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Rationale: Chronic thromboembolic pulmonary hypertension involves the formation and nonresolution of thrombus, dysregulated inflammation, angiogenesis, and the development of a small-vessel vasculopathy. Objectives: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. Methods: We conducted a genome-wide association study on 1,907 European cases and 10,363 European control subjects. We coanalyzed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism, and idiopathic pulmonary arterial hypertension. Measurements and Main Results: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our coanalysis, we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2, and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. Conclusions: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations with pulmonary embolism and deep vein thrombosis.

Although rainfall-triggered landslides are initiated by subsurface hydro-mechanical processes related to the loading, weakening, and eventual failure of slope materials, most landslide early warning systems (LEWSs) have relied solely on rainfall event information. In previous decades, several studies demonstrated the value of integrating proxies for subsurface hydrologic information to improve rainfall-based forecasting of shallow landslides. More recently, broader access to commercial sensors and telemetry for real-time data transmission has invigorated new research into hydrometeorological thresholds for LEWSs. Given the increasing number of studies across the globe using hydrologic monitoring, mathematical modeling, or both in combination, it is now possible to make some insights into the advantages versus limitations of this approach. The extensive progress demonstrates the value of in situ hydrologic information for reducing both failed and false alarms through the ability to characterize infiltration during – as well as the drainage and drying processes between – major storm events. There are also some areas for caution surrounding the long-term sustainability of subsurface monitoring in landslide-prone terrain, as well as unresolved questions in hillslope hydrologic modeling, which relies heavily on the assumptions of diffuse flow and vertical infiltration but often ignores preferential flow and lateral drainage. Here, we share a collective perspective based on our previous collaborative work across Europe, North America, Africa, and Asia to discuss these challenges and provide some guidelines for integrating knowledge of hydrology and climate into the next generation of LEWSs. We propose that the greatest opportunity for improvement is through a measure-and-model approach to develop an understanding of landslide hydro-climatology that accounts for local controls on subsurface storage dynamics. Additionally, new efforts focused on the subsurface hydrology are complementary to existing rainfall-based methods, so leveraging these with near-term precipitation forecasts is a priority for increasing lead times.

Background: In this study, agents working in positions of authority within health sector organisations shared their perspectives concerning both the involvement of experts by experience with intellectual disabilities within their own organisations and their recommendations as to how best to involve experts by experience in policy and practice. Method: Using purposive sampling, eight agents were selected for semi-structured interviews. The interviews were analysed using thematic analysis. Results: The results indicated the importance of involving experts by experience. However, they also highlighted several barriers such as a lack of emphasis on genuine attention, insufficient visibility and recognition of expertise, and a lack of support for sustainable inclusion. Conclusions: Agents are willing to involve experts by experience in health sector organisations, but practical challenges hindered them from actually doing so. This study emphasises the importance to find solutions for better inclusion in policies.

Rice (Oryza sativa L.) is an important cereal crop across East, South and Southeast Asia, from prehistory to today, and grows in a range of ecological conditions, from rainfed upland to deep water. Previous research on early rice in the Lower Yangtze River basin (LYRB) suggested shifts back and forth over time between wet and dry field conditions, and some application of animal dung and/or human feces as fertilizer. In this study, stable carbon and nitrogen isotope analysis was conducted on grains from rice of heritage landraces and modern varieties grown in a glasshouse pot experiment with three watering levels and two manuring levels, and from recent rice fields in China and South Korea including paddy and dry conditions, and with variable manuring histories. The pot experiment results indicate that there is a negative correlation between the δ13C values and watering levels in one heritage accession and three modern accessions; in the remaining two heritage accessions and one modern accession, a similar trend in δ13C values is observed between watering levels. The rice field results show that, similarly, the δ13C values of rice from paddy fields were significantly lower than those from dry fields. The results from the pot experiment also indicate that both watering and manuring tend to increase the δ15N values of rice grains, while the field samples show that intensive manuring in initial growing seasons does not have a consistent effect on rice δ15N values. Overall, stable carbon and nitrogen isotope values of rice grains appear to be useful indicators of water status, with potential in combination to disentangle watering and manuring practices.

Stable isotopes are a core method for assessing crop growing conditions in different climatic and soil environments and, thereby, for understanding past agricultural practices. However, isotopic values in plants are altered depending on distinct forms of preservation, including degrees of charring. To investigate this issue in two cereals, common millet (Panicum miliaceum L.) and foxtail millet [Setaria italica (L.) P.Beauv.], we conducted experimental charring to address key questions in millet agriculture and archaeological grain preservation. The results of the experiment under relevant and controlled conditions of charring establish that the relevant temperatures for well-preserved millets occur between 230°C and 250°C and through short-term exposures of up to 6 h of charring. The data confirm that charring increases δ13CVPDB and δ15NAIR values in both common millet and foxtail millet. Husked grains had consistently lower δ13C values than huskless grains, indicating a differential effect of charring on husks and grains, whereas δ15N values are similar regardless of husks. Stable carbon isotope values are relatively similar in uncharred and charred grains, whereas the effects of charring on stable nitrogen isotope values are greater and need to be taken into account when interpreting the values of archaeological grains and palaeodietary analysis in conjunction with human and faunal values. This study significantly advances the understanding of the isotopic effects on archaeological charred grains of common and foxtail millet within their optimal heating preservation window.

Stable isotope analysis of plant remains recovered from archaeological sites is becoming more routine. There remains a lack of consensus, however, on how to appropriately select archaeological plant remains for isotopic analysis, how to account for differences in preservation and the effect of potential contamination, and how to interpret the measured isotope values in terms of the conditions in which the plants grew. In this paper, we outline the main issues to be considered when planning and conducting an isotopic study of archaeobotanical remains. These include: (1) setting out the research question(s) that will be answerable using available analytical approaches, (2) considering the archaeological context from which plant remains derive, (3) determining appropriate sample size through consideration of estimate precision, (4) establishing the conditions in which plant remains have been preserved and potential effects on their isotope values, and (5) accounting for possible contamination during deposition. With these issues in mind, we propose some recommendations for researchers to consider when planning and conducting an isotopic study of archaeobotanical remains.

Prostate cancer with a cribriform pattern, including invasive cribriform carcinoma (ICC) and/or intraductal carcinoma (IDC) is associated with a poor prognosis, and the underlying mechanisms are unclear. Therefore, we aimed to identify biomarkers for this feature. Using a radical prostatectomy cohort, we performed within-patient differential expression analyses with RNA sequencing data to compare samples with a cribriform pattern to those with non-cribriform Gleason pattern 4 (NcGP4; n=13). ACSM1, GRIN3A, PCDHB2, and REG4 were identified as differentially expressed, and validation was performed using real-time reverse transcription polymerase chain reaction (n=99; 321 RNA samples) and RNA in situ hybridization on tissue microarrays (n=479; 2047 tissue cores). GRIN3A was significantly higher expressed in cribriform pattern vs. NcGP4, when assessed within the same patient (n=27; p=0.005) and between different patients (n=83; p=0.001). Tissue cores with IDC more often expressed GRIN3A compared to ICC, NcGP4, and benign tissue (52 % vs. ≤ 32 %). When IDC and NcGP4 was compared within the same patient (173 pairs of tissue cores; 54 patients), 38 (22 %) of the tissue microarray core pairs had GRIN3A expression in only IDC, 33 (19 %) had expression in both IDC and NcGP4, 14 (8 %) in only NcGP4 and 88 (51 %) were negative in both entities (p=0.001). GRIN3A was as well associated with biochemical recurrence (log-rank, p=0.002). In conclusion, ectopic GRIN3A expression is an RNA-based biomarker for the presence of cribriform prostate cancer, particularly for IDC.

Abstract Objectives PD‐1/PD‐L1 immune checkpoint blockade can be an effective treatment for advanced breast cancer patients. However, patients with oestrogen receptor positive (ER+) tumors often display only low lymphocyte infiltration, while a large part of triple negative (TN) breast tumors does not generate an effective immunotherapy response. Therefore, new treatment strategies have to be developed. Here, we investigate Siglec‐7 and Siglec‐9 as novel ITIM‐bearing inhibitory immune checkpoint receptors similar to PD‐1, but expressed on a broader range of immune cells. Methods We assessed Siglec‐7 and Siglec‐9 (ligand) expression in TN and ER+ breast cancer tumors and their breast cancer cell line‐induced signalling. Results We report that Siglec‐7 and Siglec‐9 are highly expressed in TN tumors, and to a low extent in ER+ tumors. Siglec‐7 was observed on myeloid cells, T cells, and NK cells and Siglec‐9 preferentially on myeloid cells. Expression of sialoglycans, including Siglec‐7 and Siglec‐9 ligands, was observed in both TN and ER+ breast cancer tissue sections. Expression levels of Siglec‐7 and Siglec‐9 ligands were higher on in vitro cultured TN cell lines than ER+ cell lines. Importantly, by applying chimeric Siglec‐7 reporter cells, we showed the induction of Siglec‐7 signalling by multiple TN cell lines, but only by one ER+ cell line. Moreover, Siglec‐7 signalling is directly related to Siglec‐7 ligand expression levels of breast cancer cell lines. Conclusion These data imply that immunotherapy targeting Siglec receptors may be particularly interesting for TN breast cancer patients not responding to current treatment strategies with tumors displaying high immune cell infiltration.

BackgroundDrug-drug interactions (DDIs) may influence the effectiveness and safety of medication treatment, which may require additional monitoring, dose adjustment or avoidance of certain drugs. DDIs involving P-glycoprotein (P-gp) affect many drugs, but current official product information is often insufficient to guide the management of these DDIs in clinical practice. The aim of this paper is to describe a protocol to assess DDIs involving P-gp and to develop and implement practice recommendations for clinically relevant P-gp-mediated DDIs that affect clinical outcomes through changes in systemic drug exposure.MethodsA combined literature review and expert opinion approach will be used according to the following seven steps: set up an expert panel (step 1), establish core concepts and definitions (step 2), select potential P-gp-modulators (i.e., P-gp-inducers and -inhibitors) and P-gp-substrates to be evaluated (step 3), select and extract evidence-based data, and present findings in standardized assessment reports (step 4), discuss and adopt classifications and practice recommendations with the expert panel (step 5), publish and integrate information and alerts in clinical decision support systems (CDSS) (step 6), (re)assessments of DDIs and potential new DDIs when new information is available or when initiated by healthcare providers (step 7).Anticipated resultsThe expert panel will classify potential P-gp-modulators and -substrates as clinically relevant P-gp-inducer, -inhibitor and/or -substrate and draw conclusions about which combinations of classified modulators and substrates will lead to clinically relevant DDIs. This may include the extrapolation of conclusions for DDIs where limited or no data are available, based on the pharmacological characteristics of these drugs. For (potential) DDIs that are considered to be clinically relevant, practice recommendations will be developed.DiscussionThis protocol describes a standardized, evidence- and expert opinion-based assessment of P-gp-mediated DDIs that affect clinical outcomes. This approach will generate alerts with practice recommendations for clinically relevant DDIs and transparent rationales for DDIs that are considered to be irrelevant. These recommendations will improve individual patient care by supporting healthcare professionals to make consistent decisions on how to manage P-gp mediated DDIs.

To better understand the processes through which eating habits during childhood are carried over into adulthood, I asked the question: under what circumstances and through which patterns do the feeding behaviors of parents become replicated and emerge as habitual in their children during young adulthood? I aim to investigate how parenting style and parent behaviors surrounding food and diet influence children’s dietary habits in the long-term. Previous research indicates that income is a major factor determining parents’ feeding behavior, so I set out to combine income level and parent feeding style in one study. I hypothesized that young adults who recalled their parents engaging in behaviors associated with the authoritative parenting style would be most likely to replicate those eating behaviors as habit from childhood into young adulthood. To better understand the process through which these variables ultimately cultivated the dietary behaviors of the young adults I interviewed, I selected three dietary habits—presence of breakfast, moderation of added sugar intake, sufficient vegetable consumption—that have been associated with positive health outcomes. II observed several distinct patterns: (i) young adults who continue to eat breakfast had previously experienced a high level of engagement from their parents surrounding the meal during childhood; (ii) young adults whose parents engaged with their children’s added sugar intake were more likely to carry similar habits and attitudes related to sugar into young adulthood; (iii) many young adults experienced external factors which also initiated a significant transition towards healthier eating habits independent of their parents’ influence.

Background/objectives: A significant number of COVID-19 cases experience persistent symptoms after the acute infection phase, a condition known as long COVID or post-acute sequelae of COVID-19. Approved prevention and treatment options for long COVID are currently lacking. Given the heterogeneous nature of long COVID, a personalized medicine approach is essential for effective disease management. This study aimed to describe trends in pharmacotherapy from pre-COVID to post-COVID phases to gain insights into COVID-19 treatment strategies and assess whether pre-COVID pharmacotherapy can predict long COVID symptoms as a health status indicator. Methods: In the Precision Medicine for more Oxygen (P4O2) COVID-19 study, 95 long COVID patients were comprehensively evaluated through post-COVID outpatient clinics and study visits. This study focused on descriptive analysis of the pharmacotherapy patterns across different phases: pre-COVID-19, acute COVID, and post-COVID. Furthermore, associations between pre-COVID medication and long COVID outcomes were analyzed with regression analyses. Results: We observed peaks in the use of certain medications during the acute infection phase, including corticosteroids and antithrombotic agents, with a decrease in the use of renin–angiotensin system inhibitors. Consistently high use of alimentary tract medications was found across all phases. Pre-COVID respiratory medications were associated with fatigue symptoms, while antiinfectives and cardiovascular drugs were linked to fewer persisting long COVID symptom categories. Conclusion: Our findings provide longitudinal, descriptive pharmacotherapy insights and suggest that medication history can be a valuable health status indicator in characterizing patients for personalized disease management strategies, considering the heterogeneous nature of long COVID.

The Charles Sturt University (CSU) Engineering programme is a new course (degree programmme) established in 2016 by a university that had not previously taught engineering. This start from scratch occasion was taken as an opportunity to build an all-new programme structure and philosophy. Students at CSU Engineering complete a sequence of three semester-long Project-Based Learning (PBL) style challenges across their time face-to-face at the university; after this point, they commence four yearlong paid industry-based work placements and continue studies in an online mode during evenings, weekends, and scheduled study days. The underlying technical curriculum for the engineering programme at Charles Sturt University is delivered mostly on-line via the RealizeIT platform and is based on a philosophy of just-in-time, self-directed learning. Students have freedom in deciding when, how and, to a large extent, which elements of the curriculum they engage within the online environment. This freedom, along with the PBL-style challenges, is enabled by the structure of the technical curriculum which is broken down into fine-grained learning activities called 'topics'. In this paper, we summarise our experiences during the first four years, and the insights gained into student behaviours when offered an opportunity to engage in self-directed learning.

Slow-moving landslides move downslope at velocities that range from mm year−1 to m year−1. Such deformations can be measured using satellite-based synthetic aperture radar interferometry (InSAR). We developed a new method to systematically detect and quantify accelerations and decelerations of slowly deforming areas using InSAR displacement time series. The displacement time series are filtered using an outlier detector and subsequently piecewise linear functions are fitted to identify changes in the displacement rate (i.e., accelerations or decelerations). Grouped accelerations and decelerations are inventoried as indicators of potential unstable areas. We tested and refined our new method using a high-quality dataset from the Mud Creek landslide, CA, USA. Our method detects accelerations and decelerations that coincide with those previously detected by manual examination. Second, we tested our method in the region around the Mazar dam and reservoir in Southeast Ecuador, where the time series data were of considerably lower quality. We detected accelerations and decelerations occurring during the entire study period near and upslope of the reservoir. Application of our method results in a wealth of information on the dynamics of the surface displacement of hillslopes and provides an objective way to identify changes in displacement rates. The displacement rates, their spatial variation, and the timing of accelerations and decelerations can be used to study the physical behavior of a slow-moving slope or for regional hazard assessment by linking the timing of changes in displacement rates to landslide causal and triggering factors.