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Objective Determine the pharmacokinetics (PK) and exposure–response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).Methods We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach.Results Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults.Conclusions We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes.Trial registration number NCT04358302.

Introduction Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.Methods Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and dissemination Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration number ClinicalTrials.gov Registry (NCT04358302).

Intramedullary nailing of diaphyseal femoral fractures is a commonly used treatment method in dogs because of its biological and biomechanical advantages compared to bone plating. To achieve adequate resistance of the intramedullary nail against torsional and axial compressive forces, additional application of transcortical screws is needed. As these interlocking screws represent a frequent cause of post-operative complications, a new expandable intramedullary nail (EXPN) was developed, which was designed to provide adequate fracture stabilisation without the need for transcortical fixation. The evaluation of the biomechanical properties of the new EXPN with regard to torsional, compressive and bending stability as well as direct comparison to the biomechanical properties of conventional Steinmann (STMN)- and interlocking (ILN) nails was carried out with different biomechanical test arrangements. No significant statistical differences regarding the torsional and bending resistance between the EXPN and ILN group were seen, which indicates that rotatory as well as bending stability of the innovative EXPN is similar to the conventional ILN. Nevertheless, the percentage deviation between the attempted and successfully reached physiological compressive forces was significantly higher (p = 0.045) in the EXPN group compared to the ILN group, which indicates that the compressive stability of the innovative EXPN might be weaker compared to the ILN. In summary, the new EXPN represents an interesting alternative to conventional intramedullary nails. However, in direct comparison to conventional interlocking nails, the EXPN has shown weaknesses in the neutralization of axial compressive forces, which indicates that at least biomechanically the interlocking nail seems advantageous. Further in-vitro and in-vivo investigations are required before clinical use can be recommended.

Herein we report, for the first time, the therapeutic response of a prostate cancer patient with the thiamine antagonist benfo-oxythiamine (B-OT) added to prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT). The patient was initially diagnosed as pT3b pN0 (0/7) M0 L0 V0 R0 G3, Gleason score 5 + 5 = 10, with an initial prostate-specific antigen (PSA) level of 4.05 ng/ml. Shortly after radical prostatectomy, 68Ga-PSMA positron emission tomography/computed tomography (PET/CT) revealed PSMA-positive lymph node metastases. Despite treatment with androgen deprivation therapy, external beam radiation therapy, palliative chemotherapy, and five cycles of PRLT (177Lu-PRLT or TANDEM-PRLT, respectively), the patient experienced progression in PSA levels as well as in PSMA PET/CT. Due to the intense PSMA expression, 177Lu-PRLT with 177Lu-PSMA-I&T was resumed for another 4 cycles (cycles 6th to 9th) and the patient was additionally treated with the thiamine antagonist benfo-oxythiamine. It was hypothesized that B-OT acts as a radiosensitizer by interfering with the repair of damaged DNA. B-OT-PRLT was well-tolerated and no substantial changes in laboratory results were observed. Additionally, the patient reported significant improvement in clinical symptoms. Post-treatment 177Lu-PSMA single-photon computed tomography (SPECT)/CT after the 7th cycle (and after 2 cycles of B-OT-PRLT) revealed regression of metastases compared to the post-treatment SPECT/CT after the 6th cycle. Before the 8th cycle, PSMA PET/CT showed a mixed response following prior uncontrollable cancer progression. Moreover, the PSA level showed a significant decline after one cycle of B-OT-PRLT. Although the patient had experienced massive progression before the first cycle of B-OT-PRLT, he survived for an additional 12 months. This case supports the hypothesis that B-OT-PRLT could overcome radiation resistance in prostate cancer patients who do not initially respond to 177Lu- or 225Ac-PRLT.

Background: Along with the ageing of society, the absolute prevalence of age-related diseases is expected to rise, leading to a substantial burden on healthcare systems and society. Thus, there is an urgent need to promote healthy ageing. As opposed to chronological age, biological age was introduced to accurately represent the ageing process, as it considers physiological deterioration that is linked to morbidity and mortality risk. Furthermore, biological age responds to various factors, including nutritional factors, which have the potential to mitigate the risk of age-related diseases. As a result, a promising biomarker of biological age known as the epigenetic clock has emerged as a suitable measure to investigate the direct relations between nutritional factors and ageing, thereby identifying potential intervention targets to improve healthy ageing. Methods: In this study, we analysed data from 3,969 postmenopausal women from the Women's Health Initiative to identify nutrients that are associated with the rate of ageing by using an accurate measure of biological age called the PhenoAge epigenetic clock. We used Copula Graphical Models, a data-driven exploratory analysis tool, to identify direct relationships between nutrient intake and age-acceleration, while correcting for every variable in the dataset. Results: We revealed that increased dietary intakes of coumestrol, beta-carotene and arachidic acid were associated with decelerated epigenetic ageing. In contrast, increased intakes of added sugar, gondoic acid, behenic acid, arachidonic acid, vitamin A and ash were associated with accelerated epigenetic ageing in postmenopausal women. Conclusion: Our study discovered direct relations between nutrients and epigenetic ageing, revealing promising areas for follow-up studies to determine the magnitude and causality of our estimated diet-epigenetic relationships.

Objective: This study evaluated interhospital variability and determinants of failure-to-rescue for patients undergoing surgical aortic valve replacement. Methods: An observational study was conducted among 28,842 patients undergoing aortic valve replacement with or without coronary artery bypass grafting between July 2011 and June 2017 across 90 hospitals participating in the Society of Thoracic Surgeons Adult Cardiac Surgery Database. Postoperative complications were defined as major (stroke, renal failure, reoperation, prolonged ventilation, sternal infection) and overall (major plus 14 other morbidities). Hospital terciles of observed to expected (O/E) mortality were compared on crude rates of major and overall complications, operative mortality, and failure to rescue (among major and overall complications). The correlation between hospital observed and expected failure-to-rescue rates was assessed. Results: Median Society of Thoracic Surgeons Adult Cardiac Surgery Database predicted mortality risk was similar across hospital O:E mortality terciles (P = .10). As expected, mortality rates significantly increased across terciles (low O/E tercile: 1.6%, high O/E tercile: 4.7%; P

Background/Objectives: It is vital to identify children whose weight status means that they may benefit from medical or behavioural support, but adult visual judgements of child weight status are inaccurate, and children are seldom routinely weighed and measured. Consequently, there is a need for validated visual tools for use in training, communication, and interventions relating to child weight. Methods: This paper presents validation data for a set of innovative photo-realistic colour body size scales depicting boys and girls aged 4–5 and 10–11. Each age- and gender-specific scale consists of 7 figures based on three-dimensional (3D) scans of 388 children to accurately represent the change in body size caused by changing adiposity. To assess scale validity, 238 adult participants (105 men, 132 women, 1 non-binary individual) undertook two tasks: rating figure adiposity using a visual analogue scale and ranking figures in ascending order of adiposity (OSF Reference: gdp9j). Results: Participants accurately estimated the relative adiposity of each figure, i.e., they were able to tell the difference between figures and correctly rank them by size. This demonstrates scale validity for use in body size tasks. One hundred and fifty-one participants also provided 3-day test–retest data, which demonstrates excellent short-term reliability. Conclusions: Overall, the MapMe child body size scales provide an anthropometrically accurate, valid, reliable, and usable tool for size-related tasks and communication with adults regarding child weight.

BackgroundWomen are less likely to have classic cardiovascular risk factors than men, and events during their reproductive and menopausal years may increase hypertension risk. The aim of this study is to examine woman-specific factors, including menstrual, reproductive and pregnancy complications, in relation to the prevalence of hypertension in mid-life Asian women.MethodsThis is a cross-sectional study of 1146 healthy women aged 45-69 years, from a multi-ethnic Asian cohort. The women completed an extensive questionnaire that included their sociodemographic details, medical history, lifestyle and physical activity, and reproductive and menopausal history. They also underwent objectively measured physical performance tests and a dual X-ray absorptiometry scan. Hypertension was defined as a systolic BP ≥140 and/or diastolic BP ≥90mm Hg, past diagnosis by a physician, or use of antihypertensive medications. Multivariable logistic regression was used to assess the independent risk factors for hypertension.ResultsThe average age of the 1146 women analysed was 56.3 (SD 6.2) years, and 55.2 percent of them were hypertensive. The prevalence of gestational diabetes and gestational hypertension was 12.6% and 9.4%, respectively. Besides age, abnormal menstrual cycle length at 25 years of age (OR:2.35, CI:1.34-4.13), preeclampsia (OR:2.46, CI:1.06-5.74), increased visceral adiposity (OR:4.21, CI:2.28-7.79) and reduced physical performance (OR:2.83, CI:1.46-5.47) were independently associated with hypertension in Asian women.ConclusionsOur findings highlight the necessity of including features of menstrual and reproductive history as possible indicators of hypertension risk in cardiovascular disease risk assessment and prevention among Asian women. Reducing visceral adiposity and exercise to improve physical performance may help women avoid developing hypertension.

Purpose: With the onset of the COVID-19 pandemic, employees suddenly had to work remotely and realize all work-related social interaction in virtual formats. The sudden shift to the virtual format came with new workplace stressors. To understand the stressors of remote work and videoconferences, we present two qualitative studies. The aim of this study is to better understand the stress associated with remote work and videoconferencing, with an emphasis on how workers cope with the added stress. Methodology: We applied thematic analysis to open-ended survey data from employees in the US (n = 349) and in-depth telephone interviews of 50 meeting leaders from the US and Germany. Findings: We identified the work–home interface, technology, and communication issues as key challenges of remote work. Further, we found camera usage, early meeting phases, and multitasking to be central stressors of videoconferences. Finally, we identified individual- and team-level coping strategies to reduce the impacts of virtual meeting stressors on employees. Originality: Our research contributes to the emerging field studying the effects of virtual work and videoconferences on employees. We provide an overview of the challenges of remote work at the early stages of the pandemic, and we present an overview of the stressors that emerge in virtual meeting environments. We discuss insights into why videoconferences may fatigue employees. Including German and US samples, our research allows a cross-cultural comparison of videoconferencing stressors. Finally, we present actionable practical recommendations to improve videoconferences.

Summary: Biological evidence supports plasma methemoglobin as a biomarker for anemia-induced tissue hypoxia. In this translational planned substudy of the multinational randomized controlled transfusion thresholds in cardiac surgery (TRICS-III) trial, which included adults undergoing cardiac surgery requiring cardiopulmonary bypass with a moderate-to-high risk of death, we investigated the relationship between perioperative hemoglobin concentration (Hb) and methemoglobin; and evaluated its association with postoperative outcomes. The primary endpoint was a composite of death, myocardial infarction, stroke, and severe acute kidney injury at 28 days. We observe weak non-linear associations between decreasing Hb and increasing methemoglobin, which were strongest in magnitude at the post-surgical time point. Increased levels of post-surgical methemoglobin were associated with a trend toward an elevated risk for stroke and exploratory neurological outcomes. Our generalizable study demonstrates post-surgical methemoglobin may be a marker of anemia-induced organ injury/dysfunction, and may have utility for guiding personalized approaches to anemia management. Clinicaltrials.gov registration NCT02042898.

IntroductionTo determine men's body ideals and the factors that influence these choices, this study used a matrix of computer generated (CG) male bodies (based on an analysis of 3D scanned real bodies) which independently varied in fat and muscle content.MethodsTwo hundred and fifty-eight male participants completed a range of psychometric measures to index body concerns and body ideal internalization and then chose the CG body that best reflected their own current body, as well as the body that reflected their personal ideal. A subset of participants was then retested to check that these judgements were stable over time.ResultsWhile judgements of the ideal body seem to be influenced by a shared appearance ideal, the degree to which this ideal was internalized showed significant variability between participants. The effect of this internalization was reflected in the difference between the estimated current body and the ideal.DiscussionHigher internalization led to a preference for higher muscle and lower fat content. This preference was most marked for fat content, although reducing adiposity also made the underlying musculature more salient. Additionally, the ideal body composition was modulated by the composition the participant believed his current body had (i.e., it seemed that a participant's ideal body was anchored by what they believed to be their current body and what change was possible from this starting point).

Introduction. Recent national guidelines recommending mitral valve replacement (MVR) for severe secondary mitral regurgitation have resulted in an increased utilization of mitral bioprosthesis. There is a paucity of data on how longitudinal clinical outcomes vary by prosthesis type. We examined long-term survival and risk of reoperation between patients having bovine vs. porcine MVR. Study Design. A retrospective analysis of MVR or MVR + coronary artery bypass graft (CABG) from 2001 to 2017 among seven hospitals reporting to a prospectively maintained clinical registry was conducted. The analytic cohort included 1,284 patients undergoing MVR (801 bovine and 483 porcine). Baseline comorbidities were balanced using 1 : 1 propensity score matching with 432 patients in each group. The primary end point was all-cause mortality. Secondary end points included in-hospital morbidity, 30-day mortality, length of stay, and risk of reoperation. Results. In the overall cohort, patients receiving porcine valves were more likely to have diabetes (19% bovine vs. 29% porcine; p2 mg/dL (4% bovine vs. 7% porcine; p=0.03), and coronary artery disease (65% bovine vs. 77% porcine; p

BackgroundThe contribution of language preference and ethnicity to muscle strength and physical performance is unclear. We examined the associations of reading language preferences with muscle strength and performance in Chinese women and compared them to other ethnicities.MethodsThe Integrated Women's Health Programme (IWHP) cohort comprised community-dwelling, midlife Singaporean women aged 45-69. Ethnic Chinese women could choose between the English or Chinese versions of the questionnaire. Malay and Indian women were presented with the English version. Sociodemographic, reproductive, anthropometric characteristics were obtained. Hand grip strength and physical performance were objectively assessed. Visceral adiposity (VAT) was determined by Dual-energy X-ray Absorptiometry. Multivariable logistic regression models were used to determine independent associations of language preference/ethnicity with muscle strength and physical performance.ResultsThe cohort comprised 1164 women (mean age: 56.3±6.2 years); 84.1% Chinese, 5.6% Malay, and 10.3% Indian. 315 Chinese participants (32.2%) had a Chinese-language reading preference (CLP). CLP women tended to be parous, of a lower socioeconomic status (lower proportions received tertiary education, lower employment rates and lower household income), and engaged in less physical activity compared to Chinese women with an English-language preference (ELP). This translated to a weaker hand grip strength (aOR: 1.56; 95%CI: 1.07-2.27), slower repeated chair stand (1.55; 1.12-2.13), poorer balance on tandem stand (2.00; 1.16-3.47), and a slower gait speed (1.62; 1.06-2.47). Compared to ELP women, Malay women had higher odds of poor hand grip strength (1.81; 1.12-2.93) while Indians had a higher odd of poor balance on one-leg stand (2.12; 1.28-3.52) and slow gait speeds on usual (1.88; 1.09-3.25) and narrow walks (1.91; 1.15-3.17).ConclusionsChinese language reading preference was associated with inferior muscle strength and physical performance. Such disparities were largest and most consistent in the CLP group, followed by Indian and Malay women compared to the ELP group. Further studies should determine if CLP-associated muscle weakness can predict adverse health outcomes.

Background Although researchers have begun to consider metacognitive insight during face matching, little is known about the underlying mechanism. Here, I investigated whether objective ability, as well as self-assessed ability, were able to predict metacognitive performance, that is, the ability to differentiate correct and incorrect responses in terms of confidence. In addition, I considered whether a training intervention resulted in improvements to both face matching performance and metacognitive insight. Methods In this experiment (N = 220), participants completed a face matching task, with either a diagnostic feature training course or a control course presented at the halfway point. In addition, a second face matching task, as well as a self-report questionnaire regarding ability, were completed to provide measures of objective and self-assessed ability respectively. Results Higher self-assessed ability with faces, as well as higher objective ability with face matching, predicted better metacognitive performance, i.e., greater confidence in correct, in comparison with incorrect, responses. This pattern of results was evident both when objective ability was measured through performance on the same task used to measure metacognitive insight and when a different task was used. Finally, the training intervention failed to produce improvements in face matching performance and showed no evidence of altering metacognitive ability. Discussion The current work begins to address the mechanism underlying individual differences in metacognitive insight during face matching. Although support was provided for a competence-based account, where better face matchers showed greater performance on the task and were more successful in monitoring their performance, further work might focus on decoupling task performance and competence in order to more conclusively explain why some people are more insightful than others.

Given the unprecedented environment of long duration space exploration (LDSE), success simply cannot occur without the coordinated efforts of multiple teams, both in flight and on the ground. These multiteam systems (MTSs) are needed to achieve the complex and dynamic tasks of spaceflight missions that will be longer and more uncertain than any previously experienced. Accordingly, research is limited in terms of how to best coordinate these teams and their dynamics—and in particular, how to best prepare LDSE teams to work across time and space effectively. To begin to address these critical questions systematically, qualitative data was extracted from a series of ten interviews with experts in spaceflight and long duration analog environments. Using thematic analysis techniques, we identified several consistent themes for affective, behavioral, and cognitive elements of teamwork occurring within and between teams. We examine each of these in detail, to identify the dynamics of what is currently known and where research needs to go to provide guidance for spaceflight organizations as well as others attempting to successfully implement MTSs in novel, complex environments.

Animals must weigh competing needs and states to generate adaptive behavioral responses to the environment. Sensorimotor circuits are thus tasked with integrating diverse external and internal cues relevant to these needs to generate context-appropriate behaviors. However, the mechanisms that underlie this integration are largely unknown. Here, we show that a wide range of states and stimuli converge upon a single Caenorhabditis elegans olfactory neuron to modulate food-seeking behavior. Using an unbiased ribotagging approach, we find that the expression of olfactory receptor genes in the AWA olfactory neuron is influenced by a wide array of states and stimuli, including feeding state, physiological stress, and recent sensory cues. We identify odorants that activate these state-dependent olfactory receptors and show that altered expression of these receptors influences food-seeking and foraging. Further, we dissect the molecular and neural circuit pathways through which external sensory information and internal nutritional state are integrated by AWA. This reveals a modular organization in which sensory and state-related signals arising from different cell types in the body converge on AWA and independently control chemoreceptor expression. The synthesis of these signals by AWA allows animals to generate sensorimotor responses that reflect the animal’s overall state. Our findings suggest a general model in which sensory- and state-dependent transcriptional changes at the sensory periphery modulate animals’ sensorimotor responses to meet their ongoing needs and states.

Objective: To compare tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) in patients undergoing cardiac surgery with cardiopulmonary bypass. Methods: Over a consecutive 2-year period, 824 adult cardiac surgery patients who received TXA during an EACA shortage were compared with 778 patients who received EACA postshortage. Patient characteristics and process and outcome variables were collected through chart review and database queries. This retrospective analysis used inverse probability of treatment weighting to control for confounding by indication, and propensity scores were calculated using a logistic regression model. Results: In adjusted models, overall transfusion rates for the TXA cohort (odds ratio [OR], 0.94; 95% confidence interval [95% CI], 0.81-1.10) and administration of platelets (OR, 1.04; 95% CI, 0.85-1.27), red blood cells (OR, 0.93; 95% CI, 0.80-1.09), fresh frozen plasma (OR, 1.00; 95% CI, 0.79-1.25), and cryoprecipitate (OR, 1.08; 95% CI, 0.71-1.64) were equivalent to the EACA cohort. In addition, there was no statistical difference with respect to stroke, seizure, mortality, reoperation for bleeding, chest tube drainage, and acute kidney injury. Patients who received TXA had shorter ventilator times (difference in medians −1.33 hours [95% CI, −1.86 to −0.80]) and lower postsurgical charges (difference of medians −$2913 [95% CI, −5147 to −679]). Conclusions: Substituting TXA for EACA during cardiac surgery with cardiopulmonary bypass did not change transfusion rate or amount, nor was there a significant difference in chest tube drainage. Patients who received TXA had a statistically significant but not clinically significant lower postoperative ventilator times and charges without an increase in mortality, stroke, reoperation for bleeding, acute kidney injury, or seizures.

To adapt to their environments, animals must generate behaviors that are closely aligned to a rapidly changing sensory world. However, behavioral states such as foraging or courtship typically persist over long time scales to ensure proper execution. It remains unclear how neural circuits generate persistent behavioral states while maintaining the flexibility to select among alternative states when the sensory context changes. Here, we elucidate the functional architecture of a neural circuit controlling the choice between roaming and dwelling states, which underlie exploration and exploitation during foraging in C. elegans. By imaging ensemble-level neural activity in freely moving animals, we identify stereotyped changes in circuit activity corresponding to each behavioral state. Combining circuit-wide imaging with genetic analysis, we find that mutual inhibition between two antagonistic neuromodulatory systems underlies the persistence and mutual exclusivity of the neural activity patterns observed in each state. Through machine learning analysis and circuit perturbations, we identify a sensory processing neuron that can transmit information about food odors to both the roaming and dwelling circuits and bias the animal towards different states in different sensory contexts, giving rise to context-appropriate state transitions. Our findings reveal a potentially general circuit architecture that enables flexible, sensory-driven control of persistent behavioral states.

In many countries, urban flooding due to local, intense rainfall is expected to become more frequent because of climate change and urbanization. Cities trying to adapt to this growing risk are challenged by a chronic lack of surface flooding data that are needed for flood risk assessment and planning. In this work, we propose a new approach that exploits existing surveillance camera systems to provide qualitative flood level trend information at scale. The approach uses a deep convolutional neural network (DCNN) to detect floodwater in surveillance footage and a novel qualitative flood index (namely, the static observer flooding index – SOFI) as a proxy for water level fluctuations visible from a surveillance camera's viewpoint. To demonstrate the approach, we trained the DCNN on 1218 flooding images collected from the Internet and applied it to six surveillance videos representing different flooding and lighting conditions. The SOFI signal obtained from the videos had a 75 % correlation to the actual water level fluctuation on average. By retraining the DCNN with a few frames from a given video, the correlation is increased to 85 % on average. The results confirm that the approach is versatile, with the potential to be applied to a variety of surveillance camera models and flooding situations without the need for on-site camera calibration. Thanks to this flexibility, this approach could be a cheap and highly scalable alternative to conventional sensing methods.

Abstract Background In recent years, fraudsters have begun to use readily accessible digital manipulation techniques in order to carry out face morphing attacks. By submitting a morph image (a 50/50 average of two people’s faces) for inclusion in an official document such as a passport, it might be possible that both people sufficiently resemble the morph that they are each able to use the resulting genuine ID document. Limited research with low-quality morphs has shown that human detection rates were poor but that training methods can improve performance. Here, we investigate human and computer performance with high-quality morphs, comparable with those expected to be used by criminals. Results Over four experiments, we found that people were highly error-prone when detecting morphs and that training did not produce improvements. In a live matching task, morphs were accepted at levels suggesting they represent a significant concern for security agencies and detection was again error-prone. Finally, we found that a simple computer model outperformed our human participants. Conclusions Taken together, these results reinforce the idea that advanced computational techniques could prove more reliable than training people when fighting these types of morphing attacks. Our findings have important implications for security authorities worldwide.

Abstract Background Iron deficiency is the most prevalent nutrient deficiency and the most common cause of anaemia worldwide. Because of the increased iron requirements during pregnancy, iron deficiency can lead to maternal anaemia and reduced newborn iron stores. We examined the proportion and risk factors of iron deficiency among pregnant women in a developed Asian country. Methods Within a prospective cohort in Singapore, 985 Asian women were assessed for iron status at 26–28 weeks’ gestation, with plasma ferritin and soluble transferrin receptor (sTfR) measurements. Iron status was determined according to plasma ferritin concentrations at ≥30 μg/L (iron sufficiency), 15 to

Radiolabeled FAPI (fibroblast activation protein inhibitors) recently gained attention as widely applicable imaging and potential therapeutic compounds targeting CAF (cancer-associated fibroblasts) or DAF (disease-associated fibroblasts in benign disorders). Moreover, the use of FAPI has distinct advantages compared to FDG (e.g., increased sensitivity in regions with high glucose metabolism, no need for fasting, and rapid imaging). In this study, we wanted to evaluate the radiochemical synthesis and the clinical properties of the new CAF-targeting tracer [68Ga]Ga-DATA5m.SA.FAPi. The compound consists of a (radio)chemically easy to use hybrid chelate DATA.SA, which can be labeled at low temperatures, making it an interesting molecule for ‘instant kit-type’ labeling, and a squaric acid moiety that provides distinct advantages for synthesis and radiolabeling. Our work demonstrates that automatic synthesis of the FAP inhibitor [68Ga]Ga-DATA5m.SA.FAPi is feasible and reproducible, providing convenient access to this new hybrid chelator-based tracer. Our studies demonstrated the diagnostic usability of [68Ga]Ga-DATA5m.SA.FAPi for the unambiguous detection of cancer-associated fibroblasts of various carcinomas and their metastases (NSCLC, liposarcoma, parotid tumors, prostate cancer, and pancreas adenocarcinoma), while physiological uptake in brain, liver, intestine, bone, and lungs was very low.

Brain research in Europe is a rapidly evolving field, and increasingly at the forefront of science. Although considerable amounts of knowledge and innovative approaches have been generated, the translation into new health interventions is hindered by excessive fragmentation. Effective and efficient collaboration and cooperation among the various initiatives are often identified as a key success factor to achieve brain research full impact. EBRA fully responds to these needs by bringing together the various stakeholders and major brain research initiatives, at European level and beyond. EBRA creates the conditions for real and effective cross fertilisation, dialogue, building consensus and exploiting research potential. At the strategic level, EBRA acts by fostering alignment and better coordination of research strategies across European and global brain initiatives. Therefore, an overview of the scale and scope of brain research activities funded in the EU framework programme and the funding initiatives of JPND, NEURON and HBP has been created. The results of the mapping exercise then underpinned the development of a Shared European Brain Research Agenda (SEBRA). The SEBRA focuses on research opportunities and research gaps to be addressed in the field, and priorities for action in the short- and long-term. It integrates pre-existing documents as well as expert (i.e., researchers, neurologists/psychiatrists, patient representatives) input that has been collected through surveys and in a dedicated expert workshop. The SEBRA will be used to provide recommendations on future areas for excellent, innovative, and translational research comprising those for maximized cooperation, reduced overlap, and fragmentation.

Brain research in Europe is a rapidly evolving field, and increasingly at the forefront of science. Although considerable amounts of knowledge and innovative approaches have been generated, the translation into new health interventions is hindered by excessive fragmentation. Effective and efficient collaboration and cooperation among the various initiatives are often identified as a key success factor to achieve brain research full impact. EBRA fully responds to these needs by bringing together the various stakeholders and major brain research initiatives, at European level and beyond. EBRA creates the conditions for real and effective cross fertilisation, dialogue, building consensus and exploiting research potential. On the operational level, EBRA facilitates the emergence of research projects in specific areas in active clusters. A cluster is understood as a research community that can be directed towards basic research, clinical research and/or methodological approaches under a common topic and disease area within brain research. EBRA support clusters to: 1. Consolidate or expand further the research community expand their community, 2. Engage with policy makers and other relevant stakeholders, 3. Build consensus on various issues (research priorities, research roadmap, data sharing, etc.), 4. Promote links with existing research infrastructures, 5. Increase the visibility of the research community through communication and dissemination activities, 6. Coordinate the development of position/consensus papers, white papers, guidelines, meeting reports and/or other cluster outcomes. EBRA currently has 6 existing clusters: EPICLUSTER, Prevention of Severe Mental Disorders (PSMD)-cluster, TRISOMY21-cluster, BRAINFOOD-cluster., PREMOS-cluster and ECIB-cluster.

We review simple methods for evaluating 4 types of biomarkers. First, we discuss the evaluation of surrogate endpoint biomarkers (to shorten a randomized trial) using 2 statistical and 3 biological criteria. Second, we discuss the evaluation of prognostic biomarkers (to predict the risk of disease) by comparing data collection costs with the anticipated net benefit of risk prediction. Third, we discuss the evaluation of predictive markers (to search for a promising subgroup in a randomized trial) using a multivariate subpopulation treatment effect pattern plot involving a risk difference or responders-only benefit function. Fourth, we discuss the evaluation of cancer screening biomarkers (to predict cancer in asymptomatic persons) using methodology to substantially reduce the sample size with stored specimens.

Abstract Background This study investigates the barriers and facilitators of the use of antibiotics in acute respiratory tract infections by general practitioners (GPs) in Germany. Methods A multidisciplinary team designed and pre-tested a written questionnaire addressing the topics awareness of antimicrobial resistance (7 items), use of antibiotics (9 items), guidelines/sources of information (9 items) and sociodemographic factors (7 items), using a five-point-Likert-scale (“never” to “very often”). The questionnaire was mailed by postally to 987 GPs with registered practices in eastern Germany in May 2015. Results 34% (340/987) of the GPs responded to this survey. Most of the participants assumed a multifactorial origin for the rise of multidrug resistant organisms. In addition, 70.2% (239/340) believed that their own prescribing behavior influenced the drug-resistance situation in their area. GPs with longer work experience (> 25 years) assumed less individual influence on drug resistance than their colleagues with less than 7 years experience as practicing physicians (Odds Ratio [OR] 0.32, 95% Confidence Interval [CI] 0.17–0.62; P

Abstract Background We assessed the impact of adopting the 2013 World Health Organization (WHO) diagnostic criteria on the rates of gestational diabetes (GDM), pregnancy outcomes and identification of women at future risk of type 2 diabetes. Methods During a period when the 1999 WHO GDM criteria were in effect, pregnant women were universally screened using a one-step 75 g 2-h oral glucose tolerance test at 26–28 weeks’ gestation. Women were retrospectively reclassified according to the 2013 criteria, but without the 1-h glycaemia measurement. Pregnancy outcomes and glucose tolerance at 4–5 years post-delivery were compared for women with GDM classified by the 1999 criteria alone, GDM by the 2013 criteria alone, GDM by both criteria and without GDM by both sets of criteria. Results Of 1092 women, 204 (18.7%) and 142 (13.0%) were diagnosed with GDM by the 1999 and 2013 WHO criteria, respectively, with 27 (2.5%) reclassified to GDM and 89 (8.2%) reclassified to non-GDM when shifting from the 1999 to 2013 criteria. Compared to women without GDM by both criteria, cases reclassified to GDM by the 2013 criteria had an increased risk of neonatal jaundice requiring phototherapy (relative risk (RR) = 2.78, 95% confidence interval (CI) 1.32, 5.86); despite receiving treatment for GDM, cases reclassified to non-GDM by the 2013 criteria had higher risks of prematurity (RR = 2.17, 95% CI 1.12, 4.24), neonatal hypoglycaemia (RR = 3.42, 95% CI 1.04, 11.29), jaundice requiring phototherapy (RR = 1.71, 95% CI 1.04, 2.82), and a higher rate of abnormal glucose tolerance at 4–5 years post-delivery (RR = 3.39, 95% CI 2.30, 5.00). Conclusions Adoption of the 2013 WHO criteria, without the 1-h glycaemia measurement, reduced the GDM rate. Lowering the fasting glucose threshold identified women who might benefit from treatment, but raising the 2-h threshold may fail to identify women at increased risk of adverse pregnancy and future metabolic outcomes. Trial registration NCT01174875. Registered 1 July 2010 (retrospectively registered).

Abstract Background Higher screen viewing time (SVT) in childhood has been associated with adverse health outcomes, but the predictors of SVT in early childhood are poorly understood. We examined the sociodemographic and behavioral predictors of total and device-specific SVT in a Singaporean cohort. Methods At ages 2 and 3 years, SVT of 910 children was reported by their parents. Interviewer-administered questionnaires assessed SVT on weekdays and weekends for television, computer, and hand-held devices. Multivariable linear mixed-effect models were used to examine the associations of total and device-specific SVT at ages 2 and 3 with predictors, including children’s sex, ethnicity, birth order, family income, and parental age, education, BMI, and television viewing time. Results At age 2, children’s total SVT averaged 2.4 ± 2.2 (mean ± SD) hours/day, including 1.6 ± 1.6 and 0.7 ± 1.0 h/day for television and hand-held devices, respectively. At age 3, hand-held device SVT was 0.3 (95% CI: 0.2, 0.4) hours/day higher, while no increases were observed for other devices. SVT tracked moderately from 2 to 3 years (r = 0.49, p

In our everyday lives, we are required to make decisions based upon our statistical intuitions. Often, these involve the comparison of two groups, such as luxury versus family cars and their suitability. Research has shown that the mean difference affects judgements where two sets of data are compared, but the variability of the data has only a minor influence, if any at all. However, prior research has tended to present raw data as simple lists of values. Here, we investigated whether displaying data visually, in the form of parallel dot plots, would lead viewers to incorporate variability information. In Experiment 1, we asked a large sample of people to compare two fictional groups (children who drank ‘Brain Juice’ versus water) in a one-shot design, where only a single comparison was made. Our results confirmed that only the mean difference between the groups predicted subsequent judgements of how much they differed, in line with previous work using lists of numbers. In Experiment 2, we asked each participant to make multiple comparisons, with both the mean difference and the pooled standard deviation varying across data sets they were shown. Here, we found that both sources of information were correctly incorporated when making responses. Taken together, we suggest that increasing the salience of variability information, through manipulating this factor across items seen, encourages viewers to consider this in their judgements. Such findings may have useful applications for best practices when teaching difficult concepts like sampling variation.

Abstract Background The association between early weight gain and later allergic outcomes has not been well studied. We examined the relation between weight gain and the subsequent development of allergic outcomes in the first 36 months of life in a Singapore birth cohort. Methods In repeated visits in the first 15 months, we measured infant weight and administered questionnaires ascertaining allergic outcomes. At ages 18 and 36 months, we administered skin prick tests (SPTs) to inhalant and food allergens. Results At 18 months, 13.5% had a positive SPT, 3.5% had wheeze and a positive SPT, 3.9% had rhinitis and a positive SPT, and 6.1% had eczema and a positive SPT. Higher weight gain from 6 to 9 months, 9 to 12 months and 12 to 15 months were independently associated with a reduced risk of developing a positive SPT at 18 months (p-trend ≤0.03). At 36 months, 23.5% had a positive SPT, 11.9% had wheeze and a positive SPT, 12.2% rhinitis and a positive SPT, and 11.5% eczema and a positive SPT. Higher weight gain from 12 to 15 months was associated with a reduced risk of developing a positive SPT at 36 months (p-trend

Background: In order to prevent age-related degenerative diseases in the aging population, their diets should be nutrient dense. For this purpose, the Elderly-Nutrient rich food (E-NRF7.3) score has been developed to assess nutrient density of diets by capturing dietary reference values for older adults. To demonstrate its practical importance such score should be validated against markers of nutritional status and health.Objective: The objective of this study was to examine the association between the E-NRF7.3 score and markers of nutritional status and inflammation.Design: This study was carried out in a sample of the NU-AGE study including 242 Dutch and 210 Polish men and women, aged 65–79 years. Dietary intake was assessed by means of 7-day food records and structured questionnaires collected data on supplement use, lifestyle, and socio-economic information. Baseline measurements included anthropometrics, physical and cognitive function tests, and a fasting venipuncture. E-NRF7.3 scores were calculated to estimate nutrient density of foods and the diet. Associations between the E-NRF7.3 scores and micronutrient status of vitamin D, folate, vitamin B12, homocysteine, and c-reactive protein (CRP) were examined using linear regression analysis while adjusting for confounders.Results: Each one unit increase in E-NRF7.3 score was associated with a 2.2% increase in serum folate in Dutch and 1.6% increase in Polish participants in the fully adjusted models (both p < 0.01). Each one unit increase in E-NRF7.3 was significantly associated with a 1.5% decrease in homocysteine levels in Dutch participants (p < 0.01), whereas, a 0.9% increase in vitamin B12 levels was observed in Polish participants only (p < 0.01). Higher E-NRF7.3 scores were not associated with vitamin D or CRP levels. Adjustment for potential confounders did not substantially alter these results.Discussion: The E-NRF7.3 was developed to reflect dietary intake of relevant nutrients for older adults. Its association with markers of nutritional status could be confirmed for folate (both populations), vitamin B12 (Poland only), and homocysteine (the Netherlands only). There was no association with vitamin D and CRP. To further demonstrate its validity and practical implication, future studies should include a wider range of nutritional status makers, health outcomes, and inflammation markers.

Objective: To develop a nutrient-rich food (NRF) score that captures dietary reference values for older adults and to validate this against a diet index that was specifically designed to assess adherence to dietary guidelines for the older population.Design: A cross-sectional study within the Dutch National Food Consumption Survey (DNFCS, n = 735 men and women aged 70–94 years, enrolled between October 2010 and February 2012) and within the NU-AGE study (n = 250 men and women aged 65–79 years, enrolled between April 2012 and March 2013). Dietary intake was assessed by means of two non-consecutive dietary record assisted 24-h recalls and 7-day food records, respectively. Structured questionnaires collected data on lifestyle and socio-economic information. Anthropometrics were measured by trained dieticians or research assistants. We evaluated Elderly NRF (E-NRF) scores against the NU-AGE index, a measure of adherence to European dietary guidelines for the aging population. The E-NRF scores were composed of nutrients that: (1) have been shown to be of inadequate intake in the aging population (>20%), (2) were defined as nutrients of public health relevance, and (3) were associated with relevant health outcomes.Results: The E-NRF score that best predicted the NU-AGE index included seven nutrients to encourage (protein, dietary fiber, folate, vitamin D, calcium, magnesium, potassium) and three nutrients to limit (saturated fat, sodium and mono- and disaccharides) on a 100-kcal basis, the E-NRF7.3 score (model R2 0.27 in DNFCS and 0.41 in NU-AGE). Food groups contributing the most to the individual E-NRF7.3 scores were vegetables, bread, potatoes and milk and milk products.Conclusion: The E-NRF7.3 score is a useful tool for assessing nutrient density of diets within the older population. No index has previously been developed with the aim of evaluating nutrient density of diets and foods specifically capturing dietary reference values for older adults.

Summary Objective Firstly, to investigate whether polycystic ovary syndrome (PCOS) shows a continuum of severity with increasing number of phenotypic features comprising the Rotterdam criteria for PCOS and secondly, to explore relationships of these phenotypes to the circadian biomarkers, cortisol and melatonin. Background Studies characterizing the spectrum of PCOS subphenotypes give little emphasis to the distinction among women who manifest zero, one or two of the three phenotypic features comprising the Rotterdam criteria. The relationship of circadian biomarkers to PCOS phenotypes is unclear. Design Cross‐sectional study of 321 participants from 2011 to 2016 conducted at the National University Hospital (NUH), Singapore. Participants Participants included women who attended a health screen for NUH staff, volunteers from the university community, and women referred for possible PCOS from gynaecological clinics at NUH and KK Women's and Children's Hospital (Singapore). Methods All participants underwent a physical examination, ovarian ultrasound scan and follicular‐phase blood testing, and completed a health and lifestyle questionnaire. Results A significant positive linear trend in all clinical and biochemical characteristics of PCOS with increasing number of phenotypic features comprising the Rotterdam criteria. We observed a similar trend in serum cortisol and melatonin, two biomarkers of the circadian rhythm. Conclusion PCOS may not be an “all‐or‐none” condition, but rather a continuous spectrum. The positive relationship between number of PCOS criteria with melatonin and cortisol merits further investigation on the role of circadian biorhythms in the pathogenesis of PCOS.