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Abstract Background Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain. Methods We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and our models, quantified purine synthesis using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT. Results DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and apparent lower activity of purine salvage demonstrated via stable isotope tracing of key metabolites in purine synthesis and by lower expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the rate-limiting enzyme of purine salvage into IMP and GMP. Inhibition of de novo guanylate synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells upregulated HGPRT expression and hypoxanthine-derived guanylate salvage but maintained high levels of guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization in cells treated with combination RT and de novo purine synthesis inhibition. Silencing HGPRT combined with RT markedly suppressed DMG-H3K27M tumor growth in vivo. Conclusions Our results indicate that DMG-H3K27M cells rely on highly active purine synthesis, both from the de novo and salvage synthesis pathways. However, highly active salvage of free purine bases into mature guanylates can bypass inhibition of the de novo synthetic pathway. We conclude that inhibiting purine salvage may be a promising strategy to overcome treatment resistance in DMG-H3K27M tumors.

Abstract Objective Alzheimer's disease neuropathologic change and alpha‐synucleinopathy commonly co‐exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta‐amyloid compared to alpha‐synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia. Methods We used digital histology to measure percent area‐occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha‐synucleinopathy, and a co‐pathology group with both Alzheimer's and alpha‐synuclein pathologic diagnoses. Multiple tau monoclonal antibodies were used to detect early (AT8, MC1) and mature (TauC3) epitopes of tangle progression. We used linear/logistic regression to compare groups and test the association between pathologies and clinical features. Results There were lower levels of tau pathology (β = 1.86–2.96, p

Abstract Purpose Percentage of positive cores involved on a systemic prostate biopsy has been established as a risk factor for adverse oncologic outcomes and is a National Comprehensive Cancer Network (NCCN) independent parameter for unfavorable intermediate-risk disease. Most data from a radiation standpoint was published in an era of conventional fractionation. We explore whether the higher biological dose delivered with SBRT can mitigate this risk factor. Methods A large single institutional database was interrogated to identify all patients diagnosed with localized prostate cancer (PCa) treated with 5-fraction SBRT without ADT. Pathology results were reviewed to determine detailed core involvement as well as Gleason score (GS). High-volume biopsy core involvement was defined as ≥ 50%. Weighted Gleason core involvement was reviewed, giving higher weight to higher-grade cancer. The PSA kinetics and oncologic outcomes were analyzed for association with core involvement. Results From 2009 to 2018, 1590 patients were identified who underwent SBRT for localized PCa. High-volume core involvement was a relatively rare event observed in 19% of our cohort, which was observed more in patients with small prostates (p

Objective: The effects of Coronavirus disease 2019 (COVID-19) infection and altered processes of care on nonelective coronary artery bypass grafting (CABG) outcomes remain unknown. We hypothesized that patients with COVID-19 infection would have longer hospital lengths of stay and greater mortality compared with COVID-negative patients, but that these outcomes would not differ between COVID-negative and pre-COVID controls. Methods: The National COVID Cohort Collaborative 2020-2022 was queried for adult patients undergoing CABG. Patients were divided into COVID-negative, COVID-active, and COVID-convalescent groups. Pre-COVID control patients were drawn from the National Surgical Quality Improvement Program database. Adjusted analysis of the 3 COVID groups was performed via generalized linear models. Results: A total of 17,293 patients underwent nonelective CABG, including 16,252 COVID-negative, 127 COVID-active, 367 COVID-convalescent, and 2254 pre-COVID patients. Compared to pre-COVID patients, COVID-negative patients had no difference in mortality, whereas COVID-active patients experienced increased mortality. Mortality and pneumonia were higher in COVID-active patients compared to COVID-negative and COVID-convalescent patients. Adjusted analysis demonstrated that COVID-active patients had higher in-hospital mortality, 30- and 90-day mortality, and pneumonia compared to COVID-negative patients. COVID-convalescent patients had a shorter length of stay but a higher rate of renal impairment. Conclusions: Traditional care processes were altered during the COVID-19 pandemic. Our data show that nonelective CABG in patients with active COVID-19 is associated with significantly increased rates of mortality and pneumonia. The equivalent mortality in COVID-negative and pre-COVID patients suggests that pandemic-associated changes in processes of care did not impact CABG outcomes. Additional research into optimal timing of CABG after COVID infection is warranted.

Background: Training programs for advanced practice providers (APP) often have significant variability in their curriculum, including electrocardiogram (ECG) education. Despite limitations in formal ECG training, APPs in the emergency department (ED) may be the first practitioner to interpret an ECG. Foundations of Emergency Medicine (FoEM) offers free, open-access curricula that are widely used for resident education. We sought to improve APP ECG interpretation skills by implementing the FoEM ECG I course. Methods: This was a single-site, pre- and post-intervention study of 23 APPs at our high-acuity, urban ED. In the fall of 2020, APP learners enrolled in a FoEM ECG I course led by faculty and senior resident instructors. The course consisted of six virtual, small-group, active-learning ECG workshops. Participants completed a 15-question multiple-choice test before, immediately after, and six months post-intervention to quantify knowledge acquisition. Additionally, a pre- and post-intervention knowledge, attitudes, and practices survey was administered on ECG interpretation skills and to evaluate the course. We evaluated change in ECG knowledge scores using a Wilcoxon signed-rank test. Changes in self-assessed knowledge were evaluated using an ordinal logistic mixed-effects regression. Results: A total of 23 APPs enrolled in the course. Knowledge assessments showed APPs improved from the pre-test (median 9/15, interquartile range [IQR] 7–11) to the post-test (median 12/15, IQR 10–13; P = 0.001). Test scores did not significantly change from the post-test to the delayed post-test (median 12/15, IQR 12–13; P = 0.30). Respondents’ subjective rating of their skill did not significantly change (P = 0.06). Respondents reported no change in their likelihood of approaching an attending when uncertain of the correct interpretation of an ECG (P = 0.16). Overall, 91% were satisfied with the course and 96% agreed that the course difficulty was appropriate. Conclusion: The FoEM ECG course provided a standardized curriculum that improved APP knowledge for interpreting ECGs. Despite this, the course did not alter APPs’ willingness to approach physicians for guidance with interpretation of abnormal ECGs. These findings may inform expansion of this concept for other programs who desire formalized APP ECG education.

Abstract Ponds are globally abundant and important to the global carbon cycle. Although ponds have large greenhouse gas emissions, they also sequester carbon in their sediments. Here, we studied organic carbon (OC) burial rates in 22 temperate experimental ponds with negligible watersheds, where carbon sequestration derives solely from autochthonous primary production. The ponds were built identically in 1964 and have since experienced different management strategies, allowing us to test how management actions influence burial rates. On average, the ponds accumulated 67.1 g OC m−2 yr−1 (range 38.3–113.6 g OC m−2 yr−1)—about double the global average burial rate for lakes and similar to global averages for wetlands. Carbon burial rates were higher in ponds with macrophytes, fish, and higher N : P loads. We contend that the global carbon sink for inland waters may be substantially underestimated due to the undervaluation of OC burial in natural and artificial ponds.

Objective: To describe the creation of a scalable framework for a Remote Patient Monitoring (RPM) program tied to a large medical practice. Patients and Methods: In July 2020, at Mayo Clinic Rochester, we initiated the process to combine human-centered design, health systems engineering, and clinical expertise to develop and refine RPM programs and explore new medical conditions where RPM could be beneficial. We report on the creation of the overarching RPM program, the development of a hybrid nursing model, the technology used for each population, and the lessons learned throughout the process. Results: Four pilot programs for hospitalized patients with cirrhosis, acute kidney injury (AKI), post-pancreatectomy, and post-gastroenterology (GI) procedures were launched. The 4 programs enrolled a range from 0 patients (post-GI procedures) to 91 patients over 5 months (AKI) for RPM programs ranging from 30 days to 96.5 days in average duration. Three of the programs continue enrollment (cirrhosis, AKI, and post-pancreatectomy), and one program was discontinued. Conclusion: RPM can uniquely facilitate the transition from hospital to home, decrease hospital length of stay, and optimize hospital capacity and staffing resources in select scenarios. To achieve positive results at the health care system level, RPM interventions require a change in the model of care. However, not all care models or medical conditions lend themselves to RPM, which should be explored in pilot testing.

ABSTRACT: Objectives: To report the in vitro susceptibility of Enterobacterales (n = 3905) and Pseudomonas aeruginosa (n = 1,109) isolates, collected from patients in sub-Saharan Africa (four countries) in 2017–2021, to a panel of 10 antimicrobial agents with a focus on ceftazidime-avibactam activity against resistant phenotypes and β-lactamase carriers. Methods: MICs were determined by CLSI broth microdilution and interpreted using both 2022 CLSI and EUCAST breakpoints. β-lactamase genes were identified in select β-lactam-nonsusceptible isolate subsets using multiplex PCR assays. Results: Among Enterobacterales, 96.2% of all isolates were ceftazidime-avibactam-susceptible (MIC90, 0.5 µg/mL), including all serine carbapenemase-positive (n = 127), 99.6% of ESBL-positive, carbapenemase-negative (n = 730), 91.9% of multidrug resistant (MDR; n = 1817), and 42.7% of DTR (difficult-to-treat resistance; n = 171) isolates. Metallo-β-lactamase (MBL) genes were identified in most (n = 136; 91.2%) ceftazidime-avibactam-resistant isolates (3.5% of all Enterobacterales isolates). Ceftazidime-avibactam percent susceptible values ranged from 99.5% (Klebsiella species other than Klebsiella pneumoniae) to 92.5% (K. pneumoniae) for the various Enterobacterial taxa examined. Greater than 90% of Enterobacterales isolates from each country (Cameroon, Ivory Coast, Nigeria, South Africa) were ceftazidime-avibactam-susceptible. Among P. aeruginosa, 88.9% of all isolates were ceftazidime-avibactam-susceptible (MIC90, 16 µg/mL). Most (88.5%) MBL-negative, meropenem-resistant (n = 78), 68.1% of MDR (n = 385), and 19.2% of DTR isolates (n = 99) were ceftazidime-avibactam-susceptible. MBL genes were identified in 43.1% of ceftazidime-avibactam-resistant isolates (n = 53; 4.8% of all P. aeruginosa isolates). Country-specific ceftazidime-avibactam percent susceptible values for P. aeruginosa ranged from 94.1% (Cameroon) to 76.2% (Nigeria). Conclusion: Reference in vitro antimicrobial susceptibility testing demonstrated that most recent Enterobacterales (96%) and P. aeruginosa (89%) clinical isolates from four sub-Saharan African countries were ceftazidime-avibactam susceptible.

AbstractPurpose Uterine serous carcinoma (USC) exhibits worse survival rates compared to the endometrioid subtype, and there is currently no effective treatment options for recurrence of this disease after platinum-based chemotherapy. Activation of PIK3CA/AKT/mTOR signaling pathway is a common biological feature in USC.Materials and Methods Ipatasertib (IPAT) is an investigational, orally administered, ATP-competitive, highly selective inhibitor of pan AKT that has demonstrated anti-proliferative activity in a variety of tumor cells and tumor models. In this study, we used IPAT, carboplatin and their combination to investigate the anti-tumor activity in SPEC-2 and ARK-1 cells.Results Our results indicate that IPAT combined with carboplatin at low doses was more effective at reducing proliferation, inducing apoptosis and causing cellular stress than IPAT or carboplatin alone. In particular, inhibition of the PIK3CA/AKT/mTOR pathway and induction of DNA damage were involved in the synergistic inhibition by combination treatment of cell viability in USC cells treated with the combination. Furthermore, IPAT in combination with carboplatin significantly reduced cell adhesion and inhibited cell invasion.Conclusions These findings suggest that the combination of IPAT and carboplatin has potential clinical implications for developing new USC treatment strategies.

ObjectiveTo determine if a single brain biopsy utilizing a freeze-core needle harvest system Cassi II under ultrasound guidance provides a diagnostic sample; to evaluate the technique's efficacy in procuring diagnostic samples in comparison with “open” surgical biopsies; and to describe intraoperative complications associated with the technique.Study designExperimental clinical study.AnimalsSeventeen dogs and four cats with magnetic resonance imaging (MRI) diagnoses of readily surgically accessible intracranial masses.MethodsImmediately prior to surgical biopsy (SB), freeze-core biopsy (FCB) sample was obtained from each patient under ultrasound guidance.ResultsHistopathology results from single FCB samples were found to be in 100% agreement with the SB samples. Freezing artifact was minimal and did not interfere with histopathologic interpretation. There were no intraoperative complications specifically attributable to the use of the FCB system.ConclusionBased on the results of this small experimental study, the FCB system is expected to safely yield diagnostic quality intracranial masses biopsy specimens.Clinical significanceThis system has the potential of obtaining diagnostic biopsies of more deeply seated brain lesions (i.e., intra-axial tumors considered inaccessible or with large risks/difficulties by standard surgical means) which would provide a definitive diagnosis to guide appropriate therapy.

Introduction: Opioid overprescribing may fuel the opioid epidemic and increase the risk of complications of opioid misuse. This study examined trends and determinants of chronic and heavy opioid use among elderly community dwellers in the U.S. Methods: Medicare Current Beneficiary Surveys data from 2006 to 2019 were used. Common opioid medications were identified in the prescription medication files (n=47,264). Patients with Chronic users were defined as those receiving 6 or more opioid prescriptions within a year or on medication for 3 or more months, and heavy users were those having an average daily dose of 90 or more morphine milligram equivalents or 3,780 morphine milligram equivalents or more per continuous treatment episode. Results: One in 6 elderly community dwellers ever used opioids during the study period. Chronic users were more likely to be women than men (68.9% vs 31.1%, p

Introduction Traditional survey-based surveillance is costly, limited in its ability to distinguish diabetes types and time-consuming, resulting in reporting delays. The Diabetes in Children, Adolescents and Young Adults (DiCAYA) Network seeks to advance diabetes surveillance efforts in youth and young adults through the use of large-volume electronic health record (EHR) data. The network has two primary aims, namely: (1) to refine and validate EHR-based computable phenotype algorithms for accurate identification of type 1 and type 2 diabetes among youth and young adults and (2) to estimate the incidence and prevalence of type 1 and type 2 diabetes among youth and young adults and trends therein. The network aims to augment diabetes surveillance capacity in the USA and assess performance of EHR-based surveillance. This paper describes the DiCAYA Network and how these aims will be achieved.Methods and analysis The DiCAYA Network is spread across eight geographically diverse US-based centres and a coordinating centre. Three centres conduct diabetes surveillance in youth aged 0–17 years only (component A), three centres conduct surveillance in young adults aged 18–44 years only (component B) and two centres conduct surveillance in components A and B. The network will assess the validity of computable phenotype definitions to determine diabetes status and type based on sensitivity, specificity, positive predictive value and negative predictive value of the phenotypes against the gold standard of manually abstracted medical charts. Prevalence and incidence rates will be presented as unadjusted estimates and as race/ethnicity, sex and age-adjusted estimates using Poisson regression.Ethics and dissemination The DiCAYA Network is well positioned to advance diabetes surveillance methods. The network will disseminate EHR-based surveillance methodology that can be broadly adopted and will report diabetes prevalence and incidence for key demographic subgroups of youth and young adults in a large set of regions across the USA.

IntroductionSleep disruption affects biological processes that facilitate carcinogenesis. This retrospective cohort study used de-identified data from the Veterans Administration (VA) electronic medical record system to test the hypothesis that patients with diagnosed sleep disorders had an increased risk of prostate, breast, colorectal, or other cancers (1999-2010, N=663,869). This study builds upon existing evidence by examining whether patients with more severe or longer-duration diagnoses were at a greater risk of these cancers relative to those with a less severe or shorter duration sleep disorder.MethodsIncident cancer cases were identified in the VA Tumor Registry and sleep disorders were defined by International Classification of Sleep Disorder codes. Analyses were performed using extended Cox regression with sleep disorder diagnosis as a time-varying covariate.ResultsSleep disorders were present among 56,055 eligible patients (8% of the study population); sleep apnea (46%) and insomnia (40%) were the most common diagnoses. There were 18,181 cancer diagnoses (41% prostate, 12% colorectal, 1% female breast, 46% other). The hazard ratio (HR) for a cancer diagnosis was 1.45 (95% confidence interval [CI]: 1.37, 1.54) among those with any sleep disorder, after adjustment for age, sex, state of residence, and marital status. Risks increased with increasing sleep disorder duration (short [2-5 years] 1.23 [1.16-1.32]; long [>5-12 years] 1.52 [1.34-1.73]). Risks also increased with increasing sleep disorder severity using cumulative sleep disorder treatments as a surrogate exposure; African Americans with more severe disorders had greater risks relative to those with fewer treatments and other race groups. Results among patients with only sleep apnea, insomnia, or another sleep disorder were similar to those for all sleep disorders combined.DiscussionThe findings are consistent with other studies indicating that sleep disruption is a cancer risk factor. Optimal sleep and appropriate sleep disorder management are modifiable risk factors that may facilitate cancer prevention.

Free public transit for older adults is a policy often advocated for to increase ridership and reduce their dependence on automobiles. In July 2023 public transit became free on the island of Montréal for older adults (65+). Drawing from longitudinal repeated survey data collected in February 2023 and September 2023 and in-depth interviews collected in November 2023, we study the impacts of free public transit fare policy on older adults’ (65+) frequency of public transit use and satisfaction with service. We did not observe any change in public transit use among those who anticipated increased use in the before period, nor among those who anticipated no change in their use after the implementation of the free fare policy. We observed a positive change in the perception of the convenience of public transit after the implementation of the free fare policy for older adults.

PurposeModern literature has demonstrated improvements in long-term biochemical outcomes with the use of prophylactic pelvic nodal irradiation followed by a brachytherapy boost in the management of high-risk prostate cancer. However, this comes at the cost of increased treatment-related toxicity. In this study, we explore the outcomes of the largest cohort to date, which uses a stereotactic body radiation therapy (SBRT) boost following pelvic nodal radiation for exclusively high-risk prostate cancer.Methods and materialsA large institutional database was interrogated to identify all patients with high-risk clinical node-negative prostate cancer treated with conventionally fractionated radiotherapy to the pelvis followed by a robotic SBRT boost to the prostate and seminal vesicles. The boost was uniformly delivered over three fractions. Toxicity was measured using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Oncologic outcomes were assessed using the Kaplan–Meier method. Cox proportional hazard models were created to evaluate associations between pretreatment characteristics and clinical outcomes.ResultsA total of 440 patients with a median age of 71 years were treated, the majority of whom were diagnosed with a grade group 4 or 5 disease. Pelvic nodal irradiation was delivered at a total dose of 4,500 cGy in 25 fractions, followed by a three-fraction SBRT boost. With an early median follow-up of 2.5 years, the crude incidence of grade 2+ genitourinary (GU) and gastrointestinal (GI) toxicity was 13% and 11%, respectively. Multivariate analysis revealed grade 2+ GU toxicity was associated with older age and a higher American Joint Committee on Cancer (AJCC) stage. Multivariate analysis revealed overall survival was associated with patient age and posttreatment prostate-specific antigen (PSA) nadir.ConclusionUtilization of an SBRT boost following pelvic nodal irradiation in the treatment of high-risk prostate cancer is oncologically effective with early follow-up and yields minimal high-grade toxicity. We demonstrate a 5-year freedom from biochemical recurrence (FFBCR) of over 83% with correspondingly limited grade 3+ GU and GI toxicity measured at 3.6% and 1.6%, respectively. Long-term follow-up is required to evaluate oncologic outcomes and late toxicity.

Many patients who are at high risk of HIV transmission do not receive pre-exposure prophylaxis (PrEP). HIV risk counselling and PrEP initiation have historically been limited to outpatient settings. Here we describe a novel quality improvement project at San Francisco’s main safety-net hospital designed to incorporate universal screening for active HIV risk factors and PrEP initiation into standard inpatient care. Interventions included education sessions and dissemination of clinical materials to increase providers’ knowledge and comfort with HIV risk screening, prevention counselling and prescribing PrEP. We implemented new workflows on the inpatient medicine service to encourage providers to universally screen all patients at the time of admission and initiate PrEP for appropriate patients during their hospitalisation. Over the first 9 months of the initiative, 14 inpatients were started on PrEP during their admission. As PrEP was initiated in particularly vulnerable patients, using inpatient admissions to engage at-risk patients in HIV prevention may help to reduce disparities in HIV outcomes.

In car dependent societies, driving cessation may reduce older adults’ independence and quality of life. One way to maintain independence for older adults after quitting driving is to encourage walking to local destinations. This paper explores how neighborhood walkability impacts older adults’ ability to maintain their lifestyles as they age. Based on data collected from the 2023 Aging in Place survey (N=3,551), we analyze the relationship between survey respondents’ perceptions of transport in their neighborhood and its Walk Score across 6 Canadian regions. We explore the association between neighborhood walkability and respondents’ perception of their independence, quality of life, and likelihood of needing to move in the future. We find that those living in walkable neighborhoods believe that they will maintain their lifestyle when they stop driving compared to those who live in less walkable areas. The results indicate that neighborhood walkability is a key element in enabling older adults to keep their independence and sustain their lifestyle.

Media reports and data from public health professional membership organizations have demonstrated high levels of harassment experienced by public health workers throughout the COVID-19 response. We documented personal and political threats to public health workers across the first 12 months of pandemic response through a longitudinal survey completed in Fall 2020 and Summer 2021. The web-based survey was distributed to respondents using the Qualtrics survey platform. Survey items measured domains including demographic information, public health roles and training, mental and physical health, and work-life balance. Respondents were also asked if they had received any personal or political threats, from whom these threats were received, and completed an open-ended question describing the nature of the threats. Among the 85 public health workers completing both surveys, threats from members of the public and from elected and appointed leaders were most prevalent at both timepoints; however, as the pandemic response progressed, the nature of threats to public health workers changed. While those remaining in the public health workforce may be more resilient to these threats, increased prevalence of personal and political threats has the potential to deter new graduates from entering the field, impacting the public health system's future response capacity.

ABSTRACTPurpose Many medical school curricula include Scholarly Concentrations (SC) programs. While studies have examined how these programs affect students’ future research involvement, the association of SC programs with students’ specialty choices is uncertain. This study examines the SC program factors associated with congruence between the specialty focus of students’ SC projects and the clinical specialty they matched into for residency.Methods The authors conducted a retrospective cohort study of all students participating in the SC program at Johns Hopkins University School of Medicine for graduating classes 2013–2020. They used data from program questionnaires to categorize students’ specialty interests (baseline) and SC program experiences (post-program). The authors categorized each student’s project into specialties according to their faculty mentors’ primary appointments, abstracted student publications from SCOPUS, and abstracted residency program rankings from Doximity Residency Navigator. The authors used multivariable logistic regression to calculate adjusted odds ratios (aOR) for specialty-congruent matching (same specialty as SC project) and for matching into a Doximity-ranked top 20 or top 10 program.Results Overall, 35.3% of the 771 students matched into the same specialty as their SC projects. Increased odds of specialty-congruent matching occurred with ‘definite’ interest in the specialty at baseline [aOR (95% CI): 1.76 (0.98–3.15)] (P = 0.06) and with increasing publications with SC mentors [aOR (95% CI): 1.16 (1.03–1.30)] (P = 0.01). Congruence between SC specialty focus and matched specialty conferred no significant difference in odds of matching to a Doximity-ranked top 20 or top 10 program.Conclusions Baseline certainty of specialty interest and research productivity were associated with specialty congruence. However, as completing an SC project in a given specialty was not associated with increased odds of matching into that specialty nor into a higher Doximity-ranked program, SC program directors should advise students to pursue SC projects in any topic of personal interest.

Policy makers worldwide are increasingly embracing the idea of a “15-Minute City” or “30-Minute City” as part of their sustainable-development strategies. These planning concepts propose an urban environment where residents can meet their essential needs within a short trip from their home using active modes of travel. However, there is limited understanding about the replicability and usefulness of these concepts in influencing the travel behaviour of residents to meet the 15- or 30-minute-city reality. Drawing from a travel-behaviour survey and open-source geospatial data from Montréal, Canada, this article seeks to identify which groups of households are living a 15- or 30-minute city lifestyle to understand the compatibility of the x-minute city planning approach with the local North American context. Findings indicate that the 15- and 30-minute city paradigms provide goals that are hardly reachable in the context of a large North American city. Very few households are able to conduct all their daily travel within close proximity to their home, even if the built environment was substantially altered. These findings suggest that the x-minute city is not a one-size-fits-all model. The findings from this study can be of interest to transport professionals aiming to apply the x-minute city as it highlights the challenges associated to meeting such target in a North American context.

IntroductionThe Sickle Cell Data Collection Program (SCDC) is a multi-state initiative utilizing multiple data sources to estimate population prevalence of Sickle Cell Disease (SCD) with the goal of improving quality of life and health outcomes among those affected. SCDC in Tennessee operates as a multi-site, interdisciplinary team using multiple sources of data to learn more about SCD in Tennessee.MethodsThis analysis characterizes the number, demographics, and proximity to specialty care of individuals living with SCD in Tennessee who have been covered by Medicaid or identified by newborn screening. We compared demographic patterns of individuals with SCD living in rural areas with those living in urban areas, as well as those living in counties contributing more than 50 individuals to the cohort, respectively, to demographic patterns of individuals with SCD in the rest of the state, using Chi-Square or Fisher’s exact tests.ResultsFindings show that overall, 66.1% of all SCD patients identified through newborn screening were residents of Davidson and Shelby counties at the time of birth, and 81.8% of those identified through Medicaid claims lived in Davidson, Hamilton, Knox, Madison, Montgomery, Rutherford, or Shelby County. In total, 8.6% of the cohort lived in rural settings and 91.4% in urban settings. Of the 95 counties in Tennessee, 75 (78.9%) had at least 1 to 40 residents with SCD, yet of these 75 counties, less than half had a hematology/oncology trained provider practicing within them.DiscussionThis analysis brings us closer to understanding how many people with SCD live in rural areas of Tennessee and the challenges they face in seeking the care needed to adequately manage their disease. Acute healthcare utilization remains highest in the young adulthood years. This analysis provides insight into how healthcare utilization patterns among individuals with SCD vary by age group and over time.

The promotion of active travel is deemed a crucial component of the transition to sustainable urban mobility. Several barriers hinder its policy implementation and uptake. Some evidence suggests that capacity building could be a useful tool for deepening sustainability efforts. This concept involves the development and deployment of skills and resources. However, a clear framework for understanding the dimensions of capacity building for active travel is lacking. Furthermore, most research and findings use cases within a Global North context, constricting implications and transferability to the Global South, especially to African cities. This study responds to the dearth of scholarly work exploring Global South cases and fills a knowledge gap regarding capacity building in the case of active travel. Through a literature review, we examined the dimensions of capacity building that are necessary to improve active travel in selected African countries. We focus on multilevel transportation governance with highlights from five African cities. Our findings suggest that the literature and policies on transport in Africa have key dimensions for capacity building for active travel but lack the introduction of key instruments and strategic pathways to meet these requirements for improved sustainable mobility. We propose a thematic guiding framework that delineates the strategic application of capacity building at three levels of governance. This framework helps integrate capacity building for active travel policies and implementation at the institutional, individual, and environmental levels.

We measure host galaxy stellar masses for a sample of five luminous quasars at z ∼ 5–7. Using JWST/NIRCam medium-band images of nearby point-spread function reference stars, we carefully subtract the contribution from the quasar light to place upper and lower limits on the flux of each host galaxy. We find that the members of our sample of quasar host galaxies have mass upper limits of 10 ^9.7 –10 ^10.8 M _⊙ , significantly less than expected from their supermassive black hole (SMBH) masses and the local M _BH – M _* relation. We additionally obtain JWST/NIRSpec integral field unit spectra of three of our quasars to calculate black hole masses, which we find are consistent with those in the literature, and to search for the presence of bright but compact galaxies via a Balmer break, for which we do not find evidence. We discuss the potential effects of dust extinction on our measured fluxes and the impact of selection effects on high-redshift quasar samples. We conclude that the masses of the SMBHs relative to the host galaxy stellar masses have a much larger scatter than locally, large enough that these selection effects cannot be responsible. This result is reinforced by other studies. Finally, we explore the potential implications of these results on the picture of SMBH–galaxy coeval growth in the early Universe.

Abstract Background Measuring what students know and retain about evolution is essential to improving our understanding of how students learn evolution. The literature shows that college students appear to have a poor understanding of evolution, answering questions on various instruments correctly only about half of the time. There is little research regarding evolution understanding among community college students and so this study examines if those students who are enrolled in life science classes, who are assessed using questions based on grade eight standards, show a better understanding of evolutionary principles than younger students and if there are differences in knowledge based on course enrollment. The authors utilized a survey of 41 items of the Life Sciences Concept Inventory that were specifically designed to measure knowledge about various aspects of evolution that relate to the 5–8 grade science standards on evolution. They administered it to 191 adult students who were enrolled in nine sections across five life sciences courses at one community college in Southern California. Results Results indicated that the students in this study possessed a fair understanding of evolution, averaging scores of nearly 70%, higher than what other researchers have found (using different instruments). Students enrolled in biology major classes scored significantly higher than those enrolled in non/mixed-major courses. There was a strong relationship between item difficulty and discrimination as well as difficulty and misconception strength. When compared with the 5–8 grade student data, the community college students showed a lower level of difficulty and higher levels of item discrimination, but the proportion choosing the most popular wrong answer (the dominant misconception), was comparable. College students showed similar patterns to the grade 5–8 students in terms of which questions and which material were the most challenging, despite performing better overall. Conclusions In this study, students possessed fair understanding of evolution. However, they were assessed with an instrument designed for 5th through 8th grade students. The results of this study support the need for more research into how community college students understand evolution and which factors impact that understanding.

Many commercially available biologics, previously delivered only intravenously, are being re-formulated for subcutaneous delivery to improve patient access and compliance. However, due to inherent solubility limitations, large volume injections (more than 2 mL) are typically required. Different strategies are being explored to improve the tolerability of such injections, including the co-formulation with hyaluronidase and/or implementing different needle designs. While there have been separate reports of measuring injection forces and using imaging to track injection delivery and tissue response, there is no current set of methods to simultaneously characterize the injection delivery (bleb) and measure injection pressures. In this study we describe the development of Computed Tomography imaging methods in minipigs to characterize the morphology of the bleb following injection, along with inline pressure measurements to assess subcutaneous pressure during injection using two different injection volumes, 4.5 mL and 9 mL. We show that these parameters change with injection volume, and that inclusion of hyaluronidase in the injection increases bleb dispersion and reduces skin distention while also lowering the injection pressure. This method will likely be a valuable tool for assessing and comparing different injection delivery methods and formulations.

Background: Although oral health-related quality of life (OHRQoL) in orthodontic patients has been assessed in the past, to date, no study has compared the OHRQoL between two nations. We aimed to compare the OHRQoL between Chinese and American orthodontic patients. Methods: We conducted a two-center questionnaire-based cross-sectional study among patients who underwent orthodontic treatments at the Chinese PLA General Hospital (PLAGH) in Beijing, China and Massachusetts General Hospital (MGH) in Boston, Massachusetts, United States. Candidate variables included the participating center, patients’' age, sex, Angle’s classification of malocclusion, evaluation stage, and appliances used. The primary outcome was patients’ OHRQoL assessed with the Oral Health Impact Profile-14 (OHIP-14). Descriptive statistics, stratification, and univariate and multivariate analyses were performed. Results: The average age was lower for PLAGH patients than for MGH patients (21.1 ​± ​7.9 vs. 33.1 ​± ​14.6 years, P

Off-target binding hinders the development of therapeutic antibodies and reproducibility in basic research settings. Here the authors develop a method to quantify and reduce the polyreactivity of antibody fragments based on protein sequence alone.

Abstract Neurodegenerative disease is increasingly prevalent and remains without disease-modifying therapies. Engaging the right target, at the right disease stage, could be an important determinant of success. We annotated targets and eligibility criteria for 3238 neurodegenerative disease trials registered at ClinicalTrials.gov from 2000 to 2020. Trials became more selective as the mean number of inclusion and exclusion criteria increased and eligible score ranges shrank. Despite a shift towards less impaired participants, only 2.7% of trials included pre-symptomatic individuals; these were depleted for drug trials and enriched for behavioral interventions. Sixteen novel, genetically supported therapeutic hypotheses tested in drug trials represent a small, non-increasing fraction of trials, and the mean lag from genetic association to first trial was 13 years. Though often linked to disease initiation, not progression, these targets were tested mostly at symptomatic disease stages. The potential for disease modification through early intervention against root molecular causes of disease remains largely unexplored.

Abstract Significant indirect healthcare costs are related to uncontrolled asthma, including productivity loss. Days with short-acting beta-agonist (SABA) use is associated with symptom-related disruptions at work, home, and school. Digital self-management platforms may support fewer days with SABA medication use and may reduce symptom-related disruptions.

Reprogramming of fatty acid metabolism promotes cell growth and metastasis through a variety of processes that stimulate signaling molecules, energy storage, and membrane biosynthesis in endometrial cancer. Oleic acid is one of the most important monounsaturated fatty acids in the human body, which appears to have both pro- and anti-tumorigenic activities in various pre-clinical models. In this study, we evaluated the potential anti-tumor effects of oleic acid in endometrial cancer cells and the LKB1fl/flp53fl/fl mouse model of endometrial cancer. Oleic acid increased lipogenesis, inhibited cell proliferation, caused cell cycle G1 arrest, induced cellular stress and apoptosis, and suppressed invasion in endometrial cancer cells. Targeting of diacylglycerol acyltransferases 1 and 2 effectively increased the cytotoxicity of oleic acid. Moreover, oleic acid significantly increased the expression of wild-type PTEN, and knockdown of PTEN by shRNA partially reversed the anti-proliferative and anti-invasive effects of oleic acid. Inhibition of the AKT/mTOR pathway by ipatasertib effectively increased the anti-tumor activity of oleic acid in endometrial cancer cells. Oleic acid treatment (10 mg/kg, daily, oral) for four weeks significantly inhibited tumor growth by 52.1% in the LKB1fl/flp53fl/fl mice. Our findings demonstrated that oleic acid exhibited anti-tumorigenic activities, dependent on the PTEN/AKT/mTOR signaling pathway, in endometrial cancer.

Changing climate and land use activity are altering inputs of colored dissolved organic carbon (cDOC) into lakes. Increased cDOC reduces water transparency (browning) and changes lake physicochemistry, with biological consequences. Identifying the drivers and effects of changing cDOC inputs is critical for mitigating the consequences of climate change on lake ecosystems through adaptive watershed management. This study focused on determining the drivers of lake browning by evaluating shifts in diatom assemblages in subtropical, oligotrophic Lake Annie (FL, United States), which is known to experience climate-driven oscillations in transparency associated with watershed inputs of cDOC. We combined long-term limnological monitoring data and paleolimnological techniques to determine how diatoms respond to changes in cDOC and to infer past cDOC fluctuations relative to records of past climate and land use changes in the watershed. Diatom assemblage composition in a 14-year phytoplankton dataset was strongly correlated with cDOC-driven transparency fluctuations. Likewise, diatom assemblages in the upper 35 cm of the sediment core, which corresponded to a 35-year lake monitoring record, were also strongly related to past water transparency, yielding a strong transfer function (paleo model, R2 = 0.72). When the model was applied to the diatom record from a 166-cm sediment core, diatom-inferred transparency and rates of nutrient input showed that localized ditching in the 1930s enhanced the effect of climate oscillations on water transparency, intensifying cyclical browning thereafter. Integration of long-term monitoring and paleoecological data provided valuable insights into the history of the aquatic ecosystem, enabling implementation of adaptive management strategies to contend with a changing climate.

IntroductionBrain metastases are the most common intracranial tumor diagnosed in adults. In patients treated with stereotactic radiosurgery, the incidence of post-treatment radionecrosis appears to be rising, which has been attributed to improved patient survival as well as novel systemic treatments. The impacts of concomitant immunotherapy and the interval between diagnosis and treatment on patient outcomes are unclear.MethodsThis single institution, retrospective study consisted of patients who received single or multi-fraction stereotactic radiosurgery for intact brain metastases. Exclusion criteria included neurosurgical resection prior to treatment and treatment of non-malignant histologies or primary central nervous system malignancies. A univariate screen was implemented to determine which factors were associated with radionecrosis. The chi-square test or Fisher’s exact test was used to compare the two groups for categorical variables, and the two-sample t-test or Mann-Whitney test was used for continuous data. Those factors that appeared to be associated with radionecrosis on univariate analyses were included in a multivariable model. Univariable and multivariable Cox proportional hazards models were used to assess potential predictors of time to local failure and time to regional failure.ResultsA total of 107 evaluable patients with a total of 256 individual brain metastases were identified. The majority of metastases were non-small cell lung cancer (58.98%), followed by breast cancer (16.02%). Multivariable analyses demonstrated increased risk of radionecrosis with increasing MRI maximum axial dimension (OR 1.10, p=0.0123) and a history of previous whole brain radiation therapy (OR 3.48, p=0.0243). Receipt of stereotactic radiosurgery with concurrent immunotherapy was associated with a decreased risk of local failure (HR 0.31, p=0.0159). Time interval between diagnostic MRI and first treatment, time interval between CT simulation and first treatment, and concurrent immunotherapy had no impact on incidence of radionecrosis or regional failure.DiscussionAn optimal time interval between diagnosis and treatment for intact brain metastases that minimizes radionecrosis and maximizes local and regional control could not be identified. Concurrent immunotherapy does not appear to increase the risk of radionecrosis and may improve local control. These data further support the safety and synergistic efficacy of stereotactic radiosurgery with concurrent immunotherapy.

Diffuse intrinsic pontine glioma (DIPG) is a rare but highly lethal pediatric and adolescent tumor located in the pons of the brainstem. DIPGs harbor unique and specific pathological and molecular alterations, such as the hallmark lysine 27-to-methionine (H3K27M) mutation in histone H3, which lead to global changes in the epigenetic landscape and drive tumorigenesis. While fractionated radiotherapy, the current standard of care, improves symptoms and delays tumor progression, DIPGs inevitably recur, and despite extensive efforts chemotherapy-driven radiosensitization strategies have failed to improve survival. Advances in our understanding of the role of epigenetics in the cellular response to radiation-induced DNA damage, however, offer new opportunities to develop combinational therapeutic strategies selective for DIPGs expressing H3K27M. In this review, we provide an overview of preclinical studies that explore potential radiosensitization strategies targeting the unique epigenetic landscape of H3K27M mutant DIPG. We further discuss opportunities to selectively radiosensitize DIPG through strategic inhibition of the radiation-induced DNA damage response. Finally, we discuss the potential for using radiation to induce anti-tumor immune responses that may be potentiated in DIPG by radiosensitizing-therapeutic strategies.

Abstract Ponds are often identified by their small size and shallow depths, but the lack of a universal evidence-based definition hampers science and weakens legal protection. Here, we compile existing pond definitions, compare ecosystem metrics (e.g., metabolism, nutrient concentrations, and gas fluxes) among ponds, wetlands, and lakes, and propose an evidence-based pond definition. Compiled definitions often mentioned surface area and depth, but were largely qualitative and variable. Government legislation rarely defined ponds, despite commonly using the term. Ponds, as defined in published studies, varied in origin and hydroperiod and were often distinct from lakes and wetlands in water chemistry. We also compared how ecosystem metrics related to three variables often seen in waterbody definitions: waterbody size, maximum depth, and emergent vegetation cover. Most ecosystem metrics (e.g., water chemistry, gas fluxes, and metabolism) exhibited nonlinear relationships with these variables, with average threshold changes at 3.7 ± 1.8 ha (median: 1.5 ha) in surface area, 5.8 ± 2.5 m (median: 5.2 m) in depth, and 13.4 ± 6.3% (median: 8.2%) emergent vegetation cover. We use this evidence and prior definitions to define ponds as waterbodies that are small (