) using a search strategy developed with librarians from three universities (Heidelberg University, Harvard University, and University of California, San Francisco). The search strategy includes terms such as ‘pool*’, ‘harmoniz*’, ‘cohort*’, ‘observational’, variations on ‘individual-level data’. Four reviewers will independently screen articles using Covidence and extract data from included articles. The extracted data will be analysed descriptively in tables and graphically to reveal the pattern in methods implementation and reporting. This protocol has been registered with PROSPERO (CRD42020143148).Ethics and dissemination No ethical approval was required as only publicly available data were used. The results will be submitted as a manuscript to a peer-reviewed journal, disseminated in conferences if relevant, and published as part of doctoral dissertations in Global Health at the Heidelberg University Hospital.

Abstract Background In the Dutch breast cancer screening program, women recalled with a BI-RADS 0 score are referred for additional imaging, while those with BI-RADS 4/5 scores are also directed to an outpatient breast clinic. Approximately six out of ten women are recalled without being diagnosed with a malignancy. However, these recalls require additional imaging and doctor visits, which result in patient anxiety and increased health care costs. Conventional types of imaging used for additional imaging are full-field digital mammography and tomosynthesis. Contrast-enhanced spectral mammography has proved to have higher sensitivity and specificity than conventional imaging in women recalled from screening. Therefore, the aim is to study if CESM instead of conventional imaging is a more accurate, patient-friendly, and cost-effective strategy in the work-up of women recalled from breast cancer screening. Methods This prospective, multicenter, randomized controlled trial will be conducted at four centers and will include 528 patients recalled for suspicious breast lesions from the Dutch breast cancer screening program. Participants are randomized in two groups: (1) standard care using conventional breast imaging techniques as initial imaging after recall versus (2) work-up primarily based on CESM. Written informed consent will be collected prior to study inclusion. The primary outcome is the diagnostic accuracy for detection of breast cancer. Secondary outcomes are numbers of additional diagnostic exams, days until final diagnosis, health care costs, and experienced patient anxiety. Discussion Based on previously published retrospective studies, we expect to demonstrate in this prospective multicenter randomized controlled trial, that using CESM as a primary work-up tool in women recalled from breast cancer screening is a more accurate, cost-effective, and patient-friendly strategy. Trial registration Netherlands Trial Register, NL6413/NTR6589. Registered on 6 July, 2017.

Abstract Background If TNF inhibitors are initiated in the early stages of psoriatic arthritis, this could potentially modulate disease and therefore allow us to discontinue the TNF inhibitor after achieving remission. Objective To investigate whether remission induced by tumour necrosis factor alpha inhibitor (TNFi) and methotrexate in patients with early psoriatic arthritis is sustained after withdrawal of TNFi. Methods Open-label extension of a recently published double-blind, randomized placebo-controlled trial. Patients with psoriatic arthritis fulfilling the CASPAR criteria and with active disease at baseline (swollen and tender joint count ≥ 3) were randomized to either golimumab and methotrexate or matched placebo and methotrexate. Patients in Disease Activity Score (DAS) remission at week 22 continued in the open-label extension on methotrexate monotherapy. The primary end point was the percentage of patients in DAS-CRP remission (DAS

IntroductionPooling (or combining) and analysing observational, longitudinal data at the individual level facilitates inference through increased sample sizes, allowing for joint estimation of study- and individual-level exposure variables, and better enabling the assessment of rare exposures and diseases. Empirical studies leveraging such methods when randomization is unethical or impractical have grown in the health sciences in recent years. The adoption of so-called "causal" methods to account for both/either measured and/or unmeasured confounders is an important addition to the methodological toolkit for understanding the distribution, progression, and consequences of infectious diseases (IDs) and interventions on IDs. In the face of the Covid-19 pandemic and in the absence of systematic randomization of exposures or interventions, the value of these methods is even more apparent. Yet to our knowledge, no studies have assessed how causal methods involving pooling individual-level, observational, longitudinal data are being applied in ID-related research. In this systematic review, we assess how these methods are used and reported in ID-related research over the last 10 years. Findings will facilitate evaluation of trends of causal methods for ID research and lead to concrete recommendations for how to apply these methods where gaps in methodological rigor are identified.Methods and analysisWe will apply MeSH and text terms to identify relevant studies from EBSCO (Academic Search Complete, Business Source Premier, CINAHL, EconLit with Full Text, PsychINFO), EMBASE, PubMed, and Web of Science. Eligible studies are those that apply causal methods to account for confounding when assessing the effects of an intervention or exposure on an ID-related outcome using pooled, individual-level data from 2 or more longitudinal, observational studies. Titles, abstracts, and full-text articles, will be independently screened by two reviewers using Covidence software. Discrepancies will be resolved by a third reviewer. This systematic review protocol has been registered with PROSPERO (CRD42020204104).

Knowledge of optimal technical performance is used to determine match strategy and the design of training programs. Previous studies in men's soccer have identified certain technical characteristics that are related to success. These studies however, have relative limited sample sizes or limited ranges of performance indicators, which may have limited the analytical approaches that were used. Research in women's soccer and our understanding of optimal technical performance, is even more limited (n = 3). Therefore, the aim of this study was to identify technical determinants of match outcome in the women's game and to compare analytical approaches using a large sample size (n = 1390 team performances) and range of variables (n = 450). Three different analytical approaches (i.e. combinations of technical performance variables) were used, a data-driven approach, a rational approach and an approach based on the literature in men's soccer. Match outcome was modelled using variables from each analytical approach, using generalised linear modelling and decision trees. It was found that the rational and data-driven approaches outperformed the literature-driven approach in predicting match outcome. The strongest determinants of match outcome were; scoring first, intentional assists relative to the opponent, the percentage of shots on goal saved by the goalkeeper relative to the opponent, shots on goal relative to the opponent and the percentage of duels that are successful. Moreover the rational and data-driven approach achieved higher prediction accuracies than comparable studies about men's soccer.

Purpose: Lower urinary tract dysfunction (LUTD) occurs frequently in girls and may display a spinning top urethra (STU) on voiding cysto-urethrogram (VCUG) in case of dysfunctional voiding. A STU presents as a narrowing of the urethra caused by a lack of relaxation of the pelvic floor musculature during micturition and may vary in length between the proximal and the distal urethra. Although a STU has been recognized since 1960 as a pathological entity on VCUG, no reports exist on the different levels of engagement of the pelvic floor muscles to the urethra as expressed by the varying length of the phenomenon. The aim of our study is to demonstrate the wide anatomical variation in the level of engagement of the pelvic floor musculature to the urethra.Materials and Methods: Dynamic ultrasound videos of pelvic floor musculature of 40 girls with LUTD were reassessed by three observers, looking for the level of engagement of the puborectalis muscle (PRM) to the urethra during coughing, Valsalva and hold-up maneuver. Three levels were defined, for the level of engagement of the pelvic floor to the urethra, proximal, mid, and distal. Intra- and inter-rater variability was analyzed using Cohen's kappa statistics.Results: A wide range of points of action was found on the assessed ultrasound videos. Intra- and inter-rater agreement showed different levels of conformity, varying over a wide spectrum (intra-rater kappa 0.145–0.546; inter-rater kappa −0.1030.724). Throughout the assessed videos, all not-corresponding intra-rater observations differed maximal one category. Of the not-corresponding inter-rater observations, 90% differed maximal one category.Conclusion: An anatomical variation in levels of engagement of the PRM to the urethra does exist. The clinical value of this finding, whether the point of engagement influences symptomatology or treatment success of LUTD, is currently being studied.

The issue of finding plants suitable for phytoremediation of inorganic contaminants can be addressed through the preparation of genetically modified plants with an increased metal accumulation potential. A HisCUP gene, which encodes for a yeast metallothionein fused with a polyhistidine tail (His), was chosen for preparation of two plant vectors. These two plant vectors were constructed and a HisCUP gene expression was subsequently investigated. We firstly prepared a vector pNOV2819/RbcS/HisCUP which enabled selection on a mannose medium and contained the HisCUP gene under an inducible Rubisco promoter. Secondly, we designed a vector pGreen0029/35S/HisCUP which enabled selection of plants on a medium with kanamycin and carried the HisCUP gene under a constitutive CaMV 35S promoter. The transient expression of the HisCUP gene in tobacco plants was confirmed at RNA and protein levels for both constructs. The relative expression of the HisCUP gene was determined by semi-quantitative real-time PCR; a higher expression was detected for the vector pNOV2819/RbcS/HisCUP.

For over half a century now, section 2(a) of the Arbitration Act 42 of 1965 has prohibited arbitration in respect of matrimonial and related matters. In this article it will be illustrated that this prohibition is clearly incompatible with present-day demands. Today there is a strong tendency in public policy towards alternative dispute resolution processes such as arbitration. As any recommendations that arbitration should be applied to family law disputes must be anchored in an analysis of the specific character of the arbitral remedy, the article begins by giving a broad overview of the nature of arbitration. This is followed by a discussion of the present-day demand for family arbitration, which examines the problems experienced with the adversarial system of litigation in resolving family law disputes, party autonomy, the development of alternative dispute resolution processes such as mediation and arbitration, the special synergy between mediation and arbitration, the success of arbitration in other fields of law and possible forerunners for family arbitration in South Africa. Inherent in the demand for family law arbitration are the many advantages of arbitration, which are also touched upon. Thirdly, current trends in England, Australia, the United States of America, Canada and India are analysed so as to identify a suitable family law arbitration model for South Africa. Special attention is paid to the matters that should be referred to arbitration – for example, should it be confined to matrimonial property and financial disputes or extended to all matters incidental to divorce or family breakdown, including children's issues? Other questions examined include whether family arbitration should comply with substantive law only, who should act as arbitrators, whether family arbitration should be voluntary or compulsory, what the court's role in the family arbitration process should be, and whether family law arbitration should be regulated by the existing Arbitration Act or by a separate statute with specialised rules for family matters. Lastly, it is concluded that although family arbitration will not have universal appeal or common application, it should be encouraged and enforceable for those who choose this private alternative dispute settlement technique to resolve their family disputes.