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ObjectivesTo explore the support needs that patients and relatives experience throughout their medical aid in dying (MAID) trajectories.MethodsA qualitative study in Belgium in 2022 using 1) semi-structured interviews with and personal written narratives of patients requesting MAID and 2) semi-structured interviews with relatives of patients requesting MAID. We performed a qualitative content analysis.ResultsWe included in our analysis the lived experiences of 15 patients and 21 of their relatives. We identified eight types of support needs: support for 1) maximizing daily functioning (only reported by patients), 2) making sense of the unbearable suffering (only reported by relatives), 3) managing meaningful activities, 4) navigating existential questions, 5) psycho-emotional regulation, 6) facilitating social interaction, 7) understanding the process toward MAID, 8) and handling organizational and practical matters.ConclusionPatients and relatives might experience multidimensional support needs throughout their MAID trajectories. Our findings suggest that they experience these trajectories more as social/existential pathways than as medical ones. A palliative care approach may be an effective way to fulfill the support needs of patients and relatives throughout their MAID trajectories.

Children with developmental language disorder (DLD) experience problems in language comprehension and/or production. In particular, storytelling or narrative ability is often impaired, as this type of discourse involves all domains of language. These problems may lead to a lower quality of social interaction and mental health. Moreover, problems in oral narrative ability during early development have a negative effect on later literacy. However, telling a story involves more than language alone. Executive functioning is thought to play an important part in stimulating narrative ability, as linguistic utterances need to be planned in a temporal and causal order, and switching is needed between multiple characters and events in the story. Research has shown that children with DLD experience problems with executive functioning, independent of their language ability. Thus, the difficulties in storytelling may be caused by both impaired language and executive functioning, as both domains follow hierarchical developmental paths during the early childhood years. In this review, we discuss three components of narrative ability (comprehension, production of macrostructure and production of microstructure) and how they may be interconnected to the three core components of executive functioning (working memory, switching and inhibition) and attention. This review shows that updating and monitoring information in working memory plays an important part in all three components of narrative ability, across multiple studies. This result may give direction in the development of narrative assessment and intervention, and urge further research to disentangle the interplay between language and executive control in DLD.

IntroductionPediatric patients with unexplained bone marrow failure (BMF) are often categorized as aplastic anemia (AA). Based on the accepted hypothesis of an auto-immune mechanism underlying AA, immune suppressive therapy (IST) might be effective. However, due to the lack of diagnostic tools to identify immune AA and prognostic markers to predict IST response together with the unequaled curative potential of hematopoietic stem cell transplantation (HSCT), most pediatric severe AA patients are momentarily treated by HSCT if available. Although several studies indicate oligoclonal T-cells with cytotoxic activities towards the hematopoietic stem cells, increasing evidence points towards defective inhibitory mechanisms failing to inhibit auto-reactive T-cells.MethodsWe aimed to investigate the role of NK- and B-cells in seven pediatric AA patients through a comprehensive analysis of paired bone marrow and peripheral blood samples with spectral flow cytometry in comparison to healthy age-matched bone marrow donors. ResultsWe observed a reduced absolute number of NK-cells in peripheral blood of AA patients with a skewed distribution towards CD56bright NK-cells in a subgroup of patients. The enriched CD56bright NK-cells had a lower expression of CD45RA and TIGIT and a higher expression of CD16, compared to healthy donors. Functional analysis revealed no differences in degranulation. However, IFN-γ production and perforin expression of NK-cells were reduced in the CD56bright-enriched patient group. The diminished NK-cell function in this subgroup might underly the auto-immunity. Importantly, NK-function of AA patients with reduced CD56bright NK-cells was comparable to healthy donors. Also, B-cell counts were lower in AA patients. Subset analysis revealed a trend towards reduction of transitional B-cells in both absolute and relative numbers compared to healthy controls. As these cells were previously hypothesized as regulatory cells in AA, decreased numbers might be involved in defective inhibition of auto-reactive T-cells. Interestingly, even in patients with normal distribution of precursor B-cells, the transitional compartment was reduced, indicating partial differentiation failure from immature to transitional B-cells or a selective loss. DiscussionOur findings provide a base for future studies to unravel the role of transitional B-cells and CD56bright NK-cells in larger cohorts of pediatric AA patients as diagnostic markers for immune AA and targets for therapeutic interventions.

Introduction: Rapid exome sequencing (rES) has become the first-choice genetic test for critically ill patients, mostly neonates, young infants, or fetuses in prenatal care, in time-sensitive situations and when it is expected that the genetic test result may guide clinical decision making. The implementation of rES has revolutionized medicine by enabling timely identification of genetic causes for various rare diseases. The utilization of rES has increasingly been recognized as an essential diagnostic tool for the identification of complex and undiagnosed genetic disorders.Methods: We conducted a retrospective evaluation of our experiences with rES performed on 575 critically ill patients from various age groups (prenatal to adulthood), over a four-year period (2016–2019). These patients presented with a wide spectrum of rare diseases, including but not limited to neurological disorders, severe combined immune deficiency, and cancer.Results: During the study period, there was a significant increase in rES referrals, with a rise from a total of two referrals in Q1-2016 to 10 referrals per week in Q4-2019. The median turnaround time (TAT) decreased from 17 to 11 days in the period 2016–2019, with an overall median TAT of 11 days (IQR 8–15 days). The overall diagnostic yield for this cohort was 30.4%, and did not significantly differ between the different age groups (e.g. adults 22.2% vs children 31.0%; p-value 0.35). However, variability in yield was observed between clinical entities: craniofacial anomalies yielded 58.3%, while for three clinical entities (severe combined immune deficiency, aneurysm, and hypogonadotropic hypogonadism) no diagnoses were obtained.Discussion: Importantly, whereas clinical significance is often only attributed to a conclusive diagnosis, we also observed impact on clinical decision-making for individuals in whom no genetic diagnosis was established. Hence, our experience shows that rES has an important role for patients of all ages and across the broad spectrum of rare diseases to impact clinical outcomes.

Background: Pregnant women have a higher risk of severe illness and adverse pregnancy outcomes due to a SARS-CoV-2 infection. COVID-19 vaccination can prevent (severe) infection. Observational studies are needed to ascertain safety of COVID-19 vaccination during pregnancy.Aim: Estimate whether COVID-19 vaccination during pregnancy is associated with the risk of preterm labor (PL).Methods: In this prospective cohort study, we included 5,910 pregnant women (mean age: 33.0 ± 3.7 years) who entered the Dutch Pregnancy Drug Register between February 2021 and August 2022. Information on COVID-19 vaccinations, PL, and confounders were self-reported using web-based questionnaires. The hazard ratio (HR) on PL, comparing those who received ≥1 COVID-19 vaccine during any moment of pregnancy to those who did not, was estimated using survival analyses with vaccination as time-varying exposure. Additionally, we estimated the risk of PL after COVID-19 vaccination prior to pregnancy, and after COVID-19 vaccination during trimester 1, 2, or 3 of pregnancy.Findings: A total of 5,227 (88%) participants received ≥1 COVID-19 vaccine between gestational week 2 and 37. We observed no statistically significant association of COVID-19 vaccination during pregnancy (adjusted HR = 0.93, 95%CI = 0.59; 1.45) nor of COVID-19 vaccination prior to pregnancy (adjusted HR = 1.09, 95%CI = 0.70; 1.71) with the risk of PL. Moreover, we observed no association between the risk of PL and COVID-19 vaccination in any trimester of pregnancy.Discussion: We demonstrated that COVID-19 vaccination prior to or during pregnancy is not associated with an increased risk of PL.Conclusion: These results add to the growing evidence supporting safety of COVID-19 vaccination during pregnancy.

The production of food from animals poses societal concern about the welfare of these animals in Western countries and increasingly also in economically developing countries. Animals and people may experience disutility from animal suffering, which can be seen as an external cost that is not (fully) included in the cost of production. Thus, consumers will consume too much of the good from an aggregate utilitarian perspective. A potential way to solve this issue is by including these external costs in the production costs. The aim of this paper was to provide a method that can be used to estimate the external costs of animal welfare (AW) of animals kept at farm level. The external costs were calculated by means of a cost function. This cost function shows the relationship between the AW score and costs of AW measures at farm level. The AW scores were calculated from principle scores of the Welfare Quality® Protocol. The method was applied to three case studies, namely dairy cattle production in Germany, pig production in the Netherlands, and broiler production in the Netherlands. The results indicate that the external costs of AW of dairy cattle systems ranged from 0.02 to 0.10 euro/kg milk, those of pig production systems from 1.00 to 1.36 euro/kg live weight and those of broiler production systems from 3.67 to 4.52 euro/kg live weight. The empirical application showed that the method was effective in estimating external animal costs. The insights obtained from the application of our method can support decision making in the development and adoption of more AW friendly production systems.

BackgroundIn most jurisdictions where assisted dying practices are legal, attending physicians must consult another practitioner to assess the patient's eligibility. Consequently, in some jurisdictions, they can rely on the expertise of trained assisted dying consultants (trained consultants). However, these peer consultations remain under-researched. We examined the characteristics and outcomes of peer consultations to assess an assisted dying request with trained consultants, and explored how these characteristics influence the performance of assisted dying.MethodsWe conducted a cross-sectional survey in 2019–2020 in Belgium among attending physicians who had consulted a trained consultant for an assisted dying request assessment (N = 904).ResultsThe valid response rate was 56% (502/903). The vast majority of attending physicians (92%) who had consulted a trained consultant were general practitioners. In more than half of the consultations (57%), the patient was diagnosed with cancer. In 66%, the patient was aged 70 or older. Reported as the patients' most important reasons to request assisted dying: suffering without prospect of improving in 49% of the consultations, loss of dignity in 11%, pain in 9%, and tiredness of life in 9%. In the vast majority of consultations (85%), the attending physician consulted the trained consultant because of the expertise, and in nearly half of the consultations (46%) because of the independence. In more than nine out of ten consultations (91%), the consultant gave a positive advice: i.e., substantive requirements for assisted dying were met. Eight out of ten consultations were followed by assisted dying. The likelihood of assisted dying was higher in consultations in which loss of dignity, loss of independence in daily living, or general weakness or tiredness were reasons for the request.ConclusionOur findings indicate that the peer consultation practice with trained consultants is most often embedded in a primary care setting. Moreover, our study corroborates previous research in that assisted dying is performed relatively less frequently in patients with cancer and more often in patients with general deterioration. Our findings suggest that attending physicians hold peer consultations with trained consultants to endorse their own decision-making and to request additional support.

Adolescents with Developmental Language Disorders (DLD) have more difficulties in social emotional functioning than their typically developing peers (TD), such as shyness and anxiety in social situations, fewer peer relations, greater risk of victimization, social isolation and depression. In addition, they are more likely to report higher levels of hyperactivity and conduct problems. These problems derive from a complex interplay between difficulties in language, social communication, underlying cognitive deficits in Theory of Mind (ToM), Executive Functioning (EF) and self-directed speech (SDS). The aim of this mini review is to provide an overview of studies examining the effectiveness of interventions targeting the factors underlying social emotional functioning of school-aged children and adolescents with DLD. We found that studies dedicated to social emotional functioning in school-aged children and adolescents with DLD were relatively scarce. Based on this overview, we give suggestions to improve social emotional functioning in adolescents with DLD. We propose that intervention programs should target the social, linguistic and cognitive functions underlying social emotional functioning and create opportunities to practice these skills in daily, real-life situations with peers.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract, and the exact pathogenesis is still unclear. It is believed that IBD develops in response to a complex interaction between the microbiota, environmental factors, and the immune system, in genetically predisposed individuals. Identifying these environmental factors will offer more insight in the development of the disease, and reveal new therapeutic targets for IBD patients. One of the environmental factors that has gained more interest over the last years is our diet. The prevalence of IBD has increased significantly and this increase is thought to be associated with a ‘Western diet', characterized by high intake of fats, added sugar, meat, and ultra-processed foods (UPFs). The UPFs now account for almost 50% of the energy intake in Westernized countries and are therefore an important characteristic of this Western diet. UPFs are characterized by higher amounts of salt, fat, sugar and the presence of different food additives. Epidemiological studies have found associations between UPF intake and a range of non-communicable diseases, including inflammatory bowel disease (IBD). Preclinical and clinical evidence suggest that non-nutritive ingredients and additives, present in UPFs, can negatively affect different components of the intestinal barrier, such as the microbiota, the mucus layer, the epithelium, and the immune cells in the lamina propria. Disruption of this barrier can cause the immune system to encounter an increased bacterial exposure, leading to an aberrant immune response. In this article, the available evidence on the possible role of UPFs and their components in the increasing incidence and prevalence of IBD is reviewed. These findings can be translated to the clinic and may be helpful to consider when giving dietary advice to IBD patients. A better understanding of the role of UPFs may lead to less restrictive diets for patients with IBD, hence increasing the dietary compliance and efficacy of exclusion diets.

BackgroundThe probability of undergoing treatment with curative intent for esophagogastric cancer has been shown to vary considerately between hospitals of diagnosis. Little is known about the factors that attribute to this variation. Since clinical decision making (CDM) partially takes place during an MDTM, the aim of this qualitative study was to assess clinician’s perspectives regarding facilitators and barriers associated with CDM during MDTM, and second, to identify factors associated with CDM during an MDTM that may potentially explain differences in hospital practice.MethodsA multiple case study design was conducted. The thematic content analysis of this qualitative study, focused on 16 MDTM observations, 30 semi-structured interviews with clinicians and seven focus groups with clinicians to complement the collected data. Interviews were transcribed ad verbatim and coded.ResultsFactors regarding team dynamics that were raised as aspects attributing to CDM were clinician’s personal characteristics such as ambition and the intention to be innovative. Clinician’s convictions regarding a certain treatment and its outcomes and previous experiences with treatment outcomes, and team dynamics within the MDTM influenced CDM. In addition, a continuum was illustrated. At one end of the continuum, teams tended to be more conservative, following the guidelines more strictly, versus the opposite in which hospitals tended towards a more invasive approach maximizing the probability of curation.ConclusionThis study contributes to the awareness that variation in team dynamics influences CDM during an MDTM.

We tested if the newly designed ToMotion task reflects a single construct and if the atypical groups differ in their performance compared to typically developing peers. Furthermore, we were interested if ToMotion maps a developmental sequence in a Theory of Mind (ToM) performance as exemplified by increasing difficulty of the questions asked in every item. The sample consisted of 13 adolescents that have been diagnosed with a developmental language disorder (DLD) and 14 adolescents that are deaf or hard of hearing (DHH). All of these adolescents were in special schools for secondary vocational education. The control group existed of 34 typical developing adolescents (TD) who were in regular intermediate vocational education, ranging from level 2 to 4. The ToMotion, available in a spoken Dutch version and in a version in Sign Language of the Netherlands (SLN), was used to map ToM abilities. An attempt has been made to fill the gap of missing studies of ToM in adolescents by developing a new measuring instrument. In conclusion, assessing ToM with the ToMotion results in a picture that DHH adolescents score lower than TD peers. However, their scores are as consistent as those of the TD peers. The picture of DLD adolescents is the reverse. They show no differences in ToM scores, but seem to be somewhat more inconsistent compared to TD peers. We provide a discussion on those results and its implications for future research. What this paper adds? The current study introduces a new visual Theory of Mind (ToM) task, ToMotion, designed specifically to assess ToM in adolescents in an ecologically valid way and adapted to the needs of adolescents with language and communication difficulties.

Glioblastoma multiforme is a challenging disease with limited treatment options and poor survival. Glioblastoma tumours are characterised by hypoxia that activates the hypoxia inducible factor (HIF) pathway and controls a myriad of genes that drive cancer progression. HIF transcription factors are regulated at the post-translation level via HIF-hydroxylases. These hydroxylases require oxygen and 2-oxoglutarate as substrates, and ferrous iron and ascorbate as cofactors. In this retrospective observational study, we aimed to determine whether ascorbate played a role in the hypoxic response of glioblastoma, and whether this affected patient outcome. We measured the ascorbate content and members of the HIF-pathway of clinical glioblastoma samples, and assessed their association with clinicopathological features and patient survival. In 37 samples (37 patients), median ascorbate content was 7.6 μg ascorbate/100 mg tissue, range 0.8 – 20.4 μg ascorbate/100 mg tissue. In tumours with above median ascorbate content, HIF-pathway activity as a whole was significantly suppressed (p = 0.005), and several members of the pathway showed decreased expression (carbonic anhydrase-9 and glucose transporter-1, both p < 0.01). Patients with either lower tumour HIF-pathway activity or higher tumour ascorbate content survived significantly longer than patients with higher HIF-pathway or lower ascorbate levels (p = 0.011, p = 0.043, respectively). Median survival for the low HIF-pathway score group was 362 days compared to 203 days for the high HIF-pathway score group, and median survival for the above median ascorbate group was 390 days, compared to the below median ascorbate group with 219 days. The apparent survival advantage associated with higher tumour ascorbate was more prominent for the first 8 months following surgery. These associations are promising, suggesting an important role for ascorbate-regulated HIF-pathway activity in glioblastoma that may impact on patient survival.

Rationale: As every season, physical performance of players of Royal Antwerp FC's first team was regularly tested and mental well-being and mood were assessed during football season 2020–2021. Just like in the general population, several professional athletes were infected by SARS-CoV-2 during that season. COVID-19 is a complex disorder affecting multiple body systems, potentially damaging lungs, affecting the cardiovascular system or causing muscle weakness. Therefore, the impact of COVID-19 on performance was a major concern for the affected football players and their entourage.Objectives: To retrospectively examine the influence of COVID-19 on physical performance and mental health in professional football athletes during the season 2020–2021.Methods: Thirty-three professional athletes (age: 25.37 ± 4.11 years; height: 182.75 ± 7.62 cm; weight: 78.90 ± 8.97 kg) of a Belgian first division football club were assessed weekly during the 2020-2021 season. Weekly assessments comprised strength values of the hamstrings, hip abductors and hip adductors, jump performance, a modified Hooper questionnaire to assess mental status and nose swab PCR tests for COVID-19. Data analysis was performed from 2 weeks prior to COVID-19 contamination up to 8 weeks after the first positive test. Post-hoc Bonferroni correction was applied when performing statistical analysis.Results: Eleven players tested positive for COVID-19. Duration of contamination was 13 ± 7 days. There was no statistically significant difference before and after COVID-19 infection for jump performance, and adductor and abductor muscle strength (p > 0.05). Functional hamstring strength improved significantly 2 weeks (MD: 41.48; 95%CI: −3.79 to 86.75; p = 0.009) and 4 weeks (MD: 34.76; 95%CI: −8.91 to 78.42; p = 0.019) after COVID-19, whereas mood (MD: −0.60; 95%CI: −1.46 to 0.26; p = 0.041), stress levels (MD: −0.83; 95%CI: −1.85 to 0.20; p = 0.020) and total wellness (MD: −2.41; 95%CI: −5.25 to 0.43; p = 0.015) showed a significant reduction 8 weeks after confirmed COVID-19.Conclusion: Physical performance varied considerably across outcomes before and 8 weeks after COVID-19 contamination in a sample of first division football players. However, affected football players' overall well-being, stress levels and mood diminished after a positive COVID-19 test.

Loss-of-function mutations in the DNA demethylase TET2 are associated with the dysregulation of hematopoietic stem cell differentiation and arise in approximately 10% of de novo acute myeloid leukemia (AML). TET2 mutations coexist with other mutations in AML, including TP53 mutations, which can indicate a particularly poor prognosis. Ascorbate can function as an epigenetic therapeutic in pathological contexts involving heterozygous TET2 mutations by restoring TET2 activity. How this response is affected when myeloid leukemia cells harbor mutations in both TET2 and TP53 is unknown. Therefore, we examined the effects of ascorbate on the SKM-1 AML cell line that has mutated TET2 and TP53. Sustained treatment with ascorbate inhibited proliferation and promoted the differentiation of these cells. Furthermore, ascorbate treatment significantly increased 5-hydroxymethylcytosine, suggesting increased TET activity as the likely mechanism. We also investigated whether ascorbate affected the cytotoxicity of Prima-1Met, a drug that reactivates some p53 mutants and is currently in clinical trials for AML. We found that the addition of ascorbate had a minimal effect on Prima-1Met–induced cytotoxicity, with small increases or decreases in cytotoxicity being observed depending on the timing of treatment. Collectively, these data suggest that ascorbate could exert a beneficial anti-proliferative effect on AML cells harboring both TET2 and TP53 mutations whilst not interfering with targeted cytotoxic therapies such as Prima-1Met.

Gliomas are a heterogeneous group of cancers that predominantly arise from glial cells in the brain, but may also arise from neural stem cells, encompassing low-grade glioma and high-grade glioblastoma. Whereas better diagnosis and new treatments have improved patient survival for many cancers, glioblastomas remain challenging with a highly unfavorable prognosis. This review discusses a super-family of enzymes, the 2-oxoglutarate dependent dioxygenase enzymes (2-OGDD) that control numerous processes including epigenetic modifications and oxygen sensing, and considers their many roles in the pathology of gliomas. We specifically describe in more detail the DNA and histone demethylases, and the hypoxia-inducible factor hydroxylases in the context of glioma, and discuss the substrate and cofactor requirements of the 2-OGDD enzymes. Better understanding of how these enzymes contribute to gliomas could lead to the development of new treatment strategies.

Many individuals with developmental language disorder (DLD) and individuals who are deaf or hard of hearing (D/HH) have social–emotional problems, such as social difficulties, and show signs of aggression, depression, and anxiety. These problems can be partly associated with their executive functions (EFs) and theory of mind (ToM). The difficulties of both groups in EF and ToM may in turn be related to self-directed speech (i.e., overt or covert speech that is directed at the self). Self-directed speech is thought to allow for the construction of non-sensory representations (i.e., representations that do not coincide with direct observation). Such non-sensory representations allow individuals to overcome the limits set upon them by the senses. This ability is constrained by the development of word meaning structure (i.e., the way words are understood). We argue that the greater ability to construct non-sensory representations may result in more enhanced forms of EF and ToM. We conclude that difficulties in EF, ToM, and social–emotional functioning in those with hearing and language problems may be accounted for in terms of word meaning impairments. We propose that word meaning structure and self-directed speech should be considered in assigning EF and ToM treatments to individuals with DLD and those who are D/HH.

Objective: In Dual Disorders (DD), which involves the co-occurrence of a disorder in substance use and a mental disorder, recurrent struggles with addictive behavior are frequent. Neuropsychological knowledge concerning the profile of inhibitory control and the irresistible urge to use substances (craving) within the DD patient group may contribute to the prevention of this recurrent addictive behavior.Methods: Inhibitory control and craving were assessed in 25 patients with DD and 25 healthy controls (HC). Inhibitory control tasks (Go/No-go task and Stop Signal Task) were performed combined with brain measurements (Event Related Potentials) mapping inhibitory control. Moreover, implicit and explicit measures concerning craving were administered. Statistical DD and HC comparisons, correlational and regression analyses on exploratory base were conducted.Results: DD patients committed more inhibitory control errors than HC when confronted with (alcohol) consumption-related picture stimuli. Furthermore, patients with DD showed higher levels of implicit and explicit craving. The number of inhibitory control errors was positively related to levels of implicit and explicit craving. Moreover, explicit craving and impulsivity (as a dimension of inhibitory control) predicted the severity of addictive behavior. Event Related Potential analyses did not show differences in inhibitory control-associated brain activity between DD patients and HC; both groups showed reduction of P300 amplitudes in response to alcohol pictures.Conclusions: Impulsivity and craving are elevated in DD patients and show predictive value for the severity of addictive behavior. One's level of impulsive action tendency may trigger less effort to control (recurrent) substance use. The findings may contribute to existing DD treatment indications by the promotion of impulse control training via “stop-think-act” methods for DD patients.

Alexithymia—reflecting deficits in cognitive emotion processing—is highly prevalent in individuals with depressive disorders. Subsequently, mixed evidence for attentional bias is found in these individuals. Alexithymia may be a potential influencing factor for attentional bias in depression. In the current study, 83 currently depressed (CD) and 76 never-depressed (ND) controls completed an eye-tracker task consisting of valenced (non)-social pictures. Alexithymia scores were also included as a moderator as both a continuous and categorical measure (so high vs. low alexithymia). No group difference or moderating effect of alexithymia was found on attentional bias. Thus, alexithymic symptoms, included both dimensionally and categorically, may not influence biased attentional processing in depression compared to ND individuals. Thus, it is important to explore other potential explaining factors for the equivocal results found on biased attentional processing of emotional information in depression.

The use of high dose ascorbate infusions in cancer patients is widespread, but without evidence of efficacy. Several mechanisms whereby ascorbate could affect tumor progression have been proposed, including: (i) the localized generation of cytotoxic quantities of H2O2; (ii) ascorbate-dependent activation of the 2-oxoglutarate-dependent dioxygenases that control the hypoxia-inducible factors (HIFs) and that are responsible for the demethylation of DNA and histones; (iii) increased oxidative stress induced by dehydroascorbic acid. We hypothesize that the dysfunctional vasculature of solid tumors results in compromised delivery of ascorbate to poorly perfused regions of the tumor and that this ascorbate deficit acts as an additional driver of the hypoxic response via upregulation of HIFs. Using a randomized “therapeutic window of opportunity” clinical study design we aimed to determine whether ascorbate infusions affected tumor ascorbate content and tumor biology. Patients with colon cancer were randomized to receive infusions of up to 1 g/kg ascorbate for 4 days before surgical resection (n = 9) or to not receive infusions (n = 6). Ascorbate was measured in plasma, erythrocytes, tumor and histologically normal mucosa at diagnostic colonoscopy and at surgery. Protein markers of tumor hypoxia or DNA damage were monitored in resected tissue. Plasma ascorbate reached millimolar levels following infusion and returned to micromolar levels over 24 h. Pre-infusion plasma ascorbate increased from 38 ± 10 µM to 241 ± 33 µM (p < 0.0001) over 4 days and erythrocyte ascorbate from 18 ± 20 µM to 2509 ± 1016 µM (p < 0.005). Tumor ascorbate increased from 15 ± 6 to 28 ± 6 mg/100 g tissue (p < 0.0001) and normal tissue from 14 ± 6 to 21 ± 4 mg/100 g (p < 0.001). A gradient of lower ascorbate was evident towards the tumor centre in both control and infusion samples. Lower expression of hypoxia-associated proteins was seen in post-infusion tumors compared with controls. There were no significant adverse events and quality of life was unaffected by ascorbate infusion. This is the first clinical study to demonstrate that tumor ascorbate levels increase following infusion, even in regions of poor diffusion, and that this could modify tumor biology.Clinical Trial RegistrationANZCTR Trial ID ACTRN12615001277538 (https://www.anzctr.org.au/).

Chronic care is an important area for cost-effective and efficient health service delivery. Matching demand and services for chronic care is not easy as patients may have different needs in different stages of the disease. More insight is needed into the complete patient journey to do justice to the services required in each stage of the disease, to the different experiences of patients in each part of the journey, and to outcomes in each stage. With patient journey we refer to the “journey” of the patient along the services received within a demand segment of chronic care. We developed a generic framework for describing patient journeys and provider networks, based on an extension of the well-known model of Donabedian, to relate demand, services, resources, behavior, and outcomes. We also developed a generic operational model for the detailed modeling of services and resources, allowing for insight into costs. The generic operational model can be tailored to the specific characteristics of patient groups. We applied this modeling approach to type 2 diabetes (T2D) patients. Diabetes care is a form of chronic care for patients suffering diabetes mellitus. We studied the performance of T2D networks, using a descriptive model template. To identify and describe demand we made use of the following demand segments within the diabetes type 2 population: patients targeted for prevention; patients with stage 1 diabetes treated by their GP with lifestyle advice; patients with diabetes stage 2 treated by their GP with lifestyle advice and oral medication; patients with stage 3 diabetes treated by their GP with lifestyle advice, oral medication, and insulin injections; patients with stage 4 diabetes with complications (treated by internal medicine specialists). We used a Markov model to describe the transitions between the different health states. The model enables the patient journey through the health care system for cohorts of newly diagnosed T2D patients to be described, and to make a projection of the resource requirements of the different demand segments over the years. We illustrate our approach with a case study on a T2D care network in The Netherlands and reflect on the role of demand segmentation to analyse the case study results, with the objective of improving the T2D service delivery.

Inner speech (IS), or the act of silently talking to yourself, occurs in humans regardless of their cultural and linguistic background, suggesting its key role in human cognition. The absence of overt articulation leads to methodological challenges to studying IS and its effects on cognitive processing. Investigating IS in children is particularly problematic due to cognitive demands of the behavioral tasks and age restrictions for collecting neurophysiological data [e.g., functional magnetic resonance imaging (fMRI) or electromyography (EMG)]; thus, the developmental aspects of IS remain poorly understood despite the long history of adult research. Studying developmental aspects of IS could shed light on the variability in types and amount of IS in adults. In addition, problems in mastering IS might account for neuropsychological deficits observed in children with neurodevelopmental conditions. For example, deviance in IS development might influence these children’s general cognitive processing, including social cognition, executive functioning, and related social–emotional functioning. The aim of the present paper is to look at IS from a developmental perspective, exploring its theory and identifying experimental paradigms appropriate for preschool and early school-aged children in Anglophone and Russian literature. We choose these two languages because the original work carried out by Vygotsky on IS was published in Russian, and Russian scientists have continued to publish on this topic since his death. Since the 1960s, much of the experimental work in this area has been published in Anglophone journals. We discuss different measurements of IS phenomena, their informativeness about subtypes of IS, and their potential for studying atypical language development. Implications for assessing and stimulating IS in clinical populations are discussed.

Adolescents with developmental language disorders (DLDs) and adolescents who are deaf or hard of hearing (D/HH) are at greater risk of social emotional problems. These problems may not only be attributed to communication and language problems but, at least in part, to Theory of Mind (ToM) deficits as well. In this mini review, an overview is provided of studies on social emotional functioning and ToM performance in adolescents with DLD and D/HH adolescents. A possible interplay between social emotional functioning and Theory of Mind is discussed. There is empirical evidence for social emotional problems and ToM problems in both adolescents with DLD and D/HH. We hypothesized that language deficits as seen in adolescents with DLD and impoverished exposure to language and communication, as seen in adolescents who are D/HH can explain differences in social emotional functioning and ToM performance. The present mini review provides a possible framework for the relation between ToM and social emotional functioning in adolescents with communication and language problems, which is mediated by their limited linguistic ability or restricted language exposure and gives suggestions for future research.

Although the Developmental Language Disorder (DLD), also known as Specific Language Impairment in children has been the focus of unceasing scientific attention for decades, the nature and mechanisms of this disorder remain unclear. Most importantly, we still cannot reliably identify children requiring urgent intervention among other ‘late talkers’ at an early age and understand the high prevalence of comorbidity with psychiatric phenomena such as Autism Spectrum Disorder. One of the main reasons for this is the traditional ‘diagnosis-by-exclusion,’ resulting in heterogeneity of the DLD population. This paper proposes an alternative approach to the diagnosis, treatment and research of DLD, claiming that it is these children’s multiple deficits in neuropsychological development, which impede the spontaneous acquisition of their first language. Specifically, this review of the state-of-the-art in DLD research demonstrates deep and systematic interconnections between the speech and other higher cognitive functions developing in early childhood, including perception, attention and executive functions. In the proposed framework, speech is, therefore, considered as one of neuropsychological abilities, and the delay in its development is explained by other neuropsychological deficits, resulting in highly individual clinical profiles. By considering DLD as a complex neuropsychological syndrome, whose successful treatment depends on a holistic approach to diagnosis and intervention, we may significantly increase the efficacy of speech therapy, and also better understand the flexibility of the developing brain, its compensatory mechanisms and hence the comorbidity of DLD with psychiatric symptoms. Implications for using this paradigm in future scientific research are discussed.

Hypoxia-inducible transcription factors (HIFs) drive angiogenesis and cancer cell growth, contributing to an aggressive tumor phenotype. HIF-α protein levels and activity are controlled at the post-translational level by HIF hydroxylases. Hydroxylated HIF-α is recognized by the von Hippel Lindau (VHL) tumor suppressor and targeted for degradation. The HIF hydroxylases are members of the iron and 2-oxoglutarate-dependent dioxygenases, which require ascorbate as cofactor for activity. Clear cell renal cell carcinomas (ccRCC) harbor mutations in the VHL gene, whereas papillary RCC (pRCC) have a functional VHL. These natural occurring VHL variants in RCC enable the testing, in clinical samples, of the hypothesis that ascorbate modulates HIF-α levels through its role as a cofactor for the HIF hydroxylases. We measured ascorbate, HIF-1α, and HIF-2α protein and HIF downstream targets BNIP3, CA9, cyclin D1, GLUT1, and VEGF (combined to generate the HIF pathway score) in VHL-defective ccRCC (n = 73) and VHL-proficient pRCC human tumor tissue (n = 41). HIF and ascorbate levels were increased in ccRCC and pRCC tumors compared to matched renal cortex. HIF-1 and total HIF pathway activation scores were decreased with higher ascorbate in pRCC tumors (Spearman r = −0.38, p < 0.05 and r = −0.35, p < 0.05). This was not evident for ccRCC tumors. In mechanistic studies in vitro, ascorbate influenced HIF-1 activity in VHL-proficient, but not VHL-defective ccRCC cells. Our results indicate that ccRCC, which lacks a functional VHL, does not respond to ascorbate-mediated modulation of the HIF response. This contrasts with the demonstrated association between ascorbate content and the HIF pathway observed in pRCC and other tumors with a functional VHL. The results support a role for ascorbate as a modulator of HIF activity and tumor aggression in cancer types with a functional hypoxic response.

Whether vitamin C (ascorbate) has a role to play as an anti-cancer agent has been debated for decades. Ascorbate has been used by cancer patients in an unregulated environment, either as a dietary supplement or in pharmacological doses administered by infusion, with numerous reports of clinical benefit, but in the absence of rigorous clinical trial data. The design of appropriate clinical trials has been hindered by a lack of understanding of the mechanism(s) of action that would inform the choice of effective dose, timing of administration and likely responsive cancer models. More recently, expanded understanding of the biological activities of ascorbate has led to a number of plausible hypotheses for mechanisms of anti-cancer activity. Prominent among these are the generation of significant quantities of hydrogen peroxide by the autoxidation of supra-physiological concentrations of ascorbate and stimulation of the 2-oxoglutarate-dependent dioxygenase family of enzymes (2-OGDDs) that have a cofactor requirement for ascorbate. Hydrogen peroxide generation is postulated to generate oxidative stress that preferentially targets cancer cells. The 2-OGDDs include the hydroxylases that regulate the hypoxic response, a major driver of tumor survival, angiogenesis, stem cell phenotype and metastasis, and the epigenetic histone and DNA demethylases. The latter are of particular interest, with recent studies suggesting a promising role for ascorbate in the regulation of the ten-eleven translocase (TET) DNA demethylases in hematological cancers. Support for these proposed mechanisms has come from many in vitro studies, and xenograft animal models have consistently shown an anti-cancer effect of ascorbate administration. However, decisive evidence for any particular mechanism(s) of action is not yet available from an in vivo setting. With a number of early phase clinical trials currently underway, evidence for potential mechanism(s) of action is required to inform the most appropriate study design and choice of cancer model. Hopefully such information will result in sound clinical data that will avert adding any further controversy to this already contentious debate.

Children with Specific Language Impairment (SLI) often experience emotional and social difficulties. In general, problems in social emotional functioning can be cognitively explained in terms of Theory of Mind (ToM). In this mini-review, an overview is provided of studies on social-emotional functioning and ToM in preschoolers (average age from 2.3 to 6.2 years) with SLI. It is concluded that, similar to school-aged children with SLI, preschoolers with SLI have several social-emotional problems and that both cognitive and affective aspects of ToM are impaired in those children. Based hereon, three possible causal models for the interrelation between language, ToM and social emotional functioning are put forward. It is proposed that future research on the construct and measurement of early ToM, social emotional functioning and language development in preschoolers with SLI is needed to achieve early detection, tailored treatment, and ultimately insight into the pathogenesis of SLI.

The classic account of language is that language processing occurs in isolation from other cognitive systems, like perception, motor action and emotion. The theme of this paper is the relationship between a participant’s emotional state and language comprehension. Does emotional context affect how we process neutral words? Recent studies showed that processing of word meaning –traditionally conceived as an automatic process– is affected by emotional state. The influence of emotional state on syntactic processing is less clear. One study reported a mood-related P600 modulation, while another study did not observe an effect of mood on syntactic processing. The goals of this study were: First, to clarify whether and if so how mood affects syntactic processing. Second, to shed light on the underlying mechanisms by separating possible effects of mood from those of attention on syntactic processing.ERPs were recorded while participants read syntactically correct or incorrect sentences. Mood (happy vs. sad) was manipulated by presenting film clips. Attention was manipulated by directing attention to syntactic features vs. physical features. The mood induction was effective. Interactions between mood, attention and syntactic correctness were obtained, showing that mood and attention modulated P600. The mood manipulation led to a reduction in P600 for sad as compared to happy mood when attention was directed at syntactic features. The attention manipulation led to a reduction in P600 when attention was directed at physical features compared to syntactic features for happy mood. From this we draw two conclusions: First, emotional state does affect syntactic processing. We propose mood-related differences in the reliance on heuristics as the underlying mechanism. Second, attention can contribute to emotion-related ERP effects in syntactic language processing. Therefore, future studies on the relation between language and emotion will have to control for effects of attention.

Recently, non-invasive brain stimulation (NBS) has been discovered as a tool to improve human performance on a wide variety of tasks. Although these observations are highly intriguing, the underlying mechanisms of such enhancements are still poorly understood. Here, we argue that in order to advance understanding of these mechanisms, it is necessary to focus on intrinsic network dynamics in the brain. Taking into account well-known network dynamics, increased excitation in one particular network or brain region may necessarily lead to inhibition of an opposing network (and vice versa). As a consequence, observed behavioral improvements due to NBS emerge from a shift in the balance between (competing) neural networks in the brain, implicating that behavioral enhancement due to stimulation most likely comes with a cost or side effect. We conclude that more elaborate experimental designs are essential for a better understanding of the relationship between network interactions and the behavioral effects of NBS.

Ascorbate is a specific cofactor for a large family of enzymes known as the Fe- and 2-oxoglutarate-dependent dioxygenases. These enzymes are found throughout biology and catalyse the addition of a hydroxyl group to various substrates. The proline hydroxylase that is involved in collagen maturation is well known, but in recent times many new enzymes and functions have been uncovered, including those involved in epigenetic control and hypoxia-inducible factor (HIF) regulation. These discoveries have provided crucial mechanistic insights into how ascorbate may affect tumour biology. In particular, there is growing evidence that HIF-1-dependent tumour progression may be inhibited by increasing tumour ascorbate levels. However, rigorous clinical intervention studies are lacking. This review will explore the physiological role of ascorbate as an enzyme cofactor and how this mechanism relates to cancer biology and treatment. The use of ascorbate in cancer should be informed by clinical studies based on such mechanistic hypotheses.

Cancer patients commonly experience a number of symptoms of disease progression and the side effects of radiation therapy and adjuvant chemotherapy, which adversely impact on their quality of life. Fatigue is one of the most common and debilitating symptoms reported by cancer patients and can affect quality of life more than pain. Several recent studies have indicated that intravenous vitamin C alleviates a number of cancer- and chemotherapy-related symptoms, such as fatigue, insomnia, loss of appetite, nausea and pain. Improvements in physical, role, cognitive, emotional and social functioning, as well as an improvement in overall health, were also observed. In this mini review we briefly cover the methods commonly used to assess health-related quality of life in cancer patients, and describe the few recent studies examining the effects of intravenous vitamin C on cancer- and chemotherapy-related quality of life. We discuss potential mechanisms that might explain an improvement in quality of life and also considerations for future studies.

Ascorbate is a co-factor for the hydroxylases that regulate the transcription factor hypoxia-inducible factor (HIF)-1, which provides cancer cells with a metabolic and survival advantage in the hypoxic environment of solid tumors. However, whether ascorbate affects tumor development is a highly debated issue. We aimed to determine whether tumor ascorbate was associated with HIF-1 activation and patient disease-free survival. In this study we undertook a retrospective observational analysis of tissue-banked tumor and paired normal tissue from 49 colorectal cancer patients, measuring ascorbate levels, HIF-1α and its downstream gene products BNIP3 and VEGF. Patient survival was monitored for the first six years after surgery. We found that ascorbate levels were lower in tumor tissue compared to normal tissue (p< 0.001) but overall levels varied considerably. HIF-1α, VEGF and BNIP3 were elevated in tumor samples (p< 0.01). There was an inverse relationship between tumor ascorbate content and HIF-1 pathway activation (p=0.002) and tumor size (p=0.018). Higher tumor ascorbate content was associated with significantly improved disease-free survival in the first 6 years after surgery (p=0.006), with 141 - 1,094 additional disease free days. This was independent of tumor grade and stage. Survival advantage was associated with the amount of ascorbate in the tumor, but not with the amount in adjacent normal tissue. Our results demonstrate that higher tumor ascorbate content is associated decreased HIF-1 activation, most likely due to the co-factor activity of ascorbate for the regulatory HIF hydroxylases. Our findings support the need for future studies to determine whether raising tumor ascorbate is possible with clinical intervention and whether this results in modification of hydroxylase-dependent pathways in the tumor.

Background: The probability of undergoing treatment with curative intent for esophagogastric cancer has been shown to vary considerately between hospitals of diagnosis. Little is known about the factors that attribute to this variation. Since clinical decision making (CDM) partially takes place during an MDTM, the aim of this qualitative study was to assess clinician's perspectives regarding facilitators and barriers associated with CDM during MDTM, and second, to identify factors associated with CDM during an MDTM thatmay potentially explain differences in hospital practice. Methods: A multiple case study design was conducted. The thematic content analysis of this qualitative study, focused on 16 MDTM observations, 30 semistructured interviews with clinicians and seven focus groups with clinicians to complement the collected data. Interviews were transcribed ad verbatim and coded. Results: Factors regarding team dynamics that were raised as aspects attributing to CDM were clinician's personal characteristics such as ambition and the intention to be innovative. Clinician's convictions regarding a certain treatment and its outcomes and previous experiences with treatment outcomes, and team dynamics within the MDTM influenced CDM. In addition, a continuum was illustrated. At one end of the continuum, teams tended to be more conservative, following the guidelines more strictly, versus the opposite in which hospitals tended towards a more invasive approach maximizing the probability of curation. Conclusion: This study contributes to the awareness that variation in team dynamics influences CDM during an MDTM. [ABSTRACT FROM AUTHOR]