The interaction of helminth infections with type 2 diabetes (T2D) has been a major area of research in the past few years. This paper, therefore, focuses on the systematic review of the effects of helminthic infections on metabolism and immune regulation related to T2D, with mechanisms through which both direct and indirect effects are mediated. Specifically, the possible therapeutic role of helminths in T2D management, probably mediated through the modulation of host metabolic pathways and immune responses, is of special interest. This paper discusses the current possibilities for translating helminth therapy from basic laboratory research to clinical application, as well as existing and future challenges. Although preliminary studies suggest the potential for helminth therapy for T2D patients, their safety and efficacy still need to be confirmed by larger-scale clinical studies.

Background: The combination of PARP inhibitor and immune checkpoint inhibitors have been proposed as a potentially synergistic combinatorial treatment in IDH mutant glioma, targeting dysregulated homologous recombination repair pathways. This study analyzed the cell-free DNA methylome of patients in a phase 2 trial using the PARP inhibitor Olaparib and the PD-1 inhibitor Durvalumab. Methods: Patients with recurrent high-grade IDH-mutant gliomas were enrolled in a phase II open-label study (NCT03991832). Serum was collected at baseline and monthly and cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed. Binomial GLMnet models were developed and model performance was assessed using validation set data. Results: 29 patients were enrolled between 2020–2023. Patients received olaparib 300mg twice daily and durvalumab 1500mg IV every 4 weeks. The overall response rate was 10% via RANO criteria. 144 plasma samples were profiled with cfMeDIP-seq along with 30 healthy controls. The enriched circulating tumour DNA methylome during response periods exhibited a highly specific signature, accurately discriminating response versus failure (AUC 0.98 ± 0.03). Additionally, samples that were taken while on treatment were able to be discriminated from samples off therapy (AUC 0.74 ± 0.11). Conclusions: The cell-free plasma DNA methylome exhibits highly specific signatures that enable accurate prediction of response to therapy.

Background: Treatment of aneurysmal subarachnoid hemorrhage (aSAH) in a high-volume center by experienced cerebrovascular and neuroendovascular surgeons improves outcomes. We studied whether rural aSAH patients experience treatment delays in British Columbia. Methods: Vancouver Ruptured Aneurysm Database (VRAD) started in 2023 to prospectively capture consecutive aSAH patients at Vancouver General Hospital (VGH), an academic neurosurgical hospital with comprehensive stroke center capabilities. We included patients ≥18 years-old, presenting ≤72h post-ictus and excluded untreated aneurysms and patients not residing in British Columbia. Patients were classified as rural or urban using the provincial government categorization of rurality. Results: We included 84 patients, 65.5% urban and 34.5% rural, with mean age 57.7 years (SD: 15.6) and 64.3% female. Aneurysm treatment consisted of 75% microsurgical clipping and 25% endovascular techniques. Median time from ictus to VGH was 5.9h [IQR: 2.6-16.6] urban and 13.2h [IQR: 8.3-27.8] rural, p=0.001. Median transfer time was 4.7h [IQR: 2.5-8.8] urban and 11.9h [IQR: 6.7-13.5] rural, p=0.006. Ictus to treatment time was 5.9h longer for rural patients, p=0.077. Conclusions: Rural aSAH patients in British Columbia take 7.3 hours longer to reach a neurosurgical center capable of comprehensive aneurysm treatment compared to urban patients. Improved inter-hospital transfer systems may reduce geographic disparities for aSAH in British Columbia.

Multicenter clinical trials are essential for evaluating interventions but often face significant challenges in study design, site coordination, participant recruitment, and regulatory compliance. To address these issues, the National Institutes of Health’s National Center for Advancing Translational Sciences established the Trial Innovation Network (TIN). The TIN offers a scientific consultation process, providing access to clinical trial and disease experts who provide input and recommendations throughout the trial’s duration, at no cost to investigators. This approach aims to improve trial design, accelerate implementation, foster interdisciplinary teamwork, and spur innovations that enhance multicenter trial quality and efficiency. The TIN leverages resources of the Clinical and Translational Science Awards (CTSA) program, complementing local capabilities at the investigator’s institution. The Initial Consultation process focuses on the study’s scientific premise, design, site development, recruitment and retention strategies, funding feasibility, and other support areas. As of 6/1/2024, the TIN has provided 431 Initial Consultations to increase efficiency and accelerate trial implementation by delivering customized support and tailored recommendations. Across a range of clinical trials, the TIN has developed standardized, streamlined, and adaptable processes. We describe these processes, provide operational metrics, and include a set of lessons learned for consideration by other trial support and innovation networks.

The outer solar system is theoretically predicted to harbour an undiscovered planet, often referred to as Planet Nine. Simulations suggest that its gravitational influence could explain the unusual clustering of minor bodies in the Kuiper Belt. However, no observational evidence for Planet Nine has been found so far, as its predicted orbit lies far beyond Neptune, where it reflects only a faint amount of Sunlight. This work aims to find Planet Nine candidates by taking advantage of two far-infrared all-sky surveys, which are IRAS and AKARI. The epochs of these two surveys were separated by 23 years, which is large enough to detect Planet Nine’s $\sim3'$/year orbital motion. We use a dedicated AKARI Far-Infrared point source list for the purpose of our Planet Nine search — AKARI-FIS Monthly Unconfirmed Source List (AKARI-MUSL), which includes sources detected repeatedly only in hours timescale, but not after months. AKARI-MUSL is more advantageous than the AKARI Bright Source Catalogue (AKARI-BSC) for detecting moving and faint objects like Planet Nine with a twice-deeper flux detection limit. We search for objects that moved slowly between IRAS and AKARI detections given in the catalogues. First, we estimated the expected flux and orbital motion of Planet Nine by assuming its mass, distance, and effective temperature to ensure it can be detected by IRAS and AKARI, then applied the positional and flux selection criteria to narrow down the number of sources from the catalogues. Next, we produced all possible candidate pairs including one IRAS source and one AKARI source whose angular separations were limited between 42′ and $69.6'$, corresponding to the heliocentric distance range of 500 – 700 AU and the mass range of 7 – 17M$_{\oplus}$. There are 13 candidate pairs obtained after the selection criteria. After image inspection, we found one good candidate, of which the IRAS source is absent from the same coordinate in the AKARI image after 23 years and vice versa. However, AKARI and IRAS detections are not enough to determine the full orbit of this candidate. This issue leads to the need for follow-up observations, which will determine the Keplerian motion of our Planet Nine candidate.

An unusual orbital element clustering of Kuiper belt objects (KBOs) has been observed. The most promising dynamic solution is the presence of a giant planet in the outer Solar system, Planet Nine. However, due to its extreme distance, intensive searches in optical have not been successful. We aim to find Planet Nine in the far-infrared, where it has the peak of the black body radiation, using the most sensitive all-sky far-infrared survey to date, AKARI. In contrast to optical searches, where the energy of reflected sunlight decreases by $d^{4}$, thermal radiation in the infrared decreases with the square of the heliocentric distance $d^{2}$. We search for moving objects in the AKARI Single Scan Detection List. We select sources from a promising region suggested by an N-body simulation from Millholland and Laughlin 2017: $30^{\circ}\lt$ R.A. $\lt50^{\circ}$ and $-20^{\circ}\lt$ Dec. $\lt20^{\circ}$. Known sources are excluded by cross-matching AKARI sources with 9 optical and infrared catalogues. Furthermore, we select sources with small background strength to avoid sources in the cirrus. Since Planet Nine is stationary in a timescale of hours but moves on a monthly scale, our primary strategy is to select slowly moving objects that are stationary in 24 h but not in six months, using multiple single scans by AKARI. The selected slowly moving AKARI sources are scrutinised for potential contamination from cosmic rays. Our analysis reveals two possible Planet Nine candidates whose positions and flux are within the theoretical prediction ranges. These candidates warrant further investigation through follow-up observations to confirm the existence and properties of Planet Nine.

Objectives/Goals: Mathematical models of airborne virus transmission lack supporting field and clinical data such as viral aerosol emission rates and airborne infectious doses. Here, we aim to measure inhalation exposure to influenza aerosols in a room shared with persons with community-acquired influenza and estimate the infectious dose via inhalation. Methods/Study Population: We recruited healthy volunteer recipients and influenza donors with polymerase chain reaction (PCR)-confirmed community-acquired infection. On admission to a hotel quarantine, recipients provided sera to determine baseline immunity to influenza virus, and donor infections were confirmed by quantitative real-time polymerase chain reaction. Donors and recipients were housed in separate rooms and interacted in an “event room” with controlled ventilation (0.2 – 0.5 air changes/hour) and relative humidity (20–40%). We collected ambient bioaerosol exposure samples using NIOSH BC-251 samplers. Donors provided exhaled breath samples collected by a Gesundheit-II (G-II). We analyzed aerosol samples using dPCR and fluorescent focus assays for influenza A and sera by hemagglutinin inhibition assay (HAI) against donor viruses and vaccine strains. Results/Anticipated Results: Among two cohorts (24b and 24c), we exposed 11 recipients (mean age: 36; 55% female) to 5 donors (mean age: 21; 80% female) infected with influenza A H1N1 or H3N2. Eight G-II and two NIOSH bioaerosol samples (1–4 µm and ≥4 µm) were PCR positive. We cultured virus from one G-II sample. Based on previous literature, we hypothesized that ~50% of immunologically naïve people (HAI Discussion/Significance of Impact: We demonstrated that it is feasible to recruit donors with community-acquired influenza and expose recipients to measurable virus quantities under controlled conditions. However, baseline immunity was high among volunteers. Our work sets the stage for designing studies with increased sample sizes comprising immunologically naïve volunteers.

Brown dwarfs are failed stars with very low mass (13–75 Jupiter mass) and an effective temperature lower than 2 500 K. Their mass range is between Jupiter and red dwarfs. Thus, they play a key role in understanding the gap in the mass function between stars and planets. However, due to their faint nature, previous searches are inevitably limited to the solar neighbourhood (20 pc). To improve our knowledge of the low mass part of the initial stellar mass function and the star formation history of the Milky Way, it is crucial to find more distant brown dwarfs. Using James Webb Space Telescope (JWST) COSMOS-Web data, this study seeks to enhance our comprehension of the physical characteristics of brown dwarfs situated at a distance of kpc scale. The exceptional sensitivity of the JWST enables the detection of brown dwarfs that are up to 100 times more distant than those discovered in the earlier all-sky infrared surveys. The large area coverage of the JWST COSMOS-Web survey allows us to find more distant brown dwarfs than earlier JWST studies with smaller area coverages. To capture prominent water absorption features around 2.7 ${\unicode{x03BC}}$m, we apply two colour criteria, $\text{F115W}-\text{F277W}+1\lt\text{F277W}-\text{F444W}$ and $\text{F277W}-\text{F444W}\gt\,0.9$. We then select point sources by CLASS_STAR, FLUX_RADIUS, and SPREAD_MODEL criteria. Faint sources are visually checked to exclude possibly extended sources. We conduct SED fitting and MCMC simulations to determine their physical properties and associated uncertainties. Our search reveals 25 T-dwarf candidates and 2 Y-dwarf candidates, more than any previous JWST brown dwarf searches. They are located from 0.3 to 4 kpc away from the Earth. The spatial number density of 900–1 050 K dwarf is $(2.0\pm0.9) \times10^{-6}\text{ pc}^{-3}$, 1 050–1 200 K dwarf is $(1.2\pm0.7) \times10^{-6}\text{ pc}^{-3}$, and 1 200–1 350 K dwarf is $(4.4\pm1.3) \times10^{-6}\text{ pc}^{-3}$. The cumulative number count of our brown dwarf candidates is consistent with the prediction from a standard double exponential model. Three of our brown dwarf candidates were detected by HST, with transverse velocities $12\pm5$, $12\pm4$, and $17\pm6$ km s$^{-1}$. Along with earlier studies, the JWST has opened a new window of brown dwarf research in the Milky Way thick disk and halo.

Procurement auctions carry substantial risk when the value of the project is highly uncertain and known only to insiders. This paper reports the results from a series of experiments comparing the performance of three auction formats in such complex and risky settings. In the experiment, every bidder knows the private value for the project but only a single insider bidder knows the common-value part. In addition to the standard second-price and English auctions we test the “qualifying auction,” a two-stage format commonly used in the sale of complex and risky assets. The qualifying auction has a fully “revealing” equilibrium that implements the revenue-maximizing outcome but it also has an uninformative “babbling” equilibrium in which bidders place arbitrarily high bids in the first stage. In the experiments, the latter equilibrium has more drawing power, which causes the qualifying auction to perform worse than the English auction and only slightly better than a sealed-bid second-price auction. Compared to the two other formats, the English auction is roughly 40% more efficient, yields 50% more revenues, avoids windfall profits for the insider, while protecting uninformed bidders from losses.

We propose a two-way Bayesian vector spatial procedure incorporating dimension reparameterization with a variable selection option to determine the dimensionality and simultaneously identify the significant covariates that help interpret the derived dimensions in the joint space map. We discuss how we solve identifiability problems in a Bayesian context that are associated with the two-way vector spatial model, and demonstrate through a simulation study how our proposed model outperforms a popular benchmark model. In addition, an empirical application dealing with consumers’ ratings of large sport utility vehicles is presented to illustrate the proposed methodology. We are able to obtain interpretable and managerially insightful results from our proposed model with variable selection in comparison with the benchmark model.

A new Bayesian multinomial probit model is proposed for the analysis of panel choice data. Using a parameter expansion technique, we are able to devise a Markov Chain Monte Carlo algorithm to compute our Bayesian estimates efficiently. We also show that the proposed procedure enables the estimation of individual level coefficients for the single-period multinomial probit model even when the available prior information is vague. We apply our new procedure to consumer purchase data and reanalyze a well-known scanner panel dataset that reveals new substantive insights. In addition, we delineate a number of advantageous features of our proposed procedure over several benchmark models. Finally, through a simulation analysis employing a fractional factorial design, we demonstrate that the results from our proposed model are quite robust with respect to differing factors across various conditions.

Metabolic enzymes are the catalysts that drive the biochemical reactions essential for sustaining life. Many of these enzymes are tightly regulated by feedback mechanisms. To fully understand their roles and modulation, it is crucial to investigate the relationship between their structure, catalytic mechanism, and function. In this perspective, by using three examples from our studies on Mycobacterium tuberculosis (Mtb) isocitrate lyase and related proteins, we highlight how an integrated approach combining structural, activity, and biophysical data provides insights into their biological functions. These examples underscore the importance of employing fast-fail experiments at the early stages of a research project, emphasise the value of complementary techniques in validating findings, and demonstrate how in vitro data combined with chemical, biochemical, and physiological knowledge can lead to a broader understanding of metabolic adaptations in pathogenic bacteria. Finally, we address the unexplored questions in Mtb metabolism and discuss how we expand our approach to include microbiological and bioanalytical techniques to further our understanding. Such an integrated and interdisciplinary strategy has the potential to uncover novel regulatory mechanisms and identify new therapeutic opportunities for the eradication of tuberculosis. The approach can also be broadly applied to investigate other biochemical networks and complex biological systems.

There is a relative lack of research, targeted models and tools to manage beaches in estuaries and bays (BEBs). Many estuaries and bays have been highly modified and urbanised, for example port developments and coastal revetments. This paper outlines the complications and opportunities for conserving and managing BEBs in modified estuaries. To do this, we focus on eight diverse case studies from North and South America, Asia, Europe, Africa and Australia combined with the broader global literature. Our key findings are as follows: (1) BEBs are diverse and exist under a great variety of tide and wave conditions that differentiate them from open-coast beaches; (2) BEBs often lack statutory protection and many have already been sacrificed to development; (3) BEBs lack specific management tools and are often managed using tools developed for open-coast beaches; and (4) BEBs have the potential to become important in “nature-based” management solutions. We set the future research agenda for BEBs, which should include broadening research to include greater diversity of BEBs than in the past, standardising monitoring techniques, including the development of global databases using citizen science and developing specific management tools for BEBs. We must recognise BEBs as unique coastal features and develop the required fundamental knowledge and tools to effectively manage them, so they can continue providing their unique ecosystem services.

Background: Primary central nervous system lymphoma (PCNSL) is highly sensitive to corticosteroid induced cell arrest, apoptosis and shrinkage. However, the precise impact of preoperative corticosteroid on accuracy of PCNSL diagnosis using tissue obtained from open or stereotactic biopsies remains debated. Methods: We conducted a systematic review and meta-analysis to determine the effect of preoperative corticosteroids on non-diagnostic biopsy rates for PCNSL in immunocompetent adults. Subgroup analyses explored whether non-diagnostic rates varied based on biopsy type. Results: Nineteen studies, comprising 1226 patients (55% male; mean age: 60.3 years), of which 679 (55.4%) received corticosteroids prior to biopsy were included. Overall, patients pretreated with corticosteroids were two times more likely to have a non-diagnostic biopsy compared to patients that were corticosteroid-naïve prior to biopsy (RR = 2.1 [95% CI: 1.1-4.1]). In the subgroup analysis limited to stereotactic biopsies, patient pretreated with corticosteroids were three times more likely to have a non-diagnostic biopsy (RR = 3.0 [95% CI: 1.2-7.5]). Whereas, in the open biopsy subgroup, there was no significant difference in non-diagnostic rates. Conclusions: Corticosteroids should be withheld, if clinically safe, prior to stereotactic biopsies in cases of suspected PCNSL. If corticosteroids are administered preoperatively, an open biopsy should be considered instead of stereotactic biopsy.