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Predicting and treating recurrence in intermediate-risk prostate cancer patients remains a challenge despite having identified genomic instability (1) and hypoxia (2,3) as risk factors. This underlies challenges in assigning the functional impact of these risk factors to mechanisms promoting prostate cancer progression. Here we show chronic hypoxia (CH), as observed in prostate tumours (4), leads to the adoption of an androgen-independent state in prostate cancer cells. Specifically, CH results in prostate cancer cells adopting transcriptional and metabolic alterations typical of castration-resistant prostate cancer cells. These changes include increased expression of transmembrane transporters for the methionine cycle and related pathways leading to increased abundance of metabolites and expression of enzymes related to glycolysis. Targeting the Glucose Transporter 1 (GLUT1) identified a dependency on glycolysis in androgen-independent cells. Overall, we identified a therapeutically targetable weakness in chronic hypoxia and androgen-independent prostate cancer. These findings may offer additional strategies for treatment development against hypoxic prostate cancer.

Goal and theoretical commentary A number of recent life cycle assessment (LCA) studies have concluded that animal-sourced foods should be restricted—or even avoided—within the human diet due to their relatively high environmental impacts (particularly those from ruminants) compared with other protein-rich foods (mainly protein-rich plant foods). From a nutritional point of view, however, issues such as broad nutrient bioavailability, amino acid balances, digestibility and even non-protein nutrient density (e.g., micronutrients) need to be accounted for before making such recommendations to the global population. This is especially important given the contribution of animal sourced foods to nutrient adequacy in the global South and vulnerable populations of high-income countries (e.g., children, women of reproductive age and elderly). Often, however, LCAs simplify this reality by using ‘protein’ as a functional unit in their models and basing their analyses on generic nutritional requirements. Even if a ‘nutritional functional unit’ (nFU) is utilised, it is unlikely to consider the complexities of amino acid composition and subsequent protein accretion. The discussion herein focuses on nutritional LCA (nLCA), particularly on the usefulness of nFUs such as ‘protein,’ and whether protein quality should be considered when adopting the nutrient as an (n)FU. Further, a novel and informative case study is provided to demonstrate the strengths and weaknesses of protein-quality adjustment. Case study methods To complement current discussions, we present an exploratory virtual experiment to determine how Digestible Indispensable Amino Acid Scores (DIAAS) might play a role in nLCA development by correcting for amino acid quality and digestibility. DIAAS is a scoring mechanism which considers the limiting indispensable amino acids (IAAs) within an IAA balance of a given food (or meal) and provides a percentage contribution relative to recommended daily intakes for IAA and subsequent protein anabolism; for clarity, we focus only on single food items (4 × animal-based products and 4 × plant-based products) in the current case exemplar. Further, we take beef as a sensitivity analysis example (which we particularly recommend when considering IAA complementarity at the meal-level) to elucidate how various cuts of the same intermediary product could affect the interpretation of nLCA results of the end-product(s). Recommendations First, we provide a list of suggestions which are intended to (a) assist with deciding whether protein-quality correction is necessary for a specific research question and (b) acknowledge additional uncertainties by providing mitigating opportunities to avoid misinterpretation (or worse, dis-interpretation) of protein-focused nLCA studies. We conclude that as relevant (primary) data availability from supply chain ‘gatekeepers’ (e.g., international agri-food distributors and processors) becomes more prevalent, detailed consideration of IAA provision of contrasting protein sources needs to be acknowledged—ideally quantitatively with DIAAS being one example—in nLCA studies utilising protein as a nFU. We also contend that future nLCA studies should discuss the complementarity of amino acid balances at the meal-level, as a minimum, rather than the product level when assessing protein metabolic responses of consumers. Additionally, a broader set of nutrients should ideally be included when evaluating “protein-rich foods” which provide nutrients that extend beyond amino acids, which is of particular importance when exploring dietary-level nLCA.

The rise of zoonotic disease-related public health crises has sparked calls for policy action, including calls to close wildlife markets. Yet, these calls often reflect limited understanding of where, precisely, exposure to risk occurs along wildlife and wild meat trade chains. They also threaten to negatively impact food security and livelihoods. From a public health perspective, it is important to understand the practices that shape food safety all along the trade chain, resulting in meat that is either safe to eat or managed as a potential vector of pathogens. This article uses ethnographic methods to examine the steps that lead a wild animal from the forest to the plate of an urban consumer in Yangambi and Kisangani in the Democratic Republic of Congo (DRC). Focusing on hunters, village-level consumers, transporters, market traders and urban consumers, we highlight specific practices that expose different actors involved in the trade chain to wild meat related health risks, including exposure to food borne illnesses from contaminated meat and zoonotic pathogens through direct contact with wild animals, and the local practices in place to reduce the same. We discuss interventions that could help prevent and mitigate zoonotic and food borne disease risks associated with wild meat trade chains.

Here we present Positron Annihilation Doppler Broadening Spectroscopy (PADBS) as a powerful method to analyse the origin and development of defect processes in porous silicon structures as a result of alloying with lithium for the use in battery anode applications. Several prepared anodes were lithiated (discharged against Li+/Li) and de-lithiated (charged) with different capacities followed by a distinct treatment procedure and an analysis using the Delft Variable Energy Positron Beam. The results presented here show that we can distinguish two different processes attributed to (1) structural changes in silicon as a result of the alloying process, and (2) the formation of defects that initiate degradation of the material. The limit at which the porous material can be used for at least the first two cycles without the occurrence of damage can thus be accurately determined by using the PADBS technique.

Traumatic brain injury (TBI) is a significant cause of mortality and morbidity worldwide and many patients with TBI require intensive care unit (ICU) management. When facing a life-threatening illness, such as TBI, a palliative care approach that focuses on noncurative aspects of care should always be considered in the ICU. Research shows that neurosurgical patients in the ICU receive palliative care less frequently than the medical patients in the ICU, which is a missed opportunity for these patients. However, providing appropriate palliative care to neurotrauma patients in an ICU can be difficult, particularly for young adult patients. The patients’ prognoses are often unclear, the likelihood of advance directives is small, and the bereaved families must act as decision-makers. This article highlights the different aspects of the palliative care approach as well as barriers and challenges that accompany the TBI patient population, with a particular focus on young adult patients with TBI and the role of their family members. The article concludes with recommendations for physicians for effective and adequate communication to successfully implement the palliative care approach into standard ICU care and to improve quality of care for patients with TBI and their families.

This narrative review aims to unravel the potential of medical hypnotherapy for the treatment of children with a variety of diseases and symptoms. Going beyond its history and assumed neurophysiology, the chances of success for hypnotherapy will be outlined per pediatric speciality, accentuated by clinical research and experiences. Future implications and recommendations are given on extracting the positive effects of medical hypnotherapy for all pediatricians. Conclusion: Medical hypnotherapy is an effective treatment for children with specified conditions such as abdominal pain or headache. Studies suggest effectiveness for other pediatric disciplines, from the first line up to third line of care. In a time in which health is defined as 'a state of complete physical, mental and social well-being’, hypnotherapy stays an underrated treatment option for children. It is a unique mind–body treatment, which true potential still needs to be unraveled. What is Known:• Mind–body health techniques become a more relevant and accepted part of treatment in pediatric patients.• Medical hypnotherapy is an effective treatment for children with specified conditions such as functional abdominal pain. What is New:• Studies suggest the effectiveness of hypnotherapy in a high variety of pediatric symptoms and disease.• Hypnotherapy is a unique mind–body treatment which potential goes far beyond its current utilization.

As in most Northern European countries, the prevalence of hemoglobinopathies in The Netherlands is increasing due to migration. Although hemoglobinopathies are severe chronic diseases with few treatment options, timely detection of carriers allows at-risk couples to make informed reproductive choices such as pre-implantation diagnosis, prenatal diagnosis or termination of affected pregnancies. Using a quantitative design, we evaluated the prevalence of hemoglobinopathies in The Hague region, The Netherlands. Patient and carrier registries from hospital, laboratory and general practitioners allowed this quantitative analysis. The highest prevalence of hemoglobinopathies was seen in immigrant neighborhoods, and a large gap was noted between estimated carrier prevalence and the actual registration of carriers in electronic patient records. Carrier prevalence was estimated to be 13,704; however, the ELAN database contains only 1542 cases with ICPC codes for sickle cell disease or thalassemia. Although more research is needed to define the requirements of the healthcare system to address this challenge, this study clearly shows the gap between estimated carrier prevalence and registration and thereby the pressing need for action.

Purpose Medulloblastomas (MB) are highly malignant brain tumors that predominantly occur in young infants. Immunotherapy to boost the immune system is emerging as a novel promising approach, but is often hampered by inhibitory immune checkpoints. In the present study, we have studied immune checkpoint B7-H3 expression in a tissue cohort of human pediatric MB. Methods Expression of B7-H3 was detected by immunohistochemistry and classified via B7-H3 staining intensity and percentage of B7-H3 positive tumor cells. Subsequently, B7-H3 protein expression was distinguished in MB molecular subtypes and correlated to immune cell infiltrates, patient characteristics, and survival. Results B7-H3 protein expression was found in 23 out of 24 (96%) human pediatric MB cases and in 17 out of 24 (71%) MB cases > 25% of tumor cells had any level of B7-H3 expression. B7-H3 protein expression was more frequent on Group-4 MB as compared with other molecular subtypes (p = 0.02). Tumors with high B7-H3 expression showed less influx of γδT cells (p = 0.002) and CD3+ T cells (p = 0.041). Conclusion Immune checkpoint B7-H3 is differentially expressed by the large majority of pediatric MB. This further warrants the development of novel B7-H3-directed (immuno)therapeutic methods for children with incurable, metastatic, or chemo-resistant MB.

Ascariasis is the most prevalent zoonotic helminthic disease worldwide, and is responsible for nutritional deficiencies, particularly hindering the physical and neurological development of children. The appearance of anthelmintic resistance in Ascaris is a risk for the target of eliminating ascariasis as a public health problem by 2030 set by the World Health Organisation. The development of a vaccine could be key to achieving this target. Here we have applied an in silico approach to design a multi-epitope polypeptide that contains T-cell and B-cell epitopes of reported novel potential vaccination targets, alongside epitopes from established vaccination candidates. An artificial toll-like receptor-4 (TLR4) adjuvant (RS09) was added to improve immunogenicity. The constructed peptide was found to be non-allergic, non-toxic, with adequate antigenic and physicochemical characteristics, such as solubility and potential expression in Escherichia coli. A tertiary structure of the polypeptide was used to predict the presence of discontinuous B-cell epitopes and to confirm the molecular binding stability with TLR2 and TLR4 molecules. Immune simulations predicted an increase in B-cell and T-cell immune response after injection. This polypeptide can now be validated experimentally and compared to other vaccine candidates to assess its possible impact in human health.

We elucidate the value orientations (VOs) towards wild meat/wildlife in the Tshopo Province of the Democratic Republic of Congo, distinguishing between the provincial capital and rural areas. Based on stories prompted by four primary emotions, the most frequently encountered VOs were: concern for safety, nutrition and taste, and caring/respect. Rural people were more likely to express anthropocentric VOs. However, their stories did not necessarily associate negatively with caring/respect, suggesting that wildlife users may also be sensitive to biocentric values. Age, gender, and wealth were good predictors for biocentric VOs, with young women from the city more likely to express biocentric values. VOs and emotions related differently to specific wildlife species. Mutualism was not frequently elucidated in the stories. The associations we found provide crucial information to understand differences in value orientations across groups, identify barriers to change, and tailor behavior change campaigns to the local context.

Funder: Kjell och Märta Beijers Stiftelse (Kjell and Marta Beijer Foundation); doi: https://doi.org/10.13039/501100006353, Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE. Magnetic susceptibility of the presumed seizure-onset zone from three patients with focal epilepsy was compared during and after seizure activity. Finally, the cellular effects of iron overload were studied in vitro using an acute mouse hippocampal slice preparation and cultured human fetal astrocytes. While iron-accumulating neurons had a pyknotic morphology, astrocytes appeared to acquire iron-sequestrating capacity as indicated by prominent ferritin expression and iron retention in the hippocampus of patients with SE or TLE. Interictal to postictal comparison revealed increased magnetic susceptibility in the seizure-onset zone of epilepsy patients. Post-SE rats had consistently higher hippocampal iron levels during the acute and chronic phase (when spontaneous recurrent seizures are evident). In vitro, in acute slices that were exposed to iron, neurons readily took up iron, which was exacerbated by induced epileptiform activity. Human astrocyte cultures challenged with iron and ROS increased their antioxidant and iron-binding capacity, but simultaneously developed a pro-inflammatory phenotype upon chronic exposure. These data suggest that seizure-mediated, chronic neuronal iron uptake might play a role in neuronal dysfunction/loss in TLE-HS. On the other hand, astrocytes sequester iron, specifically in chronic epilepsy. This function might transform astrocytes into a highly resistant, pro-inflammatory phenotype potentially contributing to pro-epileptogenic inflammatory processes. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-021-02348-6.

In the Netherlands, approximately 250,000 people are living with heart failure. About one-third of them have comorbid diabetes mellitus type 2. Until recently, the effects of antidiabetic agents on heart failure were largely unknown. This changed after an observed increased risk of heart failure and ischaemic heart disease associated with thiazolidinediones that prompted the requirement for cardiovascular outcome trials for new glucose-lowering drugs. In the past decade, three new classes of antidiabetic agents have become available (i.e. dipeptidyl peptidase‑4 inhibitors, glucagon-like peptide‑1 receptor agonists and sodium-glucose cotransporter‑2 (SGLT2) inhibitors). Although the first two classes demonstrated no beneficial effects on heart failure compared to placebo in patients with diabetes mellitus type 2, SGLT2 inhibitors significantly and consistently lowered the risk of incident and worsening heart failure. Two recent trials indicated that these favourable effects were also present in non-diabetic patients with heart failure with reduced ejection fraction, resulting in significantly lower risks of hospitalisation for heart failure and presumably also cardiovascular and all-cause mortality. SGLT2 inhibitors have been shown to be benefit on top of recommended heart failure therapy including sacubitril/valsartan and may also prove beneficial for heart failure with preserved ejection fraction. In this review, we discuss the effects of antidiabetic agents on heart failure.

Despite advances in three-dimensional (3D) imaging, it remains challenging to profile all the cells within a large 3D tissue, including the morphology and organization of the many cell types present. Here, we introduce eight-color, multispectral, large-scale single-cell resolution 3D (mLSR-3D) imaging and image analysis software for the parallelized, deep learning–based segmentation of large numbers of single cells in tissues, called segmentation analysis by parallelization of 3D datasets (STAPL-3D). Applying the method to pediatric Wilms tumor, we extract molecular, spatial and morphological features of millions of cells and reconstruct the tumor’s spatio-phenotypic patterning. In situ population profiling and pseudotime ordering reveals a highly disorganized spatial pattern in Wilms tumor compared to healthy fetal kidney, yet cellular profiles closely resembling human fetal kidney cells could be observed. In addition, we identify previously unreported tumor-specific populations, uniquely characterized by their spatial embedding or morphological attributes. Our results demonstrate the use of combining mLSR-3D and STAPL-3D to generate a comprehensive cellular map of human tumors. An imaging software for large-scale microscopy data shows how cells are organized in tissues.

Background/objectives Traditional malnutrition screening instruments, including the Malnutrition Universal Screening Tool (MUST), strongly rely on low body mass index (BMI) and weight loss. In overweight/obese patients, this may result in underdetection of malnutrition risk. Alternative instruments, like the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF), include characteristics and risk factors irrespective of BMI. Therefore, we aimed to compare performance of MUST and PG-SGA SF in malnutrition risk evaluation in overweight/obese hospitalized patients. Subjects/methods We assessed malnutrition risk using MUST (≥1 = increased risk) and PG-SGA SF (≥4 = increased risk) in adult patients at hospital admission in a university hospital. We compared results for patients with BMI 2 vs. BMI ≥ 25 kg/m2. Results Of 430 patients analyzed (58 ± 16 years, 53% male, BMI 26.9 ± 5.5 kg/m2), 35% were overweight and 25% obese. Malnutrition risk was present in 16% according to MUST and 42% according to PG-SGA SF. In patients with BMI 2, MUST identified 31% as at risk vs. 52% by PG-SGA SF. In patients with BMI ≥ 25 kg/m2, MUST identified 5% as at risk vs. 36% by PG-SGA SF. Agreement between MUST and PG-SGA SF was low (к = 0.143). Of the overweight/obese patients at risk according to PG-SGA SF, 83/92 (90%) were categorized as low risk by MUST. Conclusions More than one-third of overweight/obese patients is at risk for malnutrition at hospital admission according to PG-SGA SF. Most of them are not identified by MUST. Awareness of BMI-dependency of malnutrition screening instruments and potential underestimation of malnutrition risk in overweight/obese patients by using these instruments is warranted.

AIMS/HYPOTHESIS: It has been proposed that muscle fibre-type composition and perfusion are key determinants of insulin-stimulated muscle glucose uptake and alterations in muscle fibre-type composition and perfusion contribute to muscle, and consequently whole-body insulin resistance in people with obesity. The goal of the study was to evaluate the relationships among muscle fibre-type composition, perfusion, and insulin-stimulated glucose uptake rates in healthy, lean people and people with obesity. METHODS: We measured insulin-stimulated whole-body glucose disposal and glucose uptake and perfusion rates in five major muscle groups (erector spinae, obliques, rectus abdominis, hamstrings, quadriceps) in 15 healthy lean people and 37 people with obesity by using the hyperinsulinaemic-euglycaemic clamp procedure in conjunction with [(2)H]glucose-tracer infusion (to assess whole-body glucose disposal) and positron emission tomography after injections of [(15)O]H(2)O (to assess muscle perfusion) and [(18)F]fluorodeoxyglucose (to assess muscle glucose uptake). A biopsy from the vastus lateralis was obtained to assess fibre-type composition. RESULTS: We found: i) a two-fold difference in glucose uptake rates among muscles in both the Lean and Obese groups [rectus abdominis: 67 (51, 78) and 32 (21, 55) μmol/kg/min in the Lean and Obese groups, respectively; erector spinae: 134 (103, 160) and 66 (24, 129) μmol/kg/min, respectively; median(IQR)] that was unrelated to perfusion or fibre-type composition (assessed in the vastus only), ii) the impairment in insulin action in the Obese compared with the Lean group was not different among muscle groups, and iii) insulin-stimulated whole-body glucose disposal expressed per kg fat-free mass was linearly related with muscle glucose uptake rate (R(2)=0.65, p

Objective Young children experience physical complaints, like abdominal pain or minor injuries from playing, almost every day. These experiences may shape how they deal with health issues later in life. While models exist to explain illness perception in adults, information is lacking on the perspective of young children. This qualitative study aimed to explore important themes in the experience of everyday physical complaints in four- and five-year-old children, using children as informants. Study design 30 semi-structured interviews were performed in which four- and five-year-old children were questioned about their experiences with everyday physical complaints. The interviews were double coded using Atlas.ti and subsequently qualitative content analysis was used to define themes. Results All participating children were able to elaborate on their experiences with physical complaints. Three themes emerged from the interviews: causes of complaints, appraisal of complaints, and implications of complaints. In their appraisal of complaints, four- and five-year-old children made a distinction between visible and invisible complaints and real or pretended complaints. Conclusion Four- and five-year-old children can already give details about their experiences with everyday physical complaints. They have developed ideas about the causes and implications of complaints and try to make an appraisal.

Aims/hypothesis Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts. Methods We conducted a meta-analysis of EWASs in blood collected 7–10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK). Results The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values −7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values 1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation. Conclusions/interpretation By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development. Graphical abstract

mRNA- and vector-based vaccines are used at a large scale to prevent COVID-19. We compared Spike S1-specific (S1) IgG antibodies after vaccination with mRNA-based (Comirnaty, Spikevax) or vector-based (Janssen, Vaxzevria) vaccines, using samples from a Dutch nationwide cohort. In adults 18–64 years old (n = 2412), the median vaccination interval between the two doses was 77 days for Vaxzevria (interquartile range, IQR: 69–77), 35 days (28–35) for Comirnaty and 33 days (28–35) for Spikevax. mRNA vaccines induced faster inclines and higher S1 antibodies compared to vector-based vaccines. For all vaccines, one dose resulted in boosting of S1 antibodies in adults with a history of SARS-CoV-2 infection. For Comirnaty, two to four months following the second dose (n = 196), S1 antibodies in adults aged 18–64 years old (436 BAU/mL, IQR: 328–891) were less variable and median concentrations higher compared to those in persons ≥ 80 years old (366, 177–743), but differences were not statistically significant (p > 0.100). Nearly all participants seroconverted following COVID-19 vaccination, including the aging population. These data confirm results from controlled vaccine trials in a general population, including vulnerable groups.

Purpose Various radiolabeled prostate-specific membrane antigen (PSMA)–targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide therapy. The PSMA binding affinities, biodistribution, and DNA-damaging capacities of these radiotracers have not yet been compared in detail. A major concern of PSMA-targeting radiotracers is the toxicity in other PSMA-expressing organs, such as the salivary glands, thus demanding careful evaluation of the most optimal and safest radiotracer. In this extensive preclinical study, we evaluated the clinically applied PSMA-targeting small molecule inhibitors DOTA-PSMA-617 (PSMA-617) and DOTAGA-PSMA-I&T (PSMA-I&T) and the PSMA nanobody DOTA-JVZ-007 (JVZ-007) using PSMA-expressing cell lines, a unique set of PCa patient-derived xenografts (PDX) and healthy human tissues. Methods and results In vitro displacement studies on PSMA-expressing cells and cryosections of a PSMA-positive PDX revealed high and specific binding affinity for all three tracers labeled with lutetium-177 with IC50 values in the nanomolar range. Interestingly, [177Lu]Lu-JVZ-007 could not be displaced by PSMA-617 or PSMA-I&T, suggesting that this tracer targets an alternative binding site. Autoradiography assays on cryosections of human salivary and renal tissues revealed [177Lu]Lu-PSMA-617 to have the lowest binding to these healthy organs compared with [177Lu]Lu-PSMA-I&T. In vivo biodistribution assays confirmed the in vitro results with comparable tumor uptake of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T at all timepoints, resulting in induction of similar levels of DNA double-strand breaks in the tumors. However, [177Lu]Lu-PSMA-I&T demonstrated approximately 40× higher renal uptake at 4 and 8 h post injection resulting in an unfavorable tumor-to-kidney ratio. Conclusion [177Lu]Lu-PSMA-617 has the most favorable biodistribution in mice as well as more favorable binding characteristics in vitro in PSMA-positive cells and human kidney and salivary gland specimens compared with [177Lu]Lu-PSMA-I&T and [177Lu]Lu-JVZ-007. Based on our preclinical evaluation, [177Lu]Lu-PSMA-617 is the best performing tracer to be taken further into clinical evaluation for PSMA-targeted radiotherapeutic development although with careful evaluation of the tracer binding to PSMA-expressing organs.

Eukaryotic cells, when exposed to environmental or internal stress, activate the integrated stress response (ISR) to restore homeostasis and promote cell survival. Specific stress stimuli prompt dedicated stress kinases to phosphorylate eukaryotic initiation factor 2 (eIF2). Phosphorylated eIF2 (p-eIF2) in turn sequesters the eIF2-specific guanine exchange factor eIF2B to block eIF2 recycling, thereby halting translation initiation and reducing global protein synthesis. To circumvent stress-induced translational shutdown, viruses encode ISR antagonists. Those identified so far prevent or reverse eIF2 phosphorylation. We now describe two viral proteins-one from a coronavirus and the other from a picornavirus-that have independently acquired the ability to counteract the ISR at its very core by acting as a competitive inhibitor of p-eIF2-eIF2B interaction. This allows continued formation of the eIF2-GTP-Met-tRNAi ternary complex and unabated global translation at high p-eIF2 levels that would otherwise cause translational arrest. We conclude that eIF2 and p-eIF2 differ in their interaction with eIF2B to such effect that p-eIF2-eIF2B association can be selectively inhibited.

Global losses of natural area are primarily attributed to cropland expansion, whereas the role of urban expansion is considered minor. However, urban expansion can induce cropland displacement, potentially leading to a loss of forest elsewhere. The extent of this effect is unknown. This study shows that indirect forest losses, through cropland displacement, far exceed direct losses from urban expansion. On a global scale, urban land increased from 33.2 to 71.3 million hectares (Mha) between 1992 and 2015, leading to a direct loss of 3.3 Mha of forest and an indirect loss of 17.8 to 32.4 Mha. In addition, this urban expansion led to a direct loss of 4.6 Mha of shrubland and an indirect loss of 7.0 to 17.4 Mha. Guiding urban development towards more sustainable trajectories can thus help preserve forest and other natural area at a global scale. Urban expansion displaces agricultural land elsewhere, indirectly causing loss of natural land cover. A global study finds that this impact is more substantial than previously thought.

Het Rijksvaccinatieprogramma (RVP) in Nederland is officieel in 1957 gestart met vaccinatie tegen vier ziekten (difterie, tetanus, kinkhoest en polio). Het huidige RVP omvat vaccinatie tegen twaalf ziekten. Een hoge vaccinatiegraad is van belang voor groepsbescherming, zodat kwetsbare (nog) niet gevaccineerden ook beschermd zijn. De vaccinatiegraad is hoog (≥90%) voor pasgeborenen, kleuters en schoolkinderen, maar is in de afgelopen jaren wel met 2 tot 3% gedaald. De HPV-vaccinatiegraad voor adolescente meisjes is de afgelopen twee jaar gedaald van 61 naar 45,5%. Introductie van het RVP heeft geleid tot een afname in het voorkomen van ziekte- en sterfgevallen. Toch komen sommige ziekten nog geregeld voor, zoals kinkhoest en invasieve pneumokkokkenziekte bij ouderen. Ook zien we de afgelopen jaren een toename van meningokokken W‑ziekte. Meningokokken ACWY-vaccinatie wordt sinds 2018 aangeboden en in 2019 wordt het RVP uitgebreid met maternale kinkhoestvaccinatie, vaccinatie van 60-plussers tegen pneumokokkenziekte en rotavirusvaccinatie voor risicogroepen. Ontwikkelingen in de epidemiologie van de ziekten, nieuwe wetenschappelijke inzichten en de ontwikkeling van nieuwe vaccins en doelgroepen vragen om continue monitoring en optimalisatie van het programma en vaccinatieschema. Ook de daling in vaccinatiegraad vraagt om maatregelen om de kans op toekomstige uitbraken van RVP-ziekten te reduceren.

In Nederland zijn de afgelopen jaren minder kinderen gevaccineerd binnen het Rijksvaccinatieprogramma (RVP). Hoewel de daling voor de meeste vaccinaties beperkt is, is deze aanzienlijk voor de humaan papillomavirus (HPV) vaccinatie die meisjes wordt aangeboden. Er is nog geen sluitende verklaring gevonden voor de dalende vaccinatiegraad. Het Rijksinstituut voor Volksgezondheid en Milieu (RIVM) onderzocht met een vragenlijst onder jeugdgezondheidsorganisaties, aangevuld met gegevens uit bestaande bronnen, of organisatorische veranderingen in de jeugdgezondheidszorg (JGZ) hier mogelijk op van invloed zijn. De JGZ is immers verantwoordelijk voor het toedienen van de RVP-vaccinaties, meestal georganiseerd via de consultatiebureaus. Uit het onderzoek bleek dat er in de JGZ tussen 2013 en 2017 organisatorische veranderingen zijn geweest. Er werd echter geen verband gevonden met de daling in het aantal gevaccineerden voor verschillende vaccinaties in het RVP. Ongeveer twee derde van de JGZ-organisaties heeft aan het onderzoek meegedaan. Gezien de regionale verschillen in zowel organisatie van het RVP als de hoogte van de vaccinatiegraad zijn de uitkomsten mogelijk niet geheel representatief voor heel Nederland. De uitkomsten van dit onderzoek dienen daarom met de nodige voorzichtigheid te worden geinterpreteerd.

De afgelopen twee jaar is de vaccinatiegraad voor het humaan papillomavirus (HPV) voor adolescente meisjes sterk gedaald in Nederland. Dit artikel beschrijft wat bekend is over opkomstverhogende maatregelen met betrekking tot de HPV-vaccinatiegraad. Er is literatuuronderzoek gedaan naar de organisatie van de HPV-vaccinatie in landen uit de Europese Unie of het Europees Economisch gebied (EU/EEA), naar wereldwijde effecten van opkomstverhogende maatregelen en specifiek naar de effecten van toediening van vaccinaties op scholen en van aanbeveling van het vaccin door zorgverleners. Daarnaast werden bijeenkomsten over de daling van de HPV-vaccinatie van het Europese regiokantoor van de Wereldgezondheidsorganisatie bijgewoond. Ook werden interviews gehouden met collega’s van de publieke gezondheidsinstituten uit Ierland en Denemarken, waar de HPV-vaccinatiegraad sinds 2015 sterk gedaald is. In de EU/EEA landen varieert de leeftijd waarop meisjes gevaccineerd worden van 9 tot 15 jaar. De plaats waar wordt gevaccineerd loopt sterk uiteen. Ierland en Denemarken ontwikkelden voorlichting op maat voor publiek en professionals, zetten een alliantie op met stakeholders en waren zeer actief op sociale media. Literatuur laat zien dat het inzetten van reminders (voorafgaand aan het vaccinatiemoment), een no-show-beleid (na het vaccinatiemoment indien men niet is geweest), voorlichting op maat, terugkoppelen van de vaccinatiegraad aan professionals en het makkelijker maken om vaccinaties te halen, tot een verhoging van de HPV-vaccinatiegraad tussen 10 tot 20 % kan leiden. Het blijft erg belangrijk dat gezondheidswerkers het vaccin aanbevelen en misvattingen over HPV-vaccinaties weerleggen.

The guinea pig (Cavia porcellus) or cavy is a grass-eating rodent. Its main diet consists of grass or hay, which comprises cellulose, hemicellulose, lignin and their derivatives. Here, the microbial diversity of faecal samples of two guinea pigs and microbial enrichments made with substrates, including starch waste and dried grass, were investigated along with organic acid production profiles. The microbial communities of the faecal samples were dominated by the phyla Bacteroidetes (40%) and Firmicutes (36%). Bacteroidales S24-7 (11% in Cavy 1 and 21% in Cavy 2) was the most abundant order. At genus level, many microorganisms remained unclassified. Different carbon sources were used for organic acid production in faecal enrichments. The dominant bacterial groups in the secondary enrichments with dried grass, starch waste and xylose were closely related to Prevotella and Blautia. Acetate was the predominant organic acid from all enrichments. The organic acid production profiles corresponded to a mixed acid fermentation but differed depending on the substrate. Eight phylogenetically different isolates were obtained, including a novel Streptococcus species, strain Cavy grass 6. This strain had a low abundance (1%) in one of the faecal samples but was enriched in the dried grass enrichment (3%). Cavy grass 6, a fast-growing heterolactic bacterium, ferments cellobiose to lactate, acetate, formate and ethanol. Our results show that cavy faecal samples can be applied as microbial source for organic acid production from complex organic substrates. The cavy gut contains many as-yet-uncultivated bacteria which may be appropriate targets for future studies. Electronic supplementary material The online version of this article (10.1007/s00284-019-01630-x) contains supplementary material, which is available to authorized users.

Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Here we demonstrate that the major metabolic fate of uniformly-13C-labeled α-ketoisovalerate ([U-13C]KIV) in the heart is reamination to valine. Activation of cardiac branched-chain α-ketoacid dehydrogenase (BCKDH) by treatment with the BCKDH kinase inhibitor, BT2, does not impede the strong flux of [U-13C]KIV to valine. Sequestration of BCAA and BCKA away from mitochondrial oxidation is likely due to low levels of expression of the mitochondrial BCAA transporter SLC25A44 in the heart, as its overexpression significantly lowers accumulation of [13C]-labeled valine from [U-13C]KIV. Finally, exposure of perfused hearts to levels of BCKA found in obese rats increases phosphorylation of the translational repressor 4E-BP1 as well as multiple proteins in the MEK-ERK pathway, leading to a doubling of total protein synthesis. These data suggest that elevated BCKA levels found in obesity may contribute to pathologic cardiac hypertrophy via chronic activation of protein synthesis., Systemic modulation of branched-chain keto acid (BCKA) metabolism alters cardiac health. Here, the authors define the major fates of BCKA in the heart and demonstrate that acute exposure to BCKA levels found in obesity activates cardiac protein synthesis and markedly alters the heart phosphoproteome.

Changes in glycosylation during tumour progression are a key hallmark of cancer. One of the glycan moieties generally overexpressed in cancer are sialic acids, which can induce immunomodulatory properties via binding to Siglec receptors. We here show that Pancreatic Ductal Adenocarcinoma (PDAC) tumour cells present an increased sialylation that can be recognized by Siglec-7 and Siglec-9 on myeloid cells. We identified the expression of the α2,3 sialyltransferases ST3GAL1 and ST3GAL4 as main contributor to the synthesis of ligands for Siglec-7 and Siglec-9 in tumour cells. Analysing the myeloid composition in PDAC, using single cell and bulk transcriptomics data, we identified monocyte-derived macrophages as contributors to the poor clinical outcome. Tumour-derived sialic acids dictate monocyte to macrophage differentiation via signalling through Siglec-7 and Siglec-9. Moreover, triggering of Siglec-9 in macrophages reduce inflammatory programmes, while increasing PD-L1 and IL-10 expression, illustrating that sialic acids modulate different myeloid cells. This work highlights a critical role for sialylated glycans in controlling immune suppression and provides new potential targets for cancer immunotherapy in PDAC., Alterations in glycosylation in tumours facilitate tumour progression. Here, the authors show that pancreatic ductal adenocarcinomas present increased sialylation, which stimulates the polarisation of monocytes via Siglec receptors, resulting in the generation of immune suppressive tumour associated macrophages.

Funder: Royal Society Newton fellowship, Funder: CAPES Scholarship - Brazil, Background: Despite the importance of the mucosal interface between microbiota and the host in gut homeostasis, little is known about the mechanisms of bacterial gut colonization, involving foraging for glycans produced by epithelial cells. The slow pace of progress toward understanding the underlying molecular mechanisms is largely due to the lack of efficient discovery tools, especially those targeting the uncultured fraction of the microbiota. Results: Here, we introduce an ultra-high-throughput metagenomic approach based on droplet microfluidics, to screen fosmid libraries. Thousands of bacterial genomes can be covered in 1 h of work, with less than ten micrograms of substrate. Applied to the screening of the mucosal microbiota for β-N-acetylgalactosaminidase activity, this approach allowed the identification of pathways involved in the degradation of human gangliosides and milk oligosaccharides, the structural homologs of intestinal mucin glycans. These pathways, whose prevalence is associated with inflammatory bowel diseases, could be the result of horizontal gene transfers with Bacteroides species. Such pathways represent novel targets to study the microbiota-host interactions in the context of inflammatory bowel diseases, in which the integrity of the mucosal barrier is impaired. Conclusion: By compartmentalizing experiments inside microfluidic droplets, this method speeds up and miniaturizes by several orders of magnitude the screening process compared to conventional approaches, to capture entire metabolic pathways from metagenomic libraries. The method is compatible with all types of (meta)genomic libraries, and employs a commercially available flow cytometer instead of a custom-made sorting system to detect intracellular or extracellular enzyme activities. This versatile and generic workflow will accelerate experimental exploration campaigns in functional metagenomics and holobiomics studies, to further decipher host-microbiota relationships. BEyZgKg3YsWtKJ_ei8gXkiVideo Abstract

Faulting and earthquakes occur extensively along the flanks of the East African Rift System, including an offshore branch in the western Indian Ocean, resulting in remobilization of sediment in the form of landslides. To date, constraints on the occurrence of submarine landslides at margin scale are lacking, leaving unanswered a link between rifting and slope instability. Here, we show the first overview of landslide deposits in the post-Eocene stratigraphy of the Tanzania margin and we present the discovery of one of the biggest landslides on Earth: the Mafia mega-slide. The emplacement of multiple landslides, including the Mafia mega-slide, during the early-mid Miocene is coeval with cratonic rifting in Tanzania, indicating that plateau uplift and rifting in East Africa triggered large and potentially tsunamigenic landslides likely through earthquake activity and enhanced sediment supply. This study is a first step to evaluate the risk associated with submarine landslides in the region., The authors describe a huge submarine landslide deposit offshore Tanzania and highlight that large and potentially tsunamigenic landslide events are associated with plateau uplift and continental rifting in East Africa.

BackgroundMalaria control remains a challenge globally and in malaria-endemic countries in particular. In Rwanda, a citizen science programme has been set up to improve malaria control. Citizens are involved in collecting mosquito species and reporting mosquito nuisance. This study assessed what people benefit from such a citizen science programme. The analysis was conducted on how the citizen science programme influenced perceptions and behaviour related to malaria control.MethodsThis study employed a mixed-methods approach using dissemination workshops, a survey, and village meetings as the main data collection methods. Dissemination workshops and village meetings involved 112 volunteers of the citizen science programme and were conducted to explore: (1) the benefits of being involved in the programme and (2) different ways used to share malaria-related information to non-volunteers. The survey involved 328 people (110 volunteers and 218 non-volunteers) and was used to compare differences in malaria-related perceptions and behaviour over time (between 2017 and 2019), as well as between volunteers and non-volunteers.ResultsMalaria-related perceptions and behaviour changed significantly over time (between 2017 and 2019) and became favourable to malaria control. When the findings were compared between volunteers and non-volunteers, for perceptions, only perceived self-efficacy showed a significant difference between these two groups. However, volunteers showed significantly more social interaction, participation in malaria-related activities at the community level, and indoor residual spraying (IRS) acceptance. In addition, both volunteers and non-volunteers reported to have gained knowledge and skills about the use of malaria control measures in general, and mosquito species in particular among volunteers.ConclusionThe reported knowledge and skills gained among non-volunteers indicate a diffusion of the citizen science programme-related information in the community. Thus, the citizen science programme has the potential to provide individual and collective benefits to volunteers and society at large.

Salinization of freshwater resources is a growing water quality challenge, which may negatively impact both sectoral water-use and food security, as well as biodiversity and ecosystem services. Although monitoring of salinity is relatively common compared to many other water quality parameters, no compilation and harmonisation of available datasets for both surface and groundwater components have been made yet at the global scale. Here, we present a new global salinity database, compiled from electrical conductivity (EC) monitoring data of both surface water (rivers, lakes/reservoirs) and groundwater locations over the period 1980–2019. The data were assembled from a range of sources, including local to global salinity databases, governmental organizations, river basin management commissions and water development boards. Our resulting database comprises more than 16.3 million measurements from 45,103 surface water locations and 208,550 groundwater locations around the world. This database could provide new opportunities for meta-analyses of salinity levels of water resources, as well as for addressing data and model-driven questions related to historic and future salinization patterns and impacts., Measurement(s) electrical conductivity Technology Type(s) water monitoring station • water quality sampling Factor Type(s) date • geographic location Sample Characteristic - Environment surface water • groundwater Sample Characteristic - Location global Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.12455954

Background Campylobacter jejuni and Campylobacter coli are major global causes of bacterial gastroenteritis. Whilst several individual colonisation and virulence factors have been identified, our understanding of their role in the transmission, pathogenesis and ecology of Campylobacter has been hampered by the genotypic and phenotypic diversity within C. jejuni and C. coli. Autotransporter proteins are a family of outer membrane or secreted proteins in Gram-negative bacteria such as Campylobacter, which are associated with virulence functions. In this study we have examined the distribution and predicted functionality of the previously described capC and the newly identified, related capD autotransporter gene families in Campylobacter. Results Two capC-like autotransporter families, designated capC and capD, were identified by homology searches of genomes of the genus Campylobacter. Each family contained four distinct orthologs of CapC and CapD. The distribution of these autotransporter genes was determined in 5829 C. jejuni and 1347 C. coli genomes. Autotransporter genes were found as intact, complete copies and inactive formats due to premature stop codons and frameshift mutations. Presence of inactive and intact autotransporter genes was associated with C. jejuni and C. coli multi-locus sequence types, but for capC, inactivation was independent from the length of homopolymeric tracts in the region upstream of the capC gene. Inactivation of capC or capD genes appears to represent lineage-specific gene decay of autotransporter genes. Intact capC genes were predominantly associated with the C. jejuni ST-45 and C. coli ST-828 generalist lineages. The capD3 gene was only found in the environmental C. coli Clade 3 lineage. These combined data support a scenario of inter-lineage and interspecies exchange of capC and subsets of capD autotransporters. Conclusions In this study we have identified two novel, related autotransporter gene families in the genus Campylobacter, which are not uniformly present and exhibit lineage-specific associations and gene decay. The distribution and decay of the capC and capD genes exemplifies the erosion of species barriers between certain lineages of C. jejuni and C. coli, probably arising through co-habitation. This may have implications for the phenotypic variability of these two pathogens and provide opportunity for new, hybrid genotypes to emerge.

Zowel in Den Haag als in Haarlem en Purmerend wordt met ouderen gewerkt aan het maken van films. Werken met film is een prachtige manier om mensen samen te brengen, thema’s te onderzoeken en de deelnemers de gelegenheid te geven hun verhaal te vertellen en van waarde te zijn voor anderen. Dankzij het bedieningsgemak van de iPad is het eenvoudiger geworden om ook met weinig technische kennis een mooi beeldverhaal te maken.

Asthma prevalence in children varies substantially around the world, but the contribution of known risk factors to this international variation is uncertain. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two studied 8-12 year old children in 30 centres worldwide with parent-completed symptom and risk factor questionnaires and aeroallergen skin prick testing. We used multilevel logistic regression modelling to investigate the effect of adjustment for individual and ecological risk factors on the between-centre variation in prevalence of recent wheeze. Adjustment for single individual-level risk factors changed the centre-level variation from a reduction of up to 8.4% (and 8.5% for atopy) to an increase of up to 6.8%. Modelling the 11 most influential environmental factors among all children simultaneously, the centre-level variation changed little overall (2.4% increase). Modelling only factors that decreased the variance, the 6 most influential factors (synthetic and feather quilt, mother's smoking, heating stoves, dampness and foam pillows) in combination resulted in a 21% reduction in variance. Ecological (centre-level) risk factors generally explained higher proportions of the variation than did individual risk factors. Single environmental factors and aeroallergen sensitisation measured at the individual (child) level did not explain much of the between-centre variation in wheeze prevalence.

Purpose Severely injured patients should be treated at higher-level trauma centres, to improve chances of survival and avert life-long disabilities. Emergency medical service (EMS) providers must try to determine injury severity on-scene, using a prehospital trauma triage protocol, and decide the most appropriate type of trauma centre. The objective of this study is to investigate the role of EMS provider judgment in the prehospital triage process of trauma patients, by analysing the compliance rate to the protocol and administering a questionnaire among EMS providers. Methods All trauma patients transported to a trauma centre in two different regions of the Netherlands were analysed. Compliance rate was based on the number of patients meeting the triage criteria and transported to the corresponding level trauma centre. The questionnaire was administered among EMS providers. Descriptive statistics were used to analyse the data. Results For adult patients, the compliance rate to the level I criteria of the triage protocol was 72% in Central Netherlands and 42% in Brabant. For paediatric patients, this was 63% and 38% in Central Netherlands and Brabant, respectively. The judgment on injury severity was mostly based on the injury-type criteria. Additionally, the distance to a level I trauma centre influenced the decision for destination facility in the Brabant region. Conclusion The compliance rate varied between regions. Improvement of prehospital trauma triage depends on the accuracy of the protocol and compliance rate. A new protocol, including EMS provider judgment, might be the key to improvement in the prehospital trauma triage quality.

The triplet excited state of a new Ir-based photosensitizer with two chromenopyridinone and one bipyridine-based ligands has been studied by pump-probe X-ray absorption near edge structure (XANES) spectroscopy coupled with DFT calculations. The excited state has a lifetime of 0.5 μs in acetonitrile and is characterized by very small changes of the local atomic structure with an average metal-ligand bond length change of less than 0.01 Å. DFT-based calculations allow the interpretation of the XANES in the energy range of ∼50 eV around the absorption edge. The observed transient XANES signal arises from an additional metal-centered Ir 5d vacancy in the excited state which appears as a result of electron transfer from the metal to the ligand. The overall energy shift of the excited state spectrum originates from the shift of 2p and unoccupied states induced by screening effects. The approach for the analysis of time-resolved spectra of 5d metal complexes is quite general and can also be used if excited and ground state structures are significantly different.

Solvency II has one standard equity solvency capital requirement for type 1 or developed market stocks (39 per cent) and one for type 2 or emerging market stocks (49 per cent). As such, differences in financial economic risk of stock portfolios within developed or emerging markets do not influence solvency requirements. This encourages risk-seeking behaviour by insurance companies, and could sustain or even create structural mispricing in the cross-section of stock returns. We argue to improve Solvency II regulation by aligning it with more sophisticated European regulation that is already in place for mutual funds. Specifically, we propose to multiply the standard solvency charge of 39 per cent with the ratio of equity portfolio volatility to broad equity market volatility. This ratio will be above one for more risky portfolios and below one for less risky portfolios, meaning that high-risk stock portfolios require more solvency capital than the market, while low-risk stock portfolios require less. Our approach encompasses the existing distinction between emerging and developed markets, and reduces geography to just one of many potential sources of risk that should be recognised. The proposed approach gives better incentives to institutional investors, contributes to market efficiency, and is much less prone to regulatory arbitrage than the existing approach.

Climate change and accelerating socioeconomic developments increasingly challenge flood-risk management in the Vietnamese Mekong River Delta—a typical large, economically dynamic and highly vulnerable delta. This study identifies and addresses the emerging challenges for flood-risk management. Furthermore, we identify and analyse response solutions, focusing on meaningful configurations of the individual solutions and how they can be tailored to specific challenges using expert surveys, content analysis techniques and statistical inferences. Our findings show that the challenges for flood-risk management are diverse, but critical challenges predominantly arise from the current governance and institutional settings. The top-three challenges include weak collaboration, conflicting management objectives and low responsiveness to new issues. We identified 114 reported solutions and developed six flood management strategies that are tailored to specific challenges. We conclude that the current technology-centric flood management approach is insufficient given the rapid socioecological changes. This approach therefore should be adapted towards a more balanced management configuration where technical and infrastructural measures are combined with institutional and governance resolutions. Insights from this study contribute to the emerging repertoire of contemporary flood management solutions, especially through their configurations and tailoring to specific challenges.