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.

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.

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.

This study investigates the effect of a transverse magnetic field on high-voltage pulsed discharge in helium at a pressure of 30 Torr. A simple two-dimensional fluid model that describes the high-voltage pulsed discharge in helium in a transverse weak magnetic field (B = 0.4 T) is presented, which uses an empirical relation to account for the magnetic field. The results of using the empirical relation for the effective field agree well with the experimental results. The dynamics of discharge development in the presence of the magnetic field is also investigated. The magnetic field does not significantly affect the gas-discharge development dynamics in helium at a pressure of 30 Torr.

Enteric bacterial infections are common among people who travel internationally. During 2017–2020, the Centers for Disease Control and Prevention investigated 41 multistate outbreaks of nontyphoidal Salmonella and Shiga toxin-producing Escherichia coli linked to international travel. Resistance to one or more antimicrobial agents was detected in at least 10% of isolates in 16 of 30 (53%) nontyphoidal Salmonella outbreaks and 8 of 11 (73%) Shiga toxin-producing E. coli outbreaks evaluated by the National Antimicrobial Resistance Monitoring System. At least 10% of the isolates in 14 nontyphoidal Salmonella outbreaks conferred resistance to one or more of the clinically significant antimicrobials used in human medicine. This report describes the epidemiology and antimicrobial resistance patterns of these travel-associated multistate outbreaks. Investigating illnesses among returned travellers and collaboration with international partners could result in the implementation of public health interventions to improve hygiene practices and food safety standards and to prevent illness and spread of multidrug-resistant organisms domestically and internationally.

Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14 gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300 range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14 RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14 represents one of the most common genetic causes of LOCA uncovered to date.

Consumption of unpasteurised milk in the United States has presented a public health challenge for decades because of the increased risk of pathogen transmission causing illness outbreaks. We analysed Foodborne Disease Outbreak Surveillance System data to characterise unpasteurised milk outbreaks. Using Poisson and negative binomial regression, we compared the number of outbreaks and outbreak-associated illnesses between jurisdictions grouped by legal status of unpasteurised milk sale based on a May 2019 survey of state laws. During 2013–2018, 75 outbreaks with 675 illnesses occurred that were linked to unpasteurised milk; of these, 325 illnesses (48%) were among people aged 0–19 years. Of 74 single-state outbreaks, 58 (78%) occurred in states where the sale of unpasteurised milk was expressly allowed. Compared with jurisdictions where retail sales were prohibited (n = 24), those where sales were expressly allowed (n = 27) were estimated to have 3.2 (95% CI 1.4–7.6) times greater number of outbreaks; of these, jurisdictions where sale was allowed in retail stores (n = 14) had 3.6 (95% CI 1.3–9.6) times greater number of outbreaks compared with those where sale was allowed on-farm only (n = 13). This study supports findings of previously published reports indicating that state laws resulting in increased availability of unpasteurised milk are associated with more outbreak-associated illnesses and outbreaks.

The goal for many PhD students in archaeology is tenure-track employment. Students primarily receive their training by tenure-track or tenured professors, and they are often tacitly expected—or explicitly encouraged—to follow in the footsteps of their advisor. However, the career trajectories that current and recent PhD students follow may hold little resemblance to the ones experienced by their advisors. To understand these different paths and to provide information for current PhD students considering pursuing a career in academia, we surveyed 438 archaeologists holding tenured or tenure-track positions in the United States. The survey, recorded in 2019, posed a variety of questions regarding the personal experiences of individual professors. The results are binned by the decade in which the respondent graduated. Evident patterns are discussed in terms of change over time. The resulting portraits of academic pathways through the past five decades indicate that although broad commonalities exist in the qualifications of early career academics, there is no singular pathway to obtaining tenure-track employment. We highlight the commonalities revealed in our survey to provide a set of general qualifications that might provide a baseline set of skills and experiences for an archaeologist seeking a tenure-track job in the United States.

The incidence of scarlet fever has increased dramatically in recent years in Chongqing, China, but there has no effective method to forecast it. This study aimed to develop a forecasting model of the incidence of scarlet fever using a seasonal autoregressive integrated moving average (SARIMA) model. Monthly scarlet fever data between 2011 and 2019 in Chongqing, China were retrieved from the Notifiable Infectious Disease Surveillance System. From 2011 to 2019, a total of 5073 scarlet fever cases were reported in Chongqing, the male-to-female ratio was 1.44:1, children aged 3–9 years old accounted for 81.86% of the cases, while 42.70 and 42.58% of the reported cases were students and kindergarten children, respectively. The data from 2011 to 2018 were used to fit a SARIMA model and data in 2019 were used to validate the model. The normalised Bayesian information criterion (BIC), the coefficient of determination (R2) and the root mean squared error (RMSE) were used to evaluate the goodness-of-fit of the fitted model. The optimal SARIMA model was identified as (3, 1, 3) (3, 1, 0)12. The RMSE and mean absolute per cent error (MAPE) were used to assess the accuracy of the model. The RMSE and MAPE of the predicted values were 19.40 and 0.25 respectively, indicating that the predicted values matched the observed values reasonably well. Taken together, the SARIMA model could be employed to forecast scarlet fever incidence trend, providing support for scarlet fever control and prevention.