Search

BackgroundAutosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins.ResultsTo test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates.ConclusionsTogether, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease.

BackgroundMyocarditis is a rare but significant adverse event associated with COVID-19 vaccination, especially for men under 40. If the risk of myocarditis is not stratified by pertinent risk factors, it may be diluted for high-risk and inflated for low-risk groups. We sought to assess how the risk of myocarditis is reported in the literature.MethodsIn accordance with PRISMA standards, we reviewed primary publications in PubMed, Embase, Google Scholar and MedRxiv (through 3/2022) and included studies that estimated the incidence of myocarditis/pericarditis after receiving either the BNT162b2 (Pfizer), mRNA-1273 (Moderna) or Ad26COVS1 (Janssen) vaccine. The main outcome was the percentage of studies using 4, 3, 2, 1 or 0 stratifiers (i.e. sex, age, dose number and manufacturer) when reporting the highest risk of myocarditis. Secondary outcomes included the incidence of myocarditis in males after dose 1 and 2 of the BNT162b2 (Pfizer) or mRNA-1273 (Moderna) vaccine.ResultsThe 29 included studies originated in North America, Europe, Asia, or were Worldwide. Of them, 28% (8/29) used all four stratifiers, and 45% (13/29) used 1 or 0 stratifiers. The highest incidence of myocarditis ranged from 8.1-39 cases per 100,000 persons (or doses) in studies using four stratifiers. Six studies reported an incidence greater than 15 cases per 100,000 persons (or doses) in males aged 12-24 after dose 2 of an mRNA-based vaccine.ConclusionsOnly one in four articles reporting myocarditis used four stratifiers, and men younger than 40 receiving a second dose of an mRNA vaccine are at greatest risk.

BackgroundRadiotherapy impacts the local immune response to cancers. Prostate Stereotactic Body Radiotherapy (SBRT) is a highly focused method to deliver radiotherapy often used to treat prostate cancer. This is the first direct comparison of immune cells within prostate cancers before and after SBRT in patients.MethodsProstate cancers before and 2 weeks after SBRT are interrogated by multiplex immune fluorescence targeting various T cells and macrophages markers and analyzed by cell and pixel density, as part of a clinical trial of SBRT neoadjuvant to radical prostatectomy.ResultsTwo weeks after SBRT, CD68, and CD163 macrophages are significantly increased while CD8 T cells are decreased. SBRT markedly alters the immune environment within prostate cancers.

Cognition and brain homeostasis depends on cerebral blood flow to secure adequate oxygen and nutrient distribution to the brain tissue. Altered cerebral blood flow has previously been reported in individuals diagnosed with autism spectrum condition in comparison to non-autistics. This phenomenon might suggest cerebral blood flow as a potential biomarker for autism spectrum condition. Major technological advancement enables the non-invasive and quantitative measurement of cerebral blood flow via arterial spin labeling magnetic resonance imaging. However, most neuroimaging studies in autistic individuals exploit the indirect blood oxygen level dependent functional magnetic resonance imaging signal instead. Therefore, this review examines the use of arterial spin labeling to further investigate the neurobiology of the autism spectrum condition. Followed by a comparison of results from molecular imaging and arterial spin labeling studies and a discussion concerning the future direction and potential of arterial spin labeling in this context. We found that arterial spin labeling study results are consistent with those of molecular imaging, especially after considering the effect of age and sex. Arterial spin labeling has numerous application possibilities besides the quantification of cerebral blood flow, including assessment of functional connectivity and arterial transit time. Therefore, we encourage researchers to explore and consider the application of arterial spin labeling for future scientific studies in the quest to better understand the neurobiology of autism spectrum condition.

Abstract Introduction Patients with cancer often want to spend their final days at home. In Norway, most patients with cancer die in institutions. We hypothesized that full integration of oncology and palliative care services would result in more time spent at home during end-of-life. Methods A prospective non-randomized intervention trial was conducted in two rural regions of Mid-Norway. The hospitals’ oncology and palliative care outpatient clinics and surrounding communities participated. An intervention including information, education, and a standardized care pathway was developed and implemented. Adult non-curative patients with cancer were eligible. Proportion of last 90 days of life spent at home was the primary outcome. Results We included 129 patients in the intervention group (I) and 76 patients in the comparison group (C), of whom 82% of patients in I and 78% of patients in C died during follow-up. The mean proportion of last 90 days of life spent at home was 0.62 in I and 0.72 in C (p = 0.044), with 23% and 36% (p = 0.073), respectively, dying at home. A higher proportion died at home in both groups compared to pre-study level (12%). During the observation period the comparison region developed and implemented an alternative intervention to the study intervention, with the former more focused on end-of-life care. Conclusion A higher proportion of patients with cancer died at home in both groups compared to pre-study level. Patients with cancer in I did not spend more time at home during end-of-life compared to those in C. The study intervention focused on the whole disease trajectory, while the alternative intervention was more directed towards end-of-life care. “Simpler” and more focused interventions on end-of-life care may be relevant for future studies on integration of palliative care into oncology. Trial Registration ClinicalTrials.gov Identifier: NCT02170168.

Abstract Introduction Ultrasound measurement of the radial resistance index (RRI) in the anatomical snuffbox has been proposed as a useful method for assessing the systemic vascular resistance index (SVRI). This study aims to establish the correlation between SVRI measured by pulmonary artery catheter (PAC) and RRI. Methods A cross-sectional study included all consecutive patients undergoing postoperative (POP) cardiac surgery with hemodynamic monitoring using PAC. Hemodynamic assessment was performed using PAC, and RRI was measured with ultrasound in the anatomical snuffbox. The Pearson correlation test was used to establish the correlation between RRI and SVRI measured using PAC. Hemodynamic behavior concerning RRI with a cutoff point of 1.1 (described to estimate under SVRI) was examined. Additionally, consistency between two evaluators was assessed for RRI using the intraclass correlation coefficient and Bland-Altman analysis. Results A total of 35 measurements were obtained. The average cardiac index (CI) was 2.73 ± 0.64 L/min/m², and the average SVRI was 1967.47 ± 478.33 dyn·s·m²/cm5. The correlation between RRI and SVRI measured using PAC was 0.37 [95% CI 0.045–0.62]. The average RRI was 0.94 ± 0.11. RRI measurements > 1.1 had a mean SVRI of 2120.79 ± 673.48 dyn·s·m²/cm5, while RRI measurements ≤ 1.1 had a mean SVRI of 1953.1 ± 468.17 dyn·s·m²/cm5 (p = 0.62). The consistency between evaluators showed an intraclass correlation coefficient of 0.88 [95% CI 0.78–0.93], and Bland-Altman analysis illustrated adequate agreement of RRI evaluators. Conclusions For patients in cardiac surgery POP, the correlation between the SVRI measured using PAC and the RRI measured in the anatomical snuffbox is low. Using the RRI as a SVRI estimator for patients is not recommended in this clinical scenario.

Abstract Background Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals. Results We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity. Conclusions We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms.

Due to mild-to-moderate iodine deficiency in Denmark, health authorities initiated a voluntary iodine fortification (IF) program in 1998, which became mandatory in 2000. In line with recommendations from the World Health Organization, the Danish investigation on iodine intake and thyroid disease (DanThyr) was established to monitor the effect on thyroid health and disease. The program involved different study designs and followed two Danish sub-populations in the years before IF and up till 20 years after. Results showed that the IF was successfully implemented and increased the level of iodine intake from mild–moderate iodine deficiency to low adequacy. The level of thyroglobulin and thyroid volume decreased following IF, and there was an indication of fewer thyroid nodules. The incidence of hyperthyroidism increased transiently following IF but subsequently decreased below the pre-fortification level. Conversely, thyroid-stimulating hormone levels and the prevalence of thyroid autoimmunity increased along with an increase in the incidence of hypothyroidism. These trends were mirrored in the trends in treatments for thyroid disease. Most differences in thyroid health and disease between regions with different iodine intake levels before IF attenuated. This review illustrates the importance of a monitoring program to detect both beneficial and adverse effects and exemplifies how a monitoring program can be conducted when a nationwide health promotion program – as IF – is initiated.

Abstract In recent years, interest in studying the climate and environmental impact of organic food has grown. Here, we compared the environmental impacts of organic and conventional food using data from 100 life cycle assessment studies. Most studies focused on climate impacts, with fewer addressing biodiversity loss and ecotoxicity. Findings revealed no significant differences in global warming, eutrophication potential, and energy use per mass unit. However, organic food showed lower global warming, eutrophication potential, and energy use per area unit, with higher land use. Additionally, organic farming showed lower potential for biodiversity loss and ecotoxicity. Challenges in life cycle assessment include evaluating biodiversity, toxicity, soil quality, and carbon changes. The choice of functional units influences results, highlighting the importance of considering multiple units in assessing organic food’s environmental footprint. This study emphasizes the necessity for comprehensive assessments at both product and diet levels to support informed decisions.

The determination of optimum nitrogen (N) fertilisation rates, which maximise yields and minimise N losses, remains problematic due to unknown upcoming crop requirements and near-future supply by the soil. Remote sensing can be used for determining the crop N status and to assess the spatial variability within a field or between fields. This can be used to improve N fertilisation, provided that the optimal fertilisation rate at the time of fertiliser application for an expected yield is known. Using the APSIM-wheat model, we developed an algorithm that relates the N status of the plants at early development stages to the yield response to N. Simulations were performed for winter wheat under growth conditions in Denmark. To obtain a range of different N status in the biomass at early growth stages, the soil N in autumn was varied from 20 to 180 kg N ha−1, and at BBCH23, fertiliser was applied at a rate of 50 kg N ha−1. In a full factorial setup, additional N fertiliser was applied ranging from 0 to 150 kg N ha−1 during three different development stages (BBCH30, 32, and 37). The algorithm was evaluated by comparing model outputs with a standard N application of 50 kg N ha−1 at BBCH23 and 150 kg N ha−1 at BBCH30. The evaluation showed that, depending on the N status of the soil, the algorithm either provided higher or lower optimal N fertilisation rates when targeting 95% of the maximum yield, and these affected the grain yield and the grain N, as well as the amount of N leaching. Split application of fertiliser into three applications was generally beneficial, with decreased product-related N leaching of up to nearly 30%. Further testing of the model under different environmental conditions is needed before such an algorithm can be used to guide N fertilisation.

Abstract In the course of the Horizon 2020 project HighNESS, a second moderator concept has been developed for the European Spallation Source, which complements the currently built moderator and is optimized for high intensity with a large viewable surface area. In this work we introduce conceptual designs for neutron instruments for condensed matter research designed to make optimal use of the capabilities of this moderator. The focus is on two concepts for small-angle neutron scattering and one neutron imaging instrument, which are intended to complement corresponding instruments that are already under construction at the European Spallation Source. One small-angle neutron scattering instrument concept resembles a conventional pinhole collimator geometry and aims to profit from the proposed second moderator by enabling to illuminate larger samples and providing particularly high resolution, drawing on a 30 m collimation and corresponding detector distance. A second small-angle neutron scattering instrument concept adopts nested mirror optics that enable to efficiently exploit the large moderator size and provide high resolution by focusing on the detector. The neutron imaging instrument concept is a typical pinhole instrument that can be found at continuous sources and draws on the corresponding strengths of high flux and large homogeneous fields-of-view, while still providing moderate wavelength resolution for advanced imaging methods.

Abstract Background Anopheles gambiae, the major malaria mosquito in sub-Saharan Africa, feed largely indoors at night. Raising a house off the ground with no barriers underneath reduces mosquito-house entry. This experiment tested whether walling off the space under an elevated hut affects mosquito-hut entry. Methods Four inhabited experimental huts, each of which could be moved up and down, were used in rural Gambia. Nightly collections of mosquitoes were made using light traps and temperature and carbon dioxide levels monitored indoors and outdoors using loggers. Each night, a reference hut was kept at ground level and three huts raised 2 m above the ground; with the space under the hut left open, walled with air-permeable walls or solid walls. Treatments were rotated every four nights using a randomized block design. The experiment was conducted for 32 nights. Primary measurements were mosquito numbers and indoor temperature in each hut. Results A total of 1,259 female Anopheles gambiae sensu lato were collected in the hut at ground level, 655 in the hut with an open ground floor, 981 in the hut with air-permeable walls underneath and 873 in the hut with solid walls underneath. Multivariate analysis, adjusting for confounders, showed that a raised hut open underneath had 53% fewer mosquitoes (95% CI 47–58%), those with air-permeable walls underneath 24% fewer (95% CI 9–36%) and huts with solid walls underneath 31% fewer (95% CI 24–37%) compared with a hut on the ground. Similar results were found for Mansonia spp. and total number of female mosquitoes, but not for Culex mosquitoes where hut entry was unaffected by height or barriers. Indoor temperature and carbon dioxide levels were similar in all huts. Conclusion Raising a house 2 m from the ground reduces the entry of An. gambiae and Mansonia mosquitoes, but not Culex species. The protective effect of height is reduced if the space underneath the hut is walled off.

Abstract Pre-injured lungs are prone to injury progression in response to mechanical ventilation. Heterogeneous ventilation due to (micro)atelectases imparts injurious strains on open alveoli (known as volutrauma). Hence, recruitment of (micro)atelectases by positive end-expiratory pressure (PEEP) is necessary to interrupt this vicious circle of injury but needs to be balanced against acinar overdistension. In this study, the lung-protective potential of alveolar recruitment was investigated and balanced against overdistension in pre-injured lungs. Mice, treated with empty vector (AdCl) or adenoviral active TGF-β1 (AdTGF-β1) were subjected to lung mechanical measurements during descending PEEP ventilation from 12 to 0 cmH2O. At each PEEP level, recruitability tests consisting of two recruitment maneuvers followed by repetitive forced oscillation perturbations to determine tissue elastance (H) and damping (G) were performed. Finally, lungs were fixed by vascular perfusion at end-expiratory airway opening pressures (Pao) of 20, 10, 5 and 2 cmH2O after a recruitment maneuver, and processed for design-based stereology to quantify derecruitment and distension. H and G were significantly elevated in AdTGF-β1 compared to AdCl across PEEP levels. H was minimized at PEEP = 5–8 cmH2O and increased at lower and higher PEEP in both groups. These findings correlated with increasing septal wall folding (= derecruitment) and reduced density of alveolar number and surface area (= distension), respectively. In AdTGF-β1 exposed mice, 27% of alveoli remained derecruited at Pao = 20 cmH2O. A further decrease in Pao down to 2 cmH2O showed derecruitment of an additional 1.1 million alveoli (48%), which was linked with an increase in alveolar size heterogeneity at Pao = 2–5 cmH2O. In AdCl, decreased Pao resulted in septal folding with virtually no alveolar collapse. In essence, in healthy mice alveoli do not derecruit at low PEEP ventilation. The potential of alveolar recruitability in AdTGF-β1 exposed mice is high. H is optimized at PEEP 5–8 cmH2O. Lower PEEP folds and larger PEEP stretches septa which results in higher H and is more pronounced in AdTGF-β1 than in AdCl. The increased alveolar size heterogeneity at Pao = 5 cmH2O argues for the use of PEEP = 8 cmH2O for lung protective mechanical ventilation in this animal model.

Abstract The prevalence of hyperthyroidism and hypothyroidism and associated risk factors are unknown in liver transplant recipients. We aimed to determine the prevalence of hyperthyroidism and hypothyroidism and associated risk factors in liver transplant recipients and to compare it with controls from the general population. As part of the Danish Comorbidity in Liver Transplant Recipients (DACOLT) Study, all Danish liver transplant recipients over the age of 20 were invited for measurements of concentrations of thyrotropin and thyroid hormones. The prevalence of hyperthyroidism and hypothyroidism was compared to age- and sex-matched controls from the Copenhagen General Population Study. Using logistic regression adjusted for age, sex, smoking, and body-mass index, we investigated potential risk factors. We recruited 489 liver transplant recipients and 1808 controls. Among liver transplant recipients, 14 (2.9%) had hyperthyroidism compared with 21 (1.2%) of controls (adjusted odds ratio [aOR] 2.24, 95% confidence interval [CI] 1.05–4.75, P = 0.04), while 42 (5.7%) had hypothyroidism compared with 139 (7.7%) of controls (aOR 0.68, 95% CI 0.43–1.08, P = 0.10). Female sex, and autoimmune hepatitis and primary sclerosing cholangitis as causes of transplantation were associated with hyperthyroidism after adjustments. Age, female sex, and autoimmune liver diseases as cause of transplantation were associated with hypothyroidism after adjustments. DACOLT is registered in ClinicalTrials.gov (NCT04777032).

Abstract Arts-based research offers an innovative approach to today’s social-ecological challenges. Many authors ascertain the transformative power of arts-based research lies in its ability to generate holistic and collaborative encounters which facilitate change. To advance critical discussions around arts-based research, the following article opens up pockets of success as well as the limitations and failures of the My Mabopane photovoice project. This project intended to support urban transformation in the City of Tshwane, South Africa, by asking participants to photograph and reflect upon a nearby green space afflicted with various social and environmental challenges. Results suggest alternative ways of knowing, which contribute to transformative learning, can link arts-based research to social-ecological transformation. However, despite this promising pathway, analyses also reveal realizing social-ecological transformation with arts-based research is no walk in the park. Rather problematic assumptions around knowledge and knowledge production, emerging in tensions between art and science, often trump the emancipatory intentions of photovoice. And broader structural challenges, that arts-based research situates itself in and against, pose a strong barrier for social-ecological transformation. In response to these barriers, this article argues for a collaborative arts-based research practice centering community realities on multiple scales via a merging of art, science, and life.

Abstract Background Dentists and oral surgeons are leading prescribers of opioids to adolescents and young adults (AYA), who are at high risk for developing problematic opioid use after an initial exposure. Most opioids are prescribed after tooth extraction, but non-opioid analgesics provide similar analgesia and are recommended by multiple professional organizations. Methods This multi-site stepped wedge cluster-randomized trial will assess whether a multicomponent behavioral intervention can influence opioid prescribing behavior among dentists and oral surgeons compared to usual practice. Across up to 12 clinical practices (clusters), up to 33 dentists/oral surgeons (provider participants) who perform tooth extractions for individuals 12–25 years old will be enrolled. After enrollment, all provider participants will receive the intervention at a time based on the sequence to which their cluster is randomized. The intervention consists of prescriber education via academic detailing plus provision of standardized patient post-extraction instructions and blister packs of acetaminophen and ibuprofen. Provider participants will dispense the blister packs and distribute the patient instructions at their discretion to AYA undergoing tooth extraction, with or without additional analgesics. The primary outcome is a binary, patient-level indicator of electronic post-extraction opioid prescription. Data for the primary outcome will be collected from the provider participant’s electronic health records quarterly throughout the study. Provider participants will complete a survey before and approximately 3 months after transitioning into the intervention condition to assess implementation outcomes. AYA patients undergoing tooth extraction will be offered a survey to assess pain control and satisfaction with pain management in the week after their extraction. Primary analyses will use generalized estimating equations to compare the binary patient-level indicator of being prescribed a post-extraction opioid in the intervention condition compared to usual practice. Secondary analyses will assess provider participants’ perceptions of feasibility and appropriateness of the intervention, and patient-reported pain control and satisfaction with pain management. Analyses will adjust for patient-level factors (e.g., sex, number of teeth extracted, etc.). Discussion This real-world study will address an important need, providing information on the effectiveness of a multicomponent intervention at modifying dental prescribing behavior and reducing opioid prescriptions to AYA. ClinicalTrials.gov NCT06275191.

Abstract Background The COVID-19 pandemic produced system-level changes within the criminal legal system and community-based substance use disorder (SUD) treatment system with impacts on recovery efforts. This study examines rural and urban clinicians’ perspectives of COVID-19 on SUD treatment delivery for people on community supervision. Methods Virtual qualitative interviews were conducted between April and October 2020 with 25 community supervision clinicians employed by Kentucky’s Department of Corrections (DOC), who conduct assessments and facilitate community-based treatment linkages for individuals on probation or parole. Transcripts were analyzed in NVivo using directed content analysis methods. Results Clinicians were predominantly white (92%) and female (88%) with an average of over 9 years working in the SUD treatment field and 4.6 years in their current job. Four COVID-19 themes were identified by both rural and urban clinicians including: (1) telehealth increases the modes of communication, but (2) also creates paperwork and technological challenges, (3) telehealth requires more effort for inter/intra-agency collaboration, and (4) it limits client information (e.g., no urine drug screens). Two additional rural-specific themes emerged related to COVID-19: (5) increasing telehealth options removes SUD treatment transportation barriers and (6) requires flexibility with programmatic requirements for rural clients. Conclusions Findings indicate the need for community-based SUD treatment providers approved or contracted by DOC to support and train clients to access technology and improve information-sharing with community supervision officers. A positive lesson learned from COVID-19 transitions was a reduction in costly travel for rural clients, allowing for greater engagement and treatment adherence. Telehealth should continue to be included within the SUD continuum of care, especially to promote equitable services for individuals from rural areas.

Abstract Background After curative surgery for early-stage breast cancer, patients face a decision on whether to undergo surgery alone or to receive one or more adjuvant treatments, which may lower the risk of recurrence. Variations in survival outcomes are often marginal but there are differences in the side effects and other features of the options that patients may value differently. Hence, the patient’s values and preferences are critical in determining what option to choose. It is well-researched that the use of shared decision making and patient decision aids can support this choice in a discussion between patient and clinician. However, it is still to be investigated what impact the timing and format of the patient decision aid have on shared decision making outcomes. In this trial, we aim to investigate the impact of a digital pre-consult compared to a paper-based in-consult patient decision aid on patients’ involvement in shared decision making, decisional conflict and preparedness to make a decision. Methods The study is a randomised controlled trial with 204 patients at two Danish oncology outpatient clinics. Eligible patients are newly diagnosed with early-stage breast cancer and offered adjuvant treatments after curative surgery to lower the risk of recurrence. Participants will be randomised to receive either an in-consult paper-based patient decision aid or a pre-consult digital patient decision aid. Data collection includes patient and clinician-reported outcomes as well as observer-reported shared decision making based on audio recordings of the consultation. The primary outcome is the extent to which patients are engaged in a shared decision making process reported by the patient. Secondary aims include the length of consultation, preparation for decision making, preferred role in shared decision making and decisional conflict. Discussion This study is the first known randomised, controlled trial comparing a digital, pre-consult patient decision aid to an identical paper-based, in-consult patient decision aid. It will contribute evidence on the impact of patient decision aids in terms of investigating if pre-consult digital patient decisions aids compared to in-consult paper-based decision aids support the cancer patients in being better prepared for decision making. Trial registration ClinicalTrials.gov (NCT05573022).

The fuel sulfur content (FSC) of ocean-going and inland vessels was measured simultaneously by eight different state-of-the-art and novel monitoring systems during a 6-week campaign at the Elbe River, at a distance of about 10 km to the port of Hamburg, Germany. Both stationary and airborne systems on unoccupied aerial vehicles (UAVs) were operated by four participating partners in a side-by-side measurement setup to measure the emission factors of the same emission sources. A novel laser spectrometer, with significantly better-precision specifications as compared with the other instruments, was used for the first time for emission monitoring regarding the International Convention for the Prevention of Pollution from Ships (MARPOL) Annex VI regulations. The comparison took place in the North Sea sulfur emission control area (SECA), where the allowed FSC is limited to 0.10 %Sm/m. The unit %Sm/m relates to the percentage of mass sulfur per mass combusted fuel. In total, 966 plumes that originated from 436 different vessels were analysed in this study. At the same time, fuel samples obtained from 34 different vessels and bunker delivery notes (BDNs) from five frequently monitored vessels were used as a reference to assess the uncertainties of the different systems. Seven of the eight measurement systems tended to underestimate the FSC found from fuel samples and BDNs. A possible relation between underestimation and high relative humidities (above 80 %) was observed. The lowest systematic deviations were observed for the airborne systems and the novel laser spectrometer. The two UAV-borne systems showed total uncertainties of 0.07 %Sm/m and 0.09 %Sm/m (confidence level: 95 %). The novel laser spectrometer showed the lowest total uncertainty of 0.05 %Sm/m compared with other stationary sniffer systems, whose total uncertainties range from 0.08 %Sm/m to 0.09 %Sm/m. It was concluded that non-compliant vessels, with an actual FSC of the combusted fuel above 0.15 %Sm/m to 0.19 %Sm/m, can be detected by the compared systems with 95 % confidence.

INTRODUCTION: We previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects. METHODS: We employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment analysis was done using the GSEA software with hallmark gene sets from MSigDB. Key changes were validated at mRNA and protein levels. Human PC transcriptomes from six datasets were analyzed to determine the correlation between CYP27A1 and DNA repair gene expression signatures. DNA damage was assessed via comet assays. RESULTS: Transcriptome analysis revealed 27HC treatment downregulated Hallmark pathways related to DNA damage repair, decreased expression of FEN1 and RAD51, and induced BRCAness by downregulating genes involved in homologous recombination regulation in LNCaP cells. Consistently, we found a correlation between higher CYP27A1 expression (i.e., higher intracellular 27HC) and decreased expression of DNA repair gene signatures in castration-sensitive PC (CSPC) in human PC datasets. However, such correlation was less clear in metastatic castration-resistant PC (mCRPC). 27HC increased expression of DNA damage repair markers in PC cells, notably in AR+ cells, but no consistent effects in AR- cells and decreased expression in non-neoplastic prostate epithelial cells. While testing the clinical implications of this, we noted that 27HC treatment increased DNA damage in LNCaP cells via comet assays. Effects were reversible by adding back cholesterol, but not androgens. Finally, in combination with olaparib, a PARP inhibitor, we showed additive DNA damage effects. DISCUSSION: These results suggest 27HC induces BRCAness, a functional state thought to increase sensitivity to PARP inhibitors, and leads to increased DNA damage, especially in CSPC. Given the emerging appreciation that defective DNA damage repair can drive PC growth, future studies are needed to test whether 27HC creates a synthetic lethality to PARP inhibitors and DNA damaging agents in CSPC.

BackgroundEfforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status and heterogeneous symptom states.MethodsWe describe a consortium to quantify neuroanatomical and neurofunctional heterogeneity via the dimensions of novel multivariate coordinate system (COORDINATE-MDD). Utilizing imaging harmonization and machine learning methods in a large cohort of medication-free, deeply phenotyped MDD participants, patterns of brain alteration are defined in replicable and neurobiologically-based dimensions and offer the potential to predict treatment response at the individual level. International datasets are being shared from multi-ethnic community populations, first episode and recurrent MDD, which are medication-free, in a current depressive episode with prospective longitudinal treatment outcomes and in remission. Neuroimaging data consist of de-identified, individual, structural MRI and resting-state functional MRI with additional positron emission tomography (PET) data at specific sites. State-of-the-art analytic methods include automated image processing for extraction of anatomical and functional imaging variables, statistical harmonization of imaging variables to account for site and scanner variations, and semi-supervised machine learning methods that identify dominant patterns associated with MDD from neural structure and function in healthy participants.ResultsWe are applying an iterative process by defining the neural dimensions that characterise deeply phenotyped samples and then testing the dimensions in novel samples to assess specificity and reliability. Crucially, we aim to use machine learning methods to identify novel predictors of treatment response based on prospective longitudinal treatment outcome data, and we can externally validate the dimensions in fully independent sites.ConclusionWe describe the consortium, imaging protocols and analytics using preliminary results. Our findings thus far demonstrate how datasets across many sites can be harmonized and constructively pooled to enable execution of this large-scale project.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.