Diagnostic Algorithm for Intracranial Lesions in the Emergency Department: Effectiveness of the Relative Brain Volume and Hounsfield Unit Value Measured by Perfusion Tomography.

Background Early treatment of intracranial lesions in the emergency department is crucial, but it can be challenging to differentiate between them. This differentiation is essential because the treatment of each type of lesion is different. Cerebral computed tomography perfusion (CTP) imaging can help visualize the vascularity of brain lesions and provide absolute quantification of physiological parameters. Compared to magnetic resonance imaging, CTP has several advantages, such as simplicity, wide availability, and reproducibility. Purpose This study aimed to assess the effectiveness of Hounsfield units (HU) in measuring the density of hypercellular lesions and the ability of CTP to quantify hemodynamics in distinguishing intracranial space-occupying lesions. Methods A retrospective study was conducted from March 2016 to March 2022. All patients underwent CTP and CT scans, and relative cerebral blood volume (rCBV) and HU were obtained for intracranial lesions. Results We included a total of 244 patients in our study. This group consisted of 87 (35.7%) individuals with glioblastomas (GBs), 48 (19.7%) with primary central nervous system lymphoma (PCNSL), 45 (18.4%) with metastases (METs), and 64 (26.2) with abscesses. Our study showed that the HUs for METs were higher than those for GB (S 57.4% and E 88.5%). In addition, rCBV values for PCNSL and abscesses were lower than those for GB and METs. The HU in PCNSL was higher than those in abscesses (S 94.1% and E 96.6%). Conclusion PCT parameters provide valuable information for diagnosing brain lesions. A comprehensive assessment improves accuracy. Combining rCBV and HU enhances diagnostic accuracy, making it a valuable tool for distinguishing between lesions. PCT's widespread availability allows for the use of both anatomical and functional information with high spatial resolution for diagnosing and managing brain tumor patients.

Disengagement of somatostatin neurons from lateral septum circuitry by oxytocin and vasopressin restores social-fear extinction and suppresses aggression outbursts in Prader-Willi syndrome model.

Background: Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi Syndrome (PWS). Clinical evidence suggests aberrant pro-social behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, what neuronal mechanisms underlie impaired behavioral responses in a socially-aversive context, and how can they be corrected, remains largely unknown. Methods: Using the Magel2 knocked-out (KO) mouse model of PWS (crossed with CRE-dependent transgenic lines), we devised optogenetic, physiological and pharmacological strategies in a social-fear-conditioning paradigm. Pathway specific roles of OXT and AVP signaling were investigated converging on the lateral septum (LS), a region which receives dense hypothalamic inputs. Results: OXT and AVP signaling promoted inhibitory synaptic transmission in the LS, which failure in Magel2KO mice disinhibited somatostatin (SST) neurons and disrupted social-fear extinction. The source of OXT and AVP deficits mapped specifically in the supraoptic nucleus→LS pathway of Magel2KO mice disrupting social-fear extinction, which could be corrected by optogenetic or pharmacological inhibition of SST-neurons in the LS. Interestingly, LS SST-neurons also gated the expression of aggressive behavior, possibly as part of functional units operating beyond local septal circuits. Conclusions: SST cells in the LS play a crucial role in integration and expression of disrupted neuropeptide signals in autism, thereby altering the balance in expression of safety versus fear. Our results uncover novel mechanisms underlying dysfunction in a socially-aversive context, and provides a new framework for future treatments in autism-spectrum disorders.

Unravelling relationships between obesity, diabetes, and factors related to somatosensory functioning in knee osteoarthritis patients.

OBJECTIVE: This study explores the association between obesity, diabetes, and somatosensory functioning in patients with knee osteoarthritis (OA), aiming to understand how metabolic conditions are related to pain mechanisms in this patient population. We hypothesized that higher body mass index (BMI), fat mass, and glycated hemoglobin levels (HbA1c) are associated with signs of altered somatosensory functioning. METHODS: A cross-sectional analysis was conducted as part of a larger multicentre prospective cohort study. Data were collected from patients awaiting total knee arthroplasty in Belgium and the Netherlands. Associations between BMI, fat mass, HbA1c, and various pain-related variables were examined employing Pearson and Spearman correlation analyses which were further analyzed with linear regression techniques. RESULTS: The study included 223 participants. Analysis revealed a significant although weak negative correlation between fat mass and pressure pain thresholds (PPT) at multiple locations, suggesting a link between higher fat mass and increased mechanical hyperalgesia. There were no significant correlations between BMI and pain-related outcomes. HbA1c levels showed very weak positive correlations with pain measures but did not withstand correction for multiple testing. CONCLUSION: The findings indicate that fat mass may be closely associated with altered somatosensory functioning in patients with knee OA. However, no significant correlations were found between BMI or HbA1c levels and pain-related outcomes. Future research should focus on longitudinal studies to elucidate the causal relationships and further explore the impact of metabolic factors on pain mechanisms in this patient population. Key Points • The findings indicate that fat mass may be closely associated with altered somatosensory functioning in patients with knee OA.

TTF1 control of LncRNA synthesis delineates a tumor suppressor pathway directly regulating the ribosomal RNA genes.

The tumor suppressor p14/19ARF regulates ribosomal RNA (rRNA) synthesis by controlling the nucleolar localization of Transcription Termination Factor 1 (TTF1). However, the role played by TTF1 in regulating the rRNA genes and in potentially controlling growth has remained unclear. We now show that TTF1 expression regulates cell growth by determining the cellular complement of ribosomes. Unexpectedly, it achieves this by acting as a "roadblock" to synthesis of the noncoding LncRNA and pRNA that we show are generated from the "Spacer Promoter" duplications present upstream of the 47S pre-rRNA promoter on the mouse and human ribosomal RNA genes. Unexpectedly, the endogenous generation of these noncoding RNAs does not induce CpG methylation or gene silencing. Rather, it acts in cis to suppress 47S preinitiation complex formation and hence de novo pre-rRNA synthesis by a mechanism reminiscent of promoter interference or occlusion. Taken together, our data delineate a pathway from p19ARF to cell growth suppression via the regulation of ribosome biogenesis by noncoding RNAs and validate a key cellular growth law in mammalian cells.

Cardiovascular Burden of the V142I Transthyretin Variant.

Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments. Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population. Design, Setting, and Participants: A total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024. Exposure: V142I carrier status (n = 754, 3.2%). Main Outcomes and Measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data. Results: Among the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant. Conclusions and Relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

Comparison of rectal swabs and fecal samples for the detection of Clostridioides difficile infections with a new in-house PCR assay.

The detection of Clostridioides difficile infections (CDI) relies on testing the stool of patients by toxin antigen detection or PCR methods. Although PCR and antigenic methods have significantly reduced the time to results, delays in stool collection can significantly add to the turnaround time. The use of rectal swabs to detect C. difficile could considerably reduce the time to diagnosis of CDI. We developed a new rapid PCR assay for the detection of C. difficile and evaluated this PCR assay on both stool and rectal swab specimens. We recruited a total of 623 patients suspected of C. difficile infection. Stool samples and rectal swabs were collected from each patient and tested by our PCR assay. Stool samples were also tested by the cell cytotoxicity neutralization assay (CCNA) as a reference. The PCR assay detected C. difficile in 60 stool specimens and 61 rectal swabs for the 64 patients whose stool samples were positive for C. difficile by CCNA. The PCR assay detected an additional 35 and 36 stool and rectal swab specimens positive for C. difficile, respectively, for sensitivity with stools and rectal swabs of 93.8% and 95.3%, specificity of 93.7% and 93.6%, positive predictive values of 63.2% and 62.9%, and negative predictive values of 99.2% and 99.4%. Detection of C. difficile using PCR on stools or rectal swabs yielded reliable and similar results. The use of PCR tests on rectal swabs could reduce turnaround time for CDI detection, thus improving CDI management and control of C. difficile transmission. IMPORTANCE: Clostridioides difficile infection (CDI) is the leading cause of healthcare-associated diarrhea, resulting in high morbidity, mortality, and economic burden. In clinical laboratories, CDI testing is currently performed on stool samples collected from patients with diarrhea. However, the diagnosis of CDI can be delayed by the time required to collect stool samples. Barriers to sample collection could be overcome by using a rectal swab instead of a stool sample. Our study showed that CDI can be identified rapidly and reliably by a new PCR assay developed in our laboratory on both stool and rectal swab specimens. The use of PCR tests on rectal swabs could reduce the time for the detection of CDI and improve the management of this infection. It should also provide a useful alternative for infection-control practitioners to better control the spread of C. difficile.

New Breakthroughs in the Diagnosis of Leptomeningeal Carcinomatosis: A Review of Liquid Biopsies of Cerebrospinal Fluid.

Leptomeningeal carcinomatosis represents a terminal stage and is a devastating complication of cancer. Despite its high incidence, current diagnostic methods fail to accurately detect this condition in a timely manner. This failure to diagnose leads to the refusal of treatment and the absence of clinical trials, hampering the development of new therapy strategies. The use of liquid biopsy is revolutionizing the field of diagnostic oncology. The dynamic and non-invasive detection of tumor markers has enormous potential in cancer diagnostics and treatment. Leptomeningeal carcinomatosis is a condition where invasive tissue biopsy is not part of the routine diagnostic analysis, making liquid biopsy an essential diagnostic tool. Several elements in cerebrospinal fluid (CSF) have been investigated as potential targets of liquid biopsy, including free circulating tumor cells, free circulating nucleic acids, proteins, exosomes, and even non-tumor cells as part of the dynamic tumor microenvironment. This review aims to summarize current breakthroughs in the research on liquid biopsy, including the latest breakthroughs in the identification of tumor cells and nucleic acids, and give an overview of future directions in the diagnosis of leptomeningeal carcinomatosis.

Using Polygenic Scores for Circadian Rhythms to Predict Wellbeing, Depressive Symptoms, Chronotype, and Health.

The association between circadian rhythms and diseases has been well established, while the association with mental health is less explored. Given the heritable nature of circadian rhythms, this study aimed to investigate the relationship between genes underlying circadian rhythms and mental health outcomes, as well as a possible gene-environment correlation for circadian rhythms. Polygenic scores (PGSs) represent the genetic predisposition to develop a certain trait or disease. In a sample from the Netherlands Twin Register (N = 14,021), PGSs were calculated for two circadian rhythm measures: morningness and relative amplitude (RA). The PGSs were used to predict mental health outcomes such as subjective happiness, quality of life, and depressive symptoms. In addition, we performed the same prediction analysis in a within-family design in a subset of dizygotic twins. The PGS for morningness significantly predicted morningness (R2 = 1.55%) and depressive symptoms (R2 = 0.22%). The PGS for RA significantly predicted general health (R2 = 0.12%) and depressive symptoms (R2 = 0.20%). Item analysis of the depressive symptoms showed that 4 out of 14 items were significantly associated with the PGSs. Overall, the results showed that people with a genetic predisposition of being a morning person or with a high RA are likely to have fewer depressive symptoms. The four associated depressive symptoms described symptoms related to decision-making, energy, and feeling worthless or inferior, rather than sleep. Based on our findings future research should include a substantial role for circadian rhythms in depression research and should further explore the gene-environment correlation in circadian rhythms.

Expanding the repertoire reveals recurrent, cryptic, and hematopoietic HLA class I minor histocompatibility antigens.

ABSTRACT: Allogeneic stem cell transplantation (alloSCT) is a curative treatment for hematological malignancies. After HLA-matched alloSCT, antitumor immunity is caused by donor T cells recognizing polymorphic peptides, designated minor histocompatibility antigens (MiHAs), that are presented by HLA on malignant patient cells. However, T cells often target MiHAs on healthy nonhematopoietic tissues of patients, thereby inducing side effects known as graft-versus-host disease. Here, we aimed to identify the dominant repertoire of HLA-I-restricted MiHAs to enable strategies to predict, monitor or modulate immune responses after alloSCT. To systematically identify novel MiHAs by genome-wide association screening, T-cell clones were isolated from 39 transplanted patients and tested for reactivity against 191 Epstein-Barr virus transformed B cell lines of the 1000 Genomes Project. By discovering 81 new MiHAs, we more than doubled the antigen repertoire to 159 MiHAs and demonstrated that, despite many genetic differences between patients and donors, often the same MiHAs are targeted in multiple patients. Furthermore, we showed that one quarter of the antigens are cryptic, that is translated from unconventional open reading frames, for example long noncoding RNAs, showing that these antigen types are relevant targets in natural immune responses. Finally, using single cell RNA-seq data, we analyzed tissue expression of MiHA-encoding genes to explore their potential role in clinical outcome, and characterized 11 new hematopoietic-restricted MiHAs as potential targets for immunotherapy. In conclusion, we expanded the repertoire of HLA-I-restricted MiHAs and identified recurrent, cryptic and hematopoietic-restricted antigens, which are fundamental to predict, follow or manipulate immune responses to improve clinical outcome after alloSCT.

Tackling Infectious Diseases with Rapid Molecular Diagnosis and Innovative Prevention.

Infectious diseases (IDs) are a leading cause of death. The diversity and adaptability of microbes represent a continuing risk to health. Combining vision with passion, our transdisciplinary medical research team has been focussing its work on the better management of infectious diseases for saving human lives over the past five decades through medical discoveries and innovations that helped change the practice of medicine. The team used a multiple-faceted and integrated approach to control infectious diseases through fundamental discoveries and by developing innovative prevention tools and rapid molecular diagnostic tests to fulfill the various unmet needs of patients and health professionals in the field of ID. In this article, as objectives, we put in context two main research areas of ID management: innovative infection prevention that is woman-controlled, and the rapid molecular diagnosis of infection and resistance. We also explain how our transdisciplinary approach encompassing specialists from diverse fields ranging from biology to engineering was instrumental in achieving success. Furthermore, we discuss our vision of the future for translational research to better tackle IDs.

Long-term trajectories of densely reported depressive symptoms during an extended period of the COVID-19 pandemic in Switzerland: Social worries matter.

Previous mental health trajectory studies were mostly limited to the months before access to vaccination. They are not informing on whether public mental health has adapted to the pandemic. The aim of this analysis was to 1) investigate trajectories of monthly reported depressive symptoms from July 2020 to December 2021 in Switzerland, 2) compare average growth trajectories across regions with different stringency phases, and 3) explore the relative impact of self-reported worries related to health, economic and social domains as well as socio-economic indicators on growth trajectories. As part of the population-based Corona Immunitas program of regional, but harmonized, adult cohorts studying the pandemic course and impact, participants repeatedly reported online to the DASS-21 instrument on depressive symptomatology. Trajectories of depressive symptoms were estimated using a latent growth model, specified as a generalised linear mixed model. The time effect was modelled parametrically through a polynomial allowing to estimate trajectories for participants' missing time points. In all regions level and shape of the trajectories mirrored those of the KOF Stringency-Plus Index, which quantifies regional Covid-19 policy stringency. The higher level of average depression in trajectories of those expressing specific worries was most noticeable for the social domain. Younger age, female gender, and low household income went along with higher mean depression score trajectories throughout follow-up. Interventions to promote long-term resilience are an important part of pandemic preparedness, given the observed lack of an adaptation in mental health response to the pandemic even after the availability of vaccines in this high-income context.

A Neurological Surgery Care Protocol for the LGBTQIA+ Community.

This research aims to propose a neurological surgery care protocol for the lesbian, gay, bisexual, transgender, queer, questioning, intersex, or asexual (LGBTQIA+) community. In recent years, people belonging to the LGBTQIA+ community have started to come out and express their identity due to growing awareness and various factors like the implementation of legal protections and rights in several countries; it is well documented in the literature that this community faces unique health needs as well as barriers and inequalities in healthcare. The lack of tailored training for medical specialists affects the level of quality and access to medical care for these individuals, and neurosurgical care is no exception. This literature review included studies in scientific journals and articles discussing problems, best practices, and gaps in the existing neurological surgical care protocols for LGBTQIA+ people. Accordingly, it highlights shared challenges such as healthcare-related difficulties, communication barriers, discrimination, and stigmatization. The primary aim is to create a safe and respectful care environment that ensures fair medical treatment to all patients regardless of their sexual orientation or gender identity. The review sheds light on the need for inclusive and sensitive neurosurgical care to improve clinical outcomes and the experience of patients belonging to the LGBTQIA+ community, thereby ensuring an environment of dignified treatment and satisfactory recovery from neurosurgical events.

Beyond the factor indeterminacy problem using genome-wide association data.

Latent factors, such as general intelligence, depression and risk tolerance, are invoked in nearly all social science research where a construct is measured via aggregation of symptoms, question responses or other measurements. Because latent factors cannot be directly observed, they are inferred by fitting a specific model to empirical patterns of correlations among measured variables. A long-standing critique of latent factor theories is that the correlations used to infer latent factors can be produced by alternative data-generating mechanisms that do not include latent factors. This is referred to as the factor indeterminacy problem. Researchers have recently begun to overcome this problem by using information on the associations between individual genetic variants and measured variables. We review historical work on the factor indeterminacy problem and describe recent efforts in genomics to rigorously test the validity of latent factors, advancing the understanding of behavioural science constructs.

More than nature and nurture, indirect genetic effects on children's academic achievement are consequences of dynastic social processes.

Families transmit genes and environments across generations. When parents' genetics affect their children's environments, these two modes of inheritance can produce an 'indirect genetic effect'. Such indirect genetic effects may account for up to half of the estimated genetic variance in educational attainment. Here we tested if indirect genetic effects reflect within-nuclear-family transmission ('genetic nurture') or instead a multi-generational process of social stratification ('dynastic effects'). We analysed indirect genetic effects on children's academic achievement in their fifth to ninth years of schooling in N = 37,117 parent-offspring trios in the Norwegian Mother, Father, and Child Cohort Study (MoBa). We used pairs of genetically related families (parents were siblings, children were cousins; N = 10,913) to distinguish within-nuclear-family genetic-nurture effects from dynastic effects shared by cousins in different nuclear families. We found that indirect genetic effects on children's academic achievement cannot be explained by processes that operate exclusively within the nuclear family.

A systematic review of tools for predicting complications in patients with influenza-like illness.

Objective: To identify tools that predict the risk of complications for patients presenting to an outpatient clinic or an emergency department (ED) with influenza-like illness. Methods: We searched Medline, Embase, Cochrane Library and CINAHL from inception to July 2023. We included articles reporting on the derivation or validation of a score or algorithm used to stratify the risk of hospitalization or mortality among patients with influenza-like illness in the ED or outpatient clinic. Results: Twelve articles reporting on eight scores and six predictive models were identified. For predicting the need for hospitalization, the area under the curve (AUC) of the PMEWS and the CURB-65 ranged respectively from 0.76 to 0.94, and 0.65 to 0.88. The Community Assessment Tool had an AUC of 0.62. For predicting inpatient mortality, AUC was 0.66 for PMEWS and 0.79 for CURB-65, 0.79 for the SIRS criteria and 0.86 for the qSOFA score. Two scores were developed without external validation during the Covid-19 pandemic. The CovHos score and the Canadian Covid discharge score had an AUC ranged from 0.70 to 0.91. The predictive models performed adequately (AUC from 0.76 to 0.92) but will require external validation for clinical use. Tool diversity and study population heterogeneity precluded meta-analysis. Conclusion: Although the CURB, PMEWS and qSOFA scores appear to predict accurately the risk of complications of influenza-like illness, none were reliable enough to justify their widespread ED use. Refinement of an existing tool or development of a new tool to optimize the management of these patients is needed.

Navigating Post-Operative Outcomes: A Comprehensive Reframing of an Original Graded Prognostic Assessment in Patients with Brain Metastases.

BACKGROUND: Graded Prognostic Assessment (GPA) has been proposed for various brain metastases (BMs) tailored to the primary histology and molecular profiles. However, it does not consider whether patients have been operated on or not and does not include surgical outcomes as prognostic factors. The residual tumor burden (RTB) is a strong predictor of overall survival. We validated the GPA score and introduced "volumetric GPA" in the largest cohort of operated patients and further explored the role of RTB as an additional prognostic factor. METHODS: A total of 630 patients with BMs between 2007 and 2020 were included. The four GPA components were analyzed. The validity of the original score was assessed using Cox regression, and a modified index incorporating RTB was developed by comparing the accuracy, sensitivity, specificity, F1-score, and AUC parameters. RESULTS: GPA categories showed an association with survival: age (p < 0.001, hazard ratio (HR) 2.9, 95% confidence interval (CI) 2.5-3.3), Karnofsky performance status (KPS) (p < 0.001, HR 1.3, 95% CI 1.2-1.5), number of BMs (p = 0.019, HR 1.4, 95% CI 1.1-1.8), and the presence of extracranial manifestation (p < 0.001, HR 3, 95% CI 1.6-2.5). The median survival for GPA 0-1 was 4 months; for GPA 1.5-2, it was 12 months; for GPA 2.5-3, it was 21 months; and for GPA 3.5-4, it was 38 months (p < 0.001). RTB was identified as an independent prognostic factor. A cut-off of 2 cm3 was used for further analysis, which showed a median survival of 6 months (95% CI 4-8) vs. 13 months (95% CI 11-14, p < 0.001) for patients with RTB > 2 cm3 and <2 cm3, respectively. RTB was added as an additional component for a modified volumetric GPA score. The survival rates with the modified GPA score were: GPA 0-1: 4 months, GPA 1.5-2: 7 months, GPA 2.5-3: 18 months, and GPA 3.5-4: 34 months. Both scores showed good stratification, with the new score showed a trend towards better discrimination in patients with more favorable prognoses. CONCLUSION: The prognostic value of the original GPA was confirmed in our cohort of patients who underwent surgery for BM. The RTB was identified as a parameter of high prognostic significance and was incorporated into an updated "volumetric GPA". This score provides a novel tool for prognosis and clinical decision making in patients undergoing surgery. This method may be useful for stratification and patient selection for further treatment and in future clinical trials.

Evaluating the causal relationship between educational attainment and mental health.

We investigate the causal relationship between educational attainment (EA) and mental health using two research designs. First, we compare the relationship between EA and 18 psychiatric diagnoses within sibship in Dutch national registry data (N=1.7 million), thereby controlling for unmeasured familial factors. Second, we apply two-sample Mendelian Randomization, which uses genetic variants related to EA or psychiatric diagnosis as instrumental variables, to test whether there is a causal relation in either direction. Our results suggest that lower levels of EA causally increase the risk of MDD, ADHD, alcohol dependence, GAD and PTSD diagnoses. We also find evidence of a causal effect of ADHD on EA. For schizophrenia, anorexia nervosa, OCD, and bipolar disorder, results were inconsistent across the different approaches, highlighting the importance of using multiple research designs to understand complex relationships such as between EA and mental health.

Disentangling potential causal effects of educational duration on well-being, and mental and physical health outcomes.

BACKGROUND: Extensive research has focused on the potential benefits of education on various mental and physical health outcomes. However, whether the associations reflect a causal effect is harder to establish. METHODS: To examine associations between educational duration and specific aspects of well-being, anxiety and mood disorders, and cardiovascular health in a sample of European Ancestry UK Biobank participants born in England and Wales, we apply four different causal inference methods (a natural policy experiment leveraging the minimum school-leaving age, a sibling-control design, Mendelian randomization [MR], and within-family MR), and assess if the methods converge on the same conclusion. RESULTS: A comparison of results across the four methods reveals that associations between educational duration and these outcomes appears predominantly to be the result of confounding or bias rather than a true causal effect of education on well-being and health outcomes. Although we do consistently find no associations between educational duration and happiness, family satisfaction, work satisfaction, meaning in life, anxiety, and bipolar disorder, we do not find consistent significant associations across all methods for the other phenotypes (health satisfaction, depression, financial satisfaction, friendship satisfaction, neuroticism, and cardiovascular outcomes). CONCLUSIONS: We discuss inconsistencies in results across methods considering their respective limitations and biases, and additionally discuss the generalizability of our findings in light of the sample and phenotype limitations. Overall, this study strengthens the idea that triangulation across different methods is necessary to enhance our understanding of the causal consequences of educational duration.

Antibody-mediated delivery of viral epitopes to redirect EBV-specific CD8+ T-cell immunity towards cancer cells.

Antibody-mediated delivery of immunogenic epitopes to redirect virus-specific CD8+ T-cells towards cancer cells is an emerging and promising new therapeutic strategy. These so-called antibody-epitope conjugates (AECs) rely on the proteolytic release of the epitopes close to the tumor surface for presentation by HLA class I molecules to eventually redirect and activate virus-specific CD8+ T-cells towards tumor cells. We fused the immunogenic EBV-BRLF1 epitope preceded by a protease cleavage site to the C-terminus of the heavy and/or light chains of cetuximab and trastuzumab. We evaluated these AECs and found that, even though all AECs were able to redirect the EBV-specific T-cells, AECs with an epitope fused to the C-terminus of the heavy chain resulted in higher levels of T-cell activation compared to AECs with the same epitope fused to the light chain of an antibody. We observed that all AECs were depending on the presence of the antibody target, that the level of T-cell activation correlated with expression levels of the antibody target, and that our AECs could efficiently deliver the BRLF1 epitope to cancer cell lines from different origins (breast, ovarian, lung, and cervical cancer and a multiple myeloma). Moreover, in vivo, the AECs efficiently reduced tumor burden and increased the overall survival, which was prolonged even further in combination with immune checkpoint blockade. We demonstrate the potential of these genetically fused AECs to redirect the potent EBV-specific T-cells towards cancer in vitro and in vivo.