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Abstract Background A sense of loss of control over eating, such that eating occurs despite the intent not to, is common in people with obesity and eating disorders such as binge eating disorder and bulimia nervosa. Currently, options for management of loss of control eating are limited. We recently determined that the pro-drug N-acetylcysteine (NAC) reduces compulsive-like eating in a rat model of diet-induced obesity. We will now conduct a single site, open-label pilot study to examine the feasibility of a randomized controlled trial (RCT) of NAC for loss of control eating in humans. Methods Thirty-six adult volunteers with loss of control eating will be enrolled. All participants will receive NAC at a dose of 1200 mg orally twice daily for 12 weeks. Eating behaviors and triggers will be assessed before and after the NAC treatment period using questionnaires (Eating Loss of Control Scale, Palatable Eating Motives Scale: Coping Subscale, Food Craving Inventory, Reward-Based Eating Scale, Perceived Stress Scale, and Emotional Eating Scale) and ecological momentary assessment (EMA). The primary outcomes of this feasibility study are recruitment rate, participant retention rate at week 12, and medication adherence. The secondary outcome is change in Eating Loss of Control Scale score from baseline to week 12. Exploratory data will be collected on the change in eating behaviors from baseline to week 12. Although EMA can provide real-time data on eating behaviors compared with retrospective questionnaires, it relies on repeated daily measurement for long periods which can affect participant’s adherence to study protocol. Therefore, this feasibility study will assess the performance of EMA versus retrospective questionnaires and will determine which approach suits the purposes of the research. Discussion The results of this study will inform the feasibility of a RCT of NAC for loss of control eating using EMA. Trial registration This study was prospectively registered with the Australian and New Zealand Clinical Trials Registry in June 2022 (ACTRN12622000902796).

Abstract Most forms of clinical research examine a very minute cross section of the patient journey. Much of the knowledge and evidence base driving current genomic medicine practice entails blind spots arising from underrepresentation and lack of research participation in clinicogenomic databases. The flaws are perpetuated in AI models and clinical practice guidelines that reflect the lack of diversity in data being used. Participation in clinical research and biobanks is impeded in many populations due to a variety of factors that include knowledge, trust, healthcare access, administrative barriers, and technology gaps. A recent symposium brought industry, clinical, and research participants in clinicogenomics to discuss practical challenges and potential for new data sharing models that are patient centric and federated in nature and can address health disparities that might be perpetuated by lack of diversity in clinicogenomic research, biobanks, and datasets. Clinical data governance was recognized as a multiagent problem, and governance practices need to be more patient centric to address most barriers. Digital tools that preserve privacy, document provenance, and enable the management of data as intellectual property have great promise. Policy updates realigning and rationalizing clinical data governance practices are warranted.

Abstract Background To date, over 1.3 billion videos with the hashtag #bodyneutrality have been viewed on TikTok. Despite this, little existing literature has unpacked how body neutrality is conceptualised on TikTok. We examined how TikTok creators construct meaning and generate discourse surrounding #bodyneutrality. Methods Extending on previous works in the body neutrality space, we conducted a hybrid content/thematic analysis of TikTok videos in three different languages (English, Spanish, and Italian). Initially, 300 videos displaying “#bodyneutrality” were identified on TikTok. The first 178 TikTok videos were analysed, following the principles of data saturation and feasibility. Results We developed three themes: (1) The normalisation of diverse bodies, (2) The rejection of appearance as fundamentally important, and (3) Body neutrality is (better than) body positivity. Conclusions In line with conceptualisations of body neutrality in existing literature, some content emphasised the importance of devaluing physical appearance. Building on existing definitions, most creators also framed body neutrality as speaking to the fundamental humanness of owning a body and attempted to normalise various body shapes/sizes. Conversely, some content employed #bodyneutrality to promote or examine body positivity principles or to condemn appearance-based stigmatisation. Our study is one of the first to examine how body neutrality is understood and employed by people in the real world.

BackgroundPatients inevitably incur some cost for accessing health care, even in universal systems such as Canada. The COVID-19 pandemic dramatically shifted health care delivery from in-person to telehealth services, also shifting the proportion of costs offset by patients and their families by reducing the need to travel to in-person appointments. ObjectiveThis study aimed to develop a method for estimating the costs patients and their families incur and CO2 emissions attributed to travel needed for emergency department (ED) visits, hospitalizations, and physician appointments. MethodsWe present a method to evaluate the costs associated with in-person and telehealth care appointments from the perspective of patients, their families, and the environment. We used ED locations, road distances, and duration of appointment to account for costs paid by patients (ie, lost productivity, informal caregiving, and out-of-pocket expenses) attributed to travel to receive medical care. Costs to the environment were evaluated by calculating the amount of CO2 emitted per medical visit. Using our costs calculated per visit, we apply our method to calculate total patient costs for a simulated population over 1 year. ResultsOur method estimates that patients in British Columbia pay up to $300 (2023 CAD, CAD $1=US $0.86) on average to attend an in-person ED visit, depending on where they live; $166 may be attributed to lost productivity, $83 to informal caregiving, and $50 to out-of-pocket expenses. These estimates are higher than most observed cost estimates. In addition, avoiding in-person care diverts up to 13 kg of CO2 per medical visit, depending on the distance and frequency of travel to appointments. This translates to up to $0.70 in carbon costs per visit, or cumulatively $44,120 per year in British Columbia, conventionally not included in patient cost estimates. ConclusionsWe present a novel method for estimating patient-incurred costs and CO2 emissions from accessing health care and apply it to estimate that every year, patients in British Columbia pay upwards of 30 million dollars to access health care services, primarily for medical travel. Our method adds to the economic evaluation literature by providing a more comprehensive and context-modifiable calculation of patient costs that will allow for more informed decision-making regarding health care services.

Introduction SLE is a chronic autoimmune disease that results in sustained hyperactivation of innate and adaptive immune cells and widespread inflammatory damage. Regular exercise reduces SLE symptoms including fatigue and joint pain and improves patient quality of life. However, most individuals with SLE are not sufficiently active to achieve these benefits, and guidance on the optimal approach to exercise is limited. EXCEL will examine the feasibility of conducting a large-scale randomised controlled trial comparing the effects of a remotely monitored, home-based, exercise programme with standard of care for individuals with SLE.Methods and analysis 30 females with SLE will be recruited, and those randomised into Exercise (SLE-Ex) will codesign a progressive training plan with support from the research team. The aim of each 12-week plan will be to complete 150 min of moderate (60–70% heart rate max, HRmax) or 90 min of vigorous exercise (>70% HRmax) per week. SLE-Ex will be encouraged to exercise independently (without support) from weeks 13–18. Participants with SLE that are randomised into Control (SLE-Con) will maintain habitual activity without support for 18 weeks. Measures of feasibility and acceptability will be reported, and peripheral blood will be collected at weeks 0, 12 and 18 to explore whether the frequency, phenotype and metabolic profile of lymphocyte subsets has changed. Biomarkers of SLE activity, and self-reported measures of fatigue, sleep quality and health-related quality of life will also be monitored at these timepoints. Blood and self-reported measures will be compared with a healthy control (HC) group (n=15, age and body mass index matched) at baseline only.Ethics and dissemination A favourable ethical opinion was given by South East Scotland Research Ethics Committee (22/SS/0082). Findings will be disseminated at conferences and published in peer-reviewed journals.Trial registration number ISRCTN72757645.

Abstract Introduction This retrospective cohort study recognizes a profound need to address rising rates of maternal morbidity and mortality, especially its disproportionate impact on ethnic and racial minorities. Timely access to high-quality prenatal care is essential, the absence of which is associated with increased risk of adverse maternal and fetal outcomes. The persistence of racial and ethnic disparities in pregnancy outcomes, despite accounting for income and education level, suggests that barriers to care are also significantly limited by psychosocial and health system barriers. Methods This retrospective cohort study analyzed several potential barriers to prenatal care among postpartum patients who delivered at Loyola University Medical Center in Maywood, Illinois, such as transportation, parking, childcare, clinic wait times, scheduling difficulties, and knowledge about the impact of COVID-19 on pregnancy. Participants were screened daily for eligibility and consented to participate from February to May 2022, a total of three months. Eligible patients were given a 10-question paper survey that also assessed out-of-pocket costs and suggestions to improve prenatal care attendance and satisfaction. During the study period, there were 251 eligible deliveries. 197 patients (77.3%) were consented and participated in the survey. 194 (98.4%) were eligible for post-chart review; 21 patients (10.6%) declined to participate, 33 patients (16.8%) did not complete the survey, and 3 surveys (1.5%) were lost. Retrospective chart reviews were conducted for PNC utilization, pregnancy comorbidities and outcomes, and demographic information. Data underwent Fischer analyses, chi-squared analyses, and ANOVAs. Institutional Review Board-approved, participants consented for research and quality improvement, including medical record data use. Results Among 194 patients, average reported barriers to PNC were 2.14, with “difficulty scheduling appointments” (39.6%) and “couldn’t leave work or school” (30.2%) most common. Despite most patients reporting a similar number of barriers, timing disparities based race and ethnicity, education, and income were observed. Hispanic patients initiated PNC later than non-Hispanic White patients (13w6d vs. 10w5d; p = 0.009). Twelfth-grade education or less initiated PNC bachelor's degree holders (16w vs. 11w; p 140 k (13w3d vs. 9w1d; p = 0.02). Patients who reported “long wait times” initiated prenatal care an average of 2w2d later than patients not facing this barrier, at 14w1d vs. 12w0d, respectively (p = 0.01). Conclusions Lower socioeconomic status and ethnic minority patients exhibit delayed PNC start that are linked to adverse outcomes. Noteworthy discrepancies within the surveyed cohorts, despite comparable reported barriers, hint at the existence of supplementary, interconnected obstacles specific to these patients. Future efforts should tackle common issues specific to various sociodemographic groups to address disparities in pregnancy outcomes.

Background Brain metastases (BrM) affect up to 60% of patients with metastatic melanoma and are associated with poor prognosis. While combined immune checkpoint blockade of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) demonstrates intracranial efficacy in a proportion of patients with melanoma, the responses are rarely durable, particularly in patients with symptomatic BrM. The brain is an immune-specialized organ and immune responses are regulated differently to the periphery.Methods Using our previously established two-site model of melanoma BrM with concomitant intracranial and extracranial tumors, in which clinically observed efficacy of the combined PD-1/CTLA-4 (PC) blockade can be reproduced, we here explored the role of natural killer (NK) cells in BrM, using functional studies, immunophenotyping and molecular profiling.Results We demonstrate that NK cells are required for the intracranial efficacy of PC blockade. While both perforin and interferon gamma were necessary for the PC blockade-dependent control of intracranial tumor growth, NK cells isolated from intracranial tumors demonstrated only a limited cancer cell killing ability, and PC blockade did not alter the abundance of NK cells within tumors. However, the depletion of NK cells in PC blockade-treated mice led to tumor molecular profiles reminiscent of those observed in intracranial tumors that failed to respond to therapy. Furthermore, the depletion of NK cells resulted in a strikingly reduced abundance of CD8+ T cells within intracranial tumors, while the abundance of other immune cell populations including CD4+ T cells, macrophages and microglia remained unaltered. Adoptive T cell transfer experiments demonstrated that PC blockade-induced trafficking of CD8+ T cells to intracranial tumors was chemokine-dependent. In line with this, PC blockade enhanced intratumoral expression of several T cell-attracting chemokines and we observed high expression levels of cognate chemokine receptors on BrM-infiltrating CD8+ T cells in mice, as well as in human BrM. Importantly, the depletion of NK cells strikingly reduced the intratumoral expression levels of T cell attracting chemokines and vascular T cell entry receptors that were upregulated following PC blockade.Conclusion Our data demonstrate that NK cells underpin the efficacy of PC blockade in BrM by orchestrating the responder molecular profile in tumors, and by controlling the intratumoral abundance of CD8+ T cells through regulation of multiple key molecular mediators of T cell trafficking.

Ixodes scapularis and Ixodes pacificus are vectors of a range of pathogens of public health significance in North America. These ticks transmit pathogens to and from wild animal reservoir host species, but also bite humans and expose them to the pathogens. We describe the geographical and temporal distribution of the pathogen Babesia odocoilei, the causative agent of cervid babesiosis. Ixodes spp. ticks collected through active and passive surveillance were submitted to the National Microbiology Laboratory of the Public Health Agency of Canada for analysis of the presence of B. odocoilei from 2018 to 2021. Generalized linear models were constructed to evaluate the temporal change of B. odocoilei prevalence across Canada. Babesia odocoilei-positive I. scapularis are widespread across south-central and eastern regions of Canada, with an overall prevalence of 12.0 % in both nymphs (CI 95 % : 11.4–12.6) and adults (CI 95 % : 11.9–12.1) collected in passive surveillance and 13.2 % (CI 95 % : 12.9–13.5) and 10.0 % (CI 95 % : 9.8–10.2) in nymphs and adult, respectively, collected in active surveillance. A single I. pacificus tick tested positive in active surveillance out of 29 ticks collected in British Columbia, while no B odocoilei-positive I. scapularis were found in passive surveillance among the 11 adult ticks tested. Although B. odocoilei infection prevalence of adult I. scapularis was significantly higher in 2019 (14.1 %) than in 2018 (7.4 %), it remained stable from 2019 to 2021, suggesting that this pathogen may already be well established in endemic tick populations. The results provided in this article represent, to date, the most comprehensive picture of B. odocoilei distribution and prevalence in ticks in Canada and highlight the interest of maintaining One Health surveillance approaches to give added insight into disease transmission cycles for less well-characterized microorganisms.

Most young adults naturally mature out of high-risk substance use patterns, but it is important to identify factors that may impede normative declines. Use of alcohol and cannabis simultaneously (i.e., simultaneous alcohol and marijuana/cannabis [SAM]) is cross-sectionally associated with alcohol and cannabis concerns, and SAM use increases acute risks at the daily level. However, less is known about long-term risks of SAM use and, specifically, how SAM use relates to maturing out of alcohol and cannabis use. Using four consecutive years of survey data from young adults who reported SAM use (N=409; 1636 responses; aged 18–25 at baseline), we first estimated age-related changes in symptoms of alcohol and cannabis use disorder (AUD/CUD) using multilevel growth modeling. Findings supported a maturing out process, as both AUD and CUD symptom severity significantly declined across young adulthood, on average (4 % and 5 % per year respectively, with significant acceleration). Cross-level interactions tested whether participants’ mean SAM use frequency across all four timepoints moderated age-related trajectories in AUD/CUD symptom severity. Significant interactions indicated that, relative to less-frequent SAM use, participants with more frequent SAM use showed less steep declines in AUD (1 % decrease per year vs. 6 % per year) and CUD symptoms (0 % decrease per year vs. 7 % per year); thus, SAM frequency was associated with slower/delayed maturing out of hazardous alcohol and cannabis use. Findings highlight that SAM use may be a correlate or risk-factor for prolonged high-risk substance use during young adulthood that relates to deviations from maturing out processes.

Chimeric antigen receptor T (CAR T) cell therapy has shown remarkable success in treating various leukemias and lymphomas. Cellular kinetic (CK) and pharmacodynamic (PD) behavior of CAR T cell therapy is distinct from other therapies due to its living nature. CAR T CK is typically characterized by an exponential expansion driven by target binding, fast initial decline (contraction), and slow long-term decline (persistence). Due to the dependence of CK on target binding, CK and PD of CAR T therapies are inherently and bidirectionally linked. In this work, we develop a semi-mechanistic model of CAR T CK/PD, incorporating molecular-scale binding, T cell dynamics with multiple phenotypes, and tumor growth and killing. We calibrate this model to published CK and PD data for a CD19-targeting CAR T cell therapy. Using sensitivity analysis, we explore variability in response due to patient- and drug-specific properties. We further explore the impact of tumor characteristics on CAR T-cell expansion and efficacy through individual- and population-level parameter scans.

Introduction This paper outlines the steps necessary to assess the latest developments in artificial intelligence (AI) as well as Big Data technologies and their relevance to the opioid crisis. Fatal opioid overdoses have risen to over 82 998 annually in the USA. This highlights the need for urgent and effective data-driven solutions. AI approaches, such as machine learning, deep learning and natural language processing, have been employed to analyse patterns and trends in overdose data and facilitate timely interventions. However, a comprehensive scoping review on the effectiveness of AI-driven technologies to detect, treat, prevent or respond to the opioid crisis remains absent. Thus, it is important to identify recent advancements in AI and Big Data technologies in addressing the opioid crisis.Methods and analysis We will electronically search four scientific databases (PubMed, Web of Science, Engineering Village and PsycInfo), including finding reference lists and grey literature from 2013 to 2023. Covidence will be used for screening and selecting papers. We will extract information such as citation details, study context, data used, AI/Big Data technologies, features, algorithms and evaluation metrics. This data will be synthesised, analysed and summarised to draw meaningful conclusions and identify future directions to tackle the opioid crisis.Ethics and dissemination Ethics approval is not required. Results will be disseminated via conference presentations and peer-reviewed publication.

Based on the concept of Communities of Practice (CoPs), this study describes the design and implementation of an online academic conference, Pedagogy and Practice in Technology Enhanced Language Learning (PPTELL) 2021, as a backdrop for exploring how to effectively promote the development of academic citizenship within the PPTELL CoP. To address this, we propose a framework focusing on four interrelated and interdependent dimensions: ubiquitous technologies, social practice, knowledge building, and academic citizenship. The conference utilized Zoom, Second Life, Slido, and several social media apps for various sessions and activities. A triangulation design was employed to analyze data from a post-conference online survey and observation notes. Our findings highlighted the effectiveness of the design in fostering academic citizenship, supported by multiuser virtual worlds like Second Life that enabled social engagement and knowledge building. We also discuss potential solutions to the challenges encountered, taking into account the nature of academic and higher education environments today.

Differential equation compartmental models are crucial tools for forecasting and analyzing disease trajectories. Among these models, those dealing with only susceptible and infectious individuals are particularly useful as they offer closed-form expressions for solutions, namely the logistic equation. However, the logistic equation has limited ability to describe disease trajectories since its solutions must converge monotonically to either the disease-free or endemic equilibrium, depending on the parameters. Unfortunately, many diseases exhibit periodic cycles, and thus, do not converge to equilibria. To address this limitation, we developed a generalized susceptible-infectious-susceptible compartmental model capable of accurately incorporating the duration of infection distribution and describing both periodic and non-periodic disease trajectories. We characterized how our model's parameters influence its behavior and applied the model to predict gonorrhea incidence in the US, using Akaike Information Criteria to inform on its merit relative to the traditional SIS model. The significance of our work lies in providing a novel susceptible-infected-susceptible model whose solutions can have closed-form expressions that may be periodic or non-periodic depending on the parameterization. Our work thus provides disease modelers with a straightforward way to investigate the potential periodic behavior of many diseases and thereby may aid ongoing efforts to prevent recurrent outbreaks.

Sexually transmitted diseases (STDs) are detrimental to the health and economic well-being of society. Consequently, predicting outbreaks and identifying effective disease interventions through epidemiological tools, such as compartmental models, is of the utmost importance. Unfortunately, the ordinary differential equation compartmental models attributed to the work of Kermack and McKendrick require a duration of infection that follows the exponential or Erlang distribution, despite the biological invalidity of such assumptions. As these assumptions negatively impact the quality of predictions, alternative approaches are required that capture how the variability in the duration of infection affects the trajectory of disease and the evaluation of disease interventions. So, we apply a new family of ordinary differential equation compartmental models based on the quantity person-days of infection to predict the trajectory of disease. Importantly, this new family of models features non-exponential and non-Erlang duration of infection distributions without requiring more complex integral and integrodifferential equation compartmental model formulations. As proof of concept, we calibrate our model to recent trends of chlamydia incidence in the U.S. and utilize a novel duration of infection distribution that features periodic hazard rates. We then evaluate how increasing STD screening rates alter predictions of incidence and disability adjusted life-years over a five-year horizon. Our findings illustrate that our family of compartmental models provides a better fit to chlamydia incidence trends than traditional compartmental models, based on Akaike information criterion. They also show new asymptomatic and symptomatic infections of chlamydia peak over drastically different time frames and that increasing the annual STD screening rates from 35% to 40%-70% would annually avert 6.1-40.3 incidence while saving 1.68-11.14 disability adjusted life-years per 1000 people. This suggests increasing the STD screening rate in the U.S. would greatly aid in ongoing public health efforts to curtail the rising trends in preventable STDs.

OBJECTIVES:. The majority of PICU general follow-up occurs with primary care providers. Our objective was to investigate primary care pediatricians’: 1) comfort with and barriers to caring for children after a PICU admission, 2) knowledge of and screening for post-intensive care syndrome in pediatrics (PICS-P), and 3) resource needs. DESIGN:. Pilot cross-sectional survey study. SETTING:. Metropolitan Detroit, Michigan from September 2022 to March 2023. SUBJECTS:. Primary care pediatricians. MEASUREMENT AND MAIN RESULTS:. The survey included 15 questions on provider demographics, comfort with and barriers to caring for children after a PICU admission, knowledge of and screening practices for PICS-P, and resource needs. The median values for continuous data and frequencies for categorical data were calculated. The survey response rate was 17% (26/152). The median age was 38.5 years (interquartile range 34–52 yr) and 19 of 26 (73%) were female. In case studies, 26 of 26 (100%) were “very comfortable” resuming care for a patient with a straightforward bronchiolitis PICU admission while 8 of 26 participants (31%) were “somewhat uncomfortable” and 1 of 26 (4%) was “not at all comfortable” with caring for a patient after a complex acute respiratory distress syndrome PICU admission. Seven of 26 participants (27%) were familiar with the term “post-intensive care syndrome in pediatrics.” Over 50% screened for four of five PICS-P domains. Key barriers were care coordination with specialists, discomfort or difficulties with managing new home equipment, and inadequate or missing documentation. CONCLUSIONS:. In this pilot study, approximately one-third of primary care pediatricians had knowledge of PICS-P. Participants experienced numerous care barriers. Our findings suggest future research could engage improved study methods and designs, and focus on interventions to support primary care-provided PICU follow-up.

YouTube is widely adopted in educational settings because it can support a variety of learning practices. However, unlike traditional learning resources, YouTube videos lack a standardized quality assurance process, posing a significant concern for educational users. The responsibility of identifying suitable educational content falls on the individual user as they navigate the site and select videos. Despite its importance, the multi-step process of video selection remains poorly understood among educational users. While it is established that most users begin with a keyword search for their topic of interest, there is limited empirical evidence on how users deliberate between returned video options, considering features such as view count and comment section sentiment, to make an informed video selection. To address this knowledge gap, this study surveyed college (1) instructors (N = 61) and (2) students (N = 300) to compare their prioritization of ten YouTube video features in relation to video selection. The results revealed fundamental similarities in their prioritization of key aspects such as accuracy, content creators’ expertise, video duration, and style. However, the analyses also suggest that instructors and students may value differing platform affordances across YouTube’s features.

Background Peripheral artery disease (PAD) and microvascular disease (MVD) are highly prevalent conditions that share common risk factors. This observational study aimed to characterize patients with both conditions and determine the impact of comorbid PAD/MVD on outcomes. Methods and Results Patients admitted across 31 states January 2011 through December 2018 with a primary or secondary diagnosis of PAD or MVD were included from the National Readmissions Database and weighted to approximate a national sample. Those age 500 000 in 2018. Major and minor amputations increased ≈50% for PAD/MVD between 2011 and 2018. Compared with PAD‐only, PAD/MVD was associated with a higher risk for major amputation (odds ratio [OR], 1.30 [95% CI, 1.28–1.32]), minor amputation (OR, 2.15 [95% CI, 2.12–2.18]), major adverse cardiac events (OR, 1.04 [95% CI, 1.03–1.04]), in‐hospital mortality (OR, 1.07 [95% CI, 1.05–1.09]), and readmission (hazard ratio, 1.02 [95% CI, 1.02–1.02]) after adjustment for baseline factors. Conclusions Comorbid MVD is present in a large and growing number of patients with PAD and is associated with augmented risk for adverse outcomes. Further prospective research is merited to understand this vulnerable population.

Dual-targeting chromatin regulation and DNA damage repair signaling presents a promising avenue for cancer therapy. Applying rational drug design, we synthesized a potent dual-targeting small molecule, SP-1-303. Here, we report SP-1-303 as a class I isoform selective histone deacetylase (HDAC) inhibitor and an activator of the ataxia-telangiectasia mutated protein (ATM). In vitro enzymatic assays demonstrated selective inhibition of HDAC1 and HDAC3. Cellular growth inhibition studies show that SP-1-303 differentially inhibits growth of estrogen receptor positive breast cancer (ER+ BC) cells with effective growth inhibition concentrations (EC50) for MCF-7 and T47D cells ranging from 0.32 to 0.34 μM, compared to 1.2-2.5 μM for triple negative breast cancer cells, and ~12 μM for normal breast epithelial cells. Western analysis reveals that SP-1-303 decreases estrogen receptor alpha (ER-α) expression and increases p53 protein expression, while inducing the phosphorylation of ATM and its substrates, BRCA1 and p53, in a time-dependent manner in ER+ BC cells. Pharmacokinetic evaluation demonstrates an area under the curve (AUC) of 5227.55 ng/ml × h with an elimination half-life of 1.26 h following intravenous administration in a rat model. Collectively, SP-1-303 emerges as a novel second generation class I (HDAC1 and HDAC3) selective HDAC inhibitor, and ATM activator, capable of modulating ER expression, and inhibiting growth of ER+ BC cells. Combined targeting of class I HDACs and ATM by SP-1-303 offers a promising therapeutic approach for treating ER+ breast cancers and supports further preclinical evaluation.

Abstract Dynamic Network Analysis (DyNA) and Dynamic Hypergraphs (DyHyp) were used to define protein-level inflammatory networks at the local (wound effluent) and systemic circulation (serum) levels from 140 active-duty, injured service members (59 with TBI and 81 non-TBI). Interleukin (IL)-17A was the only biomarker elevated significantly in both serum and effluent in TBI vs. non-TBI casualties, and the mediator with the most DyNA connections in TBI wounds. DyNA combining serum and effluent data to define cross-compartment correlations suggested that IL-17A bridges local and systemic circulation at late time points. DyHyp suggested that systemic IL-17A upregulation in TBI patients was associated with tumor necrosis factor-α, while IL-17A downregulation in non-TBI patients was associated with interferon-γ. Correlation analysis suggested differential upregulation of pathogenic Th17 cells, non-pathogenic Th17 cells, and memory/effector T cells. This was associated with reduced procalcitonin in both effluent and serum of TBI patients, in support of an antibacterial effect of Th17 cells in TBI patients. Dysregulation of Th17 responses following TBI may drive cross-compartment inflammation following combat injury, counteracting wound infection at the cost of elevated systemic inflammation.

Ether solvents have poor anodic stabilities in lithium metal batteries. Here, the authors propose a non-aqueous electrolyte solution with a non-polar and non-fluorinated ether solvent. The electrolyte enables stable cycling of high-voltage Li metal batteries in pouch cell configuration.

BACKGROUND: The evolving landscape of application processes for obstetrics and gynecology residency applicants poses many challenges for applicants and advisors. The lack of data coordination among national groups creates crucial gaps in information for stakeholder groups. OBJECTIVE: This study aimed to identify the current state of the advising milieu for obstetrics and gynecology residency applicants and their career advisors, the annual Association of Professors of Gynecology and Obstetrics survey focused on US clerkship directors’ experiences advising students through these processes. STUDY DESIGN: A 23-item anonymous survey was developed that asked respondents about demographics and outcomes for the students that they advised through the 2021 application process and their experiences with dual applicants and students not matching. The survey was sent electronically to all obstetrics and gynecology clerkship directors with active Association of Professors of Gynecology and Obstetrics memberships in April 2021. RESULTS: Of 224 total clerkship directors, 143 (63.8%) responded to the survey, Of the 143 respondents, almost all (136 [95.1%]) served as career advisors, and 50 (35.0%) were aware of students dual applying. Furthermore, obstetrics and gynecology was rarely the backup to a more competitive specialty. For the 2021 application cycle, 79 of 143 respondents (55.2%) reported having students not successfully match into obstetrics and gynecology, with “academic concerns” followed by “poor communication skills” as the primary reasons cited for students not matching. CONCLUSION: This snapshot of clerkship directors’ experiences advising students in the residency application process reveals notably high rates of dual applicants and students not matching into obstetrics and gynecology. This work fills key gaps in our knowledge of current processes and highlights the importance of career advising at multiple points during the application process.

Temporary interruption of the inferior vena cava is the recommended treatment to prevent pulmonary embolism in patients with venous thromboembolism (VTE) and active contraindications for therapeutic anticoagulation. In patients with mega cava (diameter >30 mm), temporary inferior vena cava filters are contraindicated. In the present report, we have described the successful placement and retrieval of bilateral iliac vein filters in two patients with VTE, mega cava, and active contraindications for therapeutic anticoagulation. At the last follow-up, both patients had recovered without recurrent VTE and had had all filters successfully retrieved without complications.

IntroductionThe demand for appearance and performance enhancing substances, including muscle building supplements and anabolic androgenic steroids, is increasing in Australia. However, little is known about the associations between appearance and performance-based factors and appearance and performance enhancing substances (APES), particularly among adolescent boys. This study sought to examine (a) the prevalence of muscle building supplement use in a sample of adolescent boys and (b) how both performance and appearance factors relate to muscle building supplement use and favourable attitudes towards anabolic androgenic steroids in this sample.MethodN = 488 adolescent boys aged 13–16 (Mage = 14.59) from nine Australian schools completed measures of supplement use, favourable attitudes towards using steroids, muscle dissatisfaction, body fat dissatisfaction, mesomorphic ideal internalisation, weight training, and sports participation. Hierarchical logistic regressions were used to examine cross-sectional correlates of muscle building supplement use and favourable attitudes towards using anabolic androgenic steroids.ResultsIn the past three months, 12.7% of the sample had used muscle building supplements. Both appearance and performance-related factors – mesomorphic ideal internalisation and weight training – were related to muscle building supplement use. Only one appearance-related factor – body dissatisfaction – was related to favourable attitudes towards anabolic androgenic steroids.DiscussionThe findings from this study are important as they may help to guide intervention strategies regarding appearance and performance enhancing substance use by Australian adolescent boys, with the ultimate goal of ensuring this population’s safety.

Envisioning success and its pursuit as an enduring feature of human group life, this paper exam­ines success as a humanly constructed and realized social process. As framed herein, success represents the attribution by some audience of qualities associated with achievement, attainment, and/or accomplishment to social act(s) and/or social objects. Consistent with symbolic interactionist approaches to the study of deviance, success is not a quality of the situation at hand, but rather is audience-dependent. Therefore, while the social construction of success may be evidence-based, what is defined as successful outcomes and what constitutes evidence of success is subculturally located. Drawing on extended ethnographic research, an application of alternate definitions of success is examined in the context of those participating in an electorally unsuccess­ful political party—the Christian Heritage Party of Canada. Specifically, this paper examines the definition of success in terms of political influence, providing political alternatives and demonstrations of religious faithfulness as strategies of success-claiming. Framing success in process terms, this paper examines the trans-contextual and trans-historical qualities of “doing success” as a feature of everyday life.

Cardiac troponin (Tn) plays a central role in the evaluation of patients with angina presenting with acute coronary syndrome. The advent of high-sensitivity assays has improved the analytic sensitivity and precision of serum Tn measurement, but this advancement has come at the cost of poorer specificity. The role of clinical judgment is of heightened importance because, more so than ever, the interpretation of serum Tn elevation hinges on the careful integration of findings from electrocardiographic, echocardiographic, physical exam, interview, and other imaging and laboratory data to formulate a weighted differential diagnosis. A thorough understanding of the epidemiology, mechanisms, and prognostic implications of Tn elevations in each cardiac and non-cardiac etiology allows the clinician to better distinguish between presentations of myocardial ischemia and myocardial injury—an important discernment to make, as the treatment of acute coronary syndrome is vastly different from the workup and management of myocardial injury and should be directed at the underlying cause.

Drawing upon the extended symbolic interactionist tradition, this paper examines management activities in the context of office holders and teams. As researchers, if we wish to fully appreciate management in everyday life, then we must pay particular attention to teams, team creation and teamwork, for it is through people doing things together that organizational life is realized. Specifically, I examine the relevance of performance teams, legacy teams, legislated teams, mission-based teams, and the relevance of secrecy for enacting teams. Encouraging an attentiveness to perspectives and activities of office holders, this paper resists more structural renderings of organizational life and encourages researcher to attend to management in the making.

Abstract Background Mass incarceration, commonly associated with overcrowding and inadequate health resources for incarcerated people, creates a fertile environment for the spread of the coronavirus disease 2019 (COVID-19) in U.S. correctional facilities. The exact role that correctional facilities play in enhancing COVID-19 spread and enabling community re-emergence of COVID-19 is unknown. Methods We constructed a novel stochastic model of COVID-19 transmission to estimate the impact of correctional facilities, specifically jails and state prisons, for enhancing disease transmission and enabling disease re-emergence in local communities. Using our model, we evaluated scenarios of testing and quarantining infected incarcerated people at 0.0, 0.5, and 1.0 times the rate that occurs for infected people in the community for population sizes of 5, 10, and 20 thousand people. Results Our results illustrate testing and quarantining an incarcerated population of 800 would reduce the probability of a major outbreak in the local community. In addition, testing and quarantining an incarcerated population would prevent between 10 to 2640 incidences of COVID-19 per year, and annually save up to 2010 disability-adjusted life years, depending on community size. Conclusions Managing COVID-19 in correctional facilities is essential to mitigate risks to community health, and thereby stresses the importance of improving the health standards of incarcerated people.

BACKGROUND: Given the increasing complexities of the residency application processes, there is an ever-increasing need for faculty to serve in the role of fourth-year medical student career advisors. OBJECTIVE: This study aimed to investigate obstetrics and gynecology clerkship directors’ confidence and fulfillment with serving in the role of faculty career advisors. STUDY DESIGN: A 25-item electronic survey was developed and distributed to the 225 US obstetrics and gynecology clerkship directors in university-based and community-based medical schools with active memberships in the Association of Professors of Gynecology and Obstetrics. Items queried respondents on demographics, confidence in fourth-year advising, satisfaction with this aspect of their career, and resources used for advising. RESULTS: Of 225 clerkship directors, 143 (63.6%) responded to the survey. Nearly all clerkship directors (136/143 [95%]) reported advising fourth-year students. A median of 5.0 hours (interquartile range, 3.0–10.0) was spent per student in this advisory role, with 29 of 141 clerkship directors (20.5%) reporting some form of compensation for advising. Confidence in the ability to advise fourth-year medical students correlated significantly with number of years as a faculty, number of years as a clerkship director, and a higher full-time equivalent allotted as clerkship director. Fulfillment as a faculty career advisor was correlated with number of years as a clerkship director and a higher number of students advised. CONCLUSION: Obstetrics and gynecology clerkship directors regularly serve in the crucial role of faculty career advisor. Confidence in advising fourth-year students, advising fulfillment, and satisfaction with advising resources were all significantly correlated. We recommend that clerkship directors review resources available for advising and that they be provided academic time to serve as career advisors.

Abstract Background This study explores the long term anatomic and functional results of patients who were switched to intravitreal aflibercept injections (IAI) after being initially managed with other anti-VEGF agents for neovascular age-related macular degeneration (nAMD). Methods Patients with nAMD were included if they started with another anti-VEGF agent and were switched to IAI. Subjects had at least 3 years of consistent therapy with IAI and at least 1 injection quarterly. Results Eighty-eight patients had at least 3 years of treatment while 58 of those patients, had at least 4 years of IAI. Average treatment time with other anti-VEGF agents was 32 months prior to switching. Baseline best corrected vision (VA) was 59.4 letters (20/70 + 2). At time of switch, VA increased significantly to 66.7 letters (20/50 + 2). At 3 months after switch, VA increased significantly to 69.0 (20/40−) letters. After 3 years of consistent IAI, vision was 67.5 letters (20/40−2), and for those patients that completed 4 years of therapy, the average VA was 66.0 letters (20/50 + 2), with a gain of 6.6 letters over baseline vision. 32.1% of patients gained 3 or more lines of vision. Initial central macular thickness (CMT) was 369 µm, which improved to 347 µm at time of switch, and further improved at 3 months to 301 µm and was maintained over time. Conclusion Patients switched to IAI can maintain vision over the long term. Patients treated on average for 5.7 years, had a visual gain of 8.1 letters after 3 years and 6.6 letters after 4 years of IAI therapy. CMT significantly improved following the switch and was maintained.

Antiangiogenic therapy began as an effort to inhibit VEGF signaling, which was thought to be the sole factor driving tumor angiogenesis. It has become clear that there are more pro-angiogenic growth factors that can substitute for VEGF during tumor vascularization. This has led to the development of multi-kinase inhibitors which simultaneously target multiple growth factor receptors. These inhibitors perform better than monotherapies yet to date no multi-kinase inhibitor targets all receptors known to be involved in pro-angiogenic signaling and resistance inevitably occurs. Given the large number of pro-angiogenic growth factors identified, it may be impossible to simultaneously target all pro-angiogenic growth factor receptors. Here we search for kinase targets, some which may be intracellularly localized, that are critical in endothelial cell proliferation irrespective of the growth factor used. We develop a quantitative endothelial cell proliferation assay and combine it with “kinome regression” or KIR, a recently developed method capable of identifying kinases that influence a quantitative phenotype. We report the kinases implicated by KIR and provide orthogonal evidence of their importance in endothelial cell proliferation. Our approach may point to a new strategy to develop a more complete anti-angiogenic blockade.

The calcium-selective ion channel Orai1 has a complex role in bone homeostasis, with defects in both bone production and resorption detected in Orai1 germline knock-out mice. To determine whether Orai1 has a direct, cell-intrinsic role in osteoblast differentiation and function, we bred Orai1 flox/flox (Orai1fl/fl) mice with Runx2-cre mice to eliminate its expression in osteoprogenitor cells. Interestingly, Orai1 was expressed in a mosaic pattern in Orai1fl/fl-Runx2-cre bone. Specifically, antibody labeling for Orai1 in vertebral sections was uniform in wild type animals, but patchy regions in Orai1fl/fl-Runx2-cre bone revealed Orai1 loss while in other areas expression persisted. Nevertheless, by micro-CT, bones from Orai1fl/fl-Runx2-cre mice showed reduced bone mass overall, with impaired bone formation identified by dynamic histomorphometry. Cortical surfaces of Orai1fl/fl-Runx2-cre vertebrae however exhibited patchy defects. In cell culture, Orai1-negative osteoblasts showed profound reductions in store-operated Ca2+ entry, exhibited greatly decreased alkaline phosphatase activity, and had markedly impaired substrate mineralization. We conclude that defective bone formation observed in the absence of Orai1 reflects an intrinsic role for Orai1 in differentiating osteoblasts.

Cosmetic surgery is extremely popular. Despite this, negative attitudes towards cosmetic surgery recipients prevail. Across two pre-registered studies, we examined whether intrasexual competitiveness explains these negative attitudes. Participants in Study 1 were 343 (mean age = 24.74) single heterosexual American women and participants in Study 2 were 445 (mean age = 19.03) single heterosexual Australian women. Participants in both studies were primed for either low or high intrasexual competitiveness. Contrary to our predictions, we found that priming condition did not influence participants’ derogation and social exclusion of cosmetic surgery recipients. We did, however, find evidence for a ‘relative attractiveness’ halo effect: participants engaged in less derogation and social exclusion when they assumed cosmetic surgery recipients were more attractive than themselves. This suggests that 'pretty privilege' extends not only to women who meet conventional beauty standards, but also to those who are perceived as relatively closer to meeting these standards than the individual with whom they are engaging. Overall, we concluded that intrasexual competitiveness does not encourage the stigmatisation of cosmetic surgery recipients and examined alternative explanations for this phenomenon.

The high cost of noble metals is a barrier to widespread commercialization of polymer electrolyte membrane fuel cells. Platinum-group-metal-free catalysts are a promising low-cost alternative for catalyzing the oxygen reduction reaction (ORR). Herein, we report a high activity Fe-N-C cathode catalyst derived from a Fe-porphyrinic framework prepared using low-cost precursors and facile one pot synthesis followed by a single heat treatment. The final product has atomically dispersed iron in proximity to nitrogen groups that share transition metal characteristics, as described by electron energy loss spectrometry and x-ray absorption near edge structure results. Electrochemical studies on a rotating ring-disk electrode indicate a four-electron transfer mechanism for the ORR. Membrane electrode assembly testing of the Fe-porphyrin-derived cathode catalyst shows a high kinetic current density of 22 mA cm^{−2} at 0.9 V in H_{2}-O_{2} fuel cells.

Abstract Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1–16.2] for BRCA1, 4.0 [1.9–9.1] for BRCA2, 3.4 [1.4–8.4] for ATM and 4.3 [1.0–17.0] for PALB2. Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes.

Rarely are communications networks point-to-point. In most cases, transceiver relay stations exist between transmitter and receiver end-points. These relay stations, while essential for controlling cost and adding flexibility to network architectures, reduce the overall security of the respective network. In an effort to quantify that reduction, we extend the Quality of Secure Service (QoSS) model to these complex networks, specifically multi-hop networks. In this approach, the quantification of security is based upon probabilities that adversarial listeners and disruptors gain access to or manipulate transmitted data on one or more of these multi-hop channels. Message fragmentation and duplication across available channels provides a security performance trade-space, with its consequent QoSS. This work explores that trade-space and the corresponding QoSS model to describe it.

Introduction Individuals living with and beyond cancer from rural and remote areas lack accessibility to supportive cancer care resources compared with those in urban areas. Exercise is an evidence-based intervention that is a safe and effective supportive cancer care resource, improving physical fitness and function, well-being and quality of life. Thus, it is imperative that exercise oncology programs are accessible for all individuals living with cancer, regardless of geographical location. To improve accessibility to exercise oncology programs, we have designed the EXercise for Cancer to Enhance Living Well (EXCEL) study.Methods and analysis EXCEL is a hybrid effectiveness-implementation study. Exercise-based oncology knowledge from clinical exercise physiologists supports healthcare professionals and community-based qualified exercise professionals, facilitating exercise oncology education, referrals and programming. Recruitment began in September 2020 and will continue for 5 years with the goal to enroll ~1500 individuals from rural and remote areas. All tumour groups are eligible, and participants must be 18 years or older. Participants take part in a 12-week multimodal progressive exercise intervention currently being delivered online. The reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework is used to determine the impact of EXCEL at participant and institutional levels. Physical activity, functional fitness and patient-reported outcomes are assessed at baseline and 12-week time points of the EXCEL exercise intervention.Ethics and dissemination The study was approved by the Health Research Ethics Board of Alberta. Our team will disseminate EXCEL information through quarterly newsletters to stakeholders, including participants, qualified exercise professionals, healthcare professionals and community networks. Ongoing outreach includes community presentations (eg, support groups, fitness companies) that provide study updates and exercise resources. Our team will publish manuscripts and present at conferences on EXCEL’s ongoing implementation efforts across the 5-year study.Trial registration number NCT04478851.

Abstract RTS,S/AS01 is an advanced pre-erythrocytic malaria vaccine candidate with demonstrated vaccine efficacy up to 86.7% in controlled human malaria infection (CHMI) studies; however, reproducible immune correlates of protection (CoP) are elusive. To identify candidates of humoral correlates of vaccine mediated protection, we measured antibody magnitude, subclass, and avidity for Plasmodium falciparum (Pf) circumsporozoite protein (CSP) by multiplex assays in two CHMI studies with varying RTS,S/AS01B vaccine dose and timing regimens. Central repeat (NANP6) IgG1 magnitude correlated best with protection status in univariate analyses and was the most predictive for protection in a multivariate model. NANP6 IgG3 magnitude, CSP IgG1 magnitude, and total serum antibody dissociation phase area-under-the-curve for NANP6, CSP, NPNA3, and N-interface binding were also associated with protection status in the regimen adjusted univariate analysis. Identification of multiple immune response features that associate with protection status, such as antibody subclasses, fine specificity and avidity reported here may accelerate development of highly efficacious vaccines against P. falciparum.

Background: Physical inactivity is an important risk factor for cardiovascular disease (CVD). Atlantic Canada is a region with lower physical activity (PA) levels and poorer CVD outcomes than the rest of Canada. Yet, within-region variation is expected. This study aimed to assess the association between PA and CVD and how this relationship varied on a regional level. Methods: This cross-sectional study used data from the Atlantic Partnership for Tomorrow’s Health (PATH) Study. The cohort included 823 CVD cases and 2469 age-, sex-, and province of residence-matched controls between the ages 35 and 69. Data collected included self-reported CVD and PA levels as well as information on sociodemographic characteristics, health status, and lifestyle behaviours. Simple and multiple logistic regression were used to assess the association between PA and CVD. Results: High PA levels were associated with a 26% reduction in the mean probability of CVD compared with low PA levels across the total population. Compared with high PA levels, moderate and low PA levels were associated with increased odds of CVD across all 4 provinces. However, regional variation was observed, with higher odds of CVD for low-to-moderate PA levels in Newfoundland and Labrador and New Brunswick compared with Nova Scotia and Prince Edward Island. Conclusions: Atlantic Canadians experience regional inequalities in the association between PA and CVD. Future work needs to explore underlying pathways driving these regional differences, which may be the impetus for interventions that mitigate risk and CVD burden in populations of greatest need. Résumé: Introduction: L’inactivité physique est un facteur de risque important de maladies cardiovasculaires (MCV). Le Canada atlantique est une région où les taux d’activité physique (AP) sont faibles et les issues des MCV sont moins bonnes que dans le reste du pays. Cependant, on s’attend à des variations entre les régions. La présente étude a pour objectif d’évaluer l’association entre l’AP et les MCV, et la façon dont cette relation varie sur le plan régional. Méthodes: Cette étude transversale a utilisé les données de l’étude La VOIE atlantique (le Partenariat de l’Atlantique pour la santé de demain). La cohorte comptait 823 cas de MCV et 2 469 témoins de 35 à 69 ans appariés selon l’âge, le sexe et la province de résidence. Les données collectées étaient les suivantes : les MCV et les taux d’AP, ainsi que les renseignements sur les caractéristiques sociodémographiques, l’état de santé et les comportements liés au mode de vie. Nous avons utilisé la régression logistique simple et multiple pour évaluer l’association entre l’AP et les MCV. Résultats: Les taux élevés d’AP ont été associés à une réduction de 26 % de la probabilité moyenne des MCV comparativement à des taux faibles d’AP dans l’ensemble de la population. Comparativement à des taux élevés d’AP, les taux faibles et modérés d’AP ont été associés à une probabilité accrue de MCV dans les 4 provinces. Toutefois, nous avons observé des variations régionales lors de taux faibles à modérés d’AP, soit une probabilité plus élevée de MCV à Terre-Neuve-et-Labrador et au Nouveau-Brunswick qu’en Nouvelle-Écosse et à l’Île-du-Prince-Édouard. Conclusions: Les Canadiens de l’Atlantique montrent des inégalités régionales dans l’association entre l’AP et les MCV. D’autres travaux sont nécessaires pour étudier les voies sous-jacentes entraînant ces différences régionales et peuvent donner lieu à des interventions qui allègent le risque et le fardeau des MCV au sein des populations dont les besoins sont les plus grands.

Although not common today, communications networks could adjust security postures based on changing mission security requirements, environmental conditions, or adversarial capability, through the coordinated use of multiple channels. This will require the ability to measure the security of communications networks in a meaningful way. To address this need, in this paper, we introduce the Quality of Secure Service (QoSS) model, a methodology to evaluate how well a system meets its security requirements. This construct enables a repeatable and quantifiable measure of security in a single- or multi-channel network under static configurations. In this approach, the quantification of security is based upon the probabilities that adversarial listeners and disruptors may gain access to or manipulate transmitted data. The initial model development, albeit a snap-shot of the network security, provides insights into what may affect end-to-end security and to what degree. The model was compared against the performance and expected security of several point-to-point networks, and three simplified architectures are presented as examples. Message fragmentation and duplication across the available channels provides a security performance trade-space, with an accompanying comprehensive measurement of the QoSS. The results indicate that security may be improved with message fragmentation across multiple channels when compared to the number of adversarial listeners or disruptors. This, in turn, points to the need, in future work, to build a full simulation environment with specific protocols and networks to validate the initial modeled results.

Stoneflies (Plecoptera) are often associated with inhabiting cold perennial streams, but many species also inhabit intermittent streams that experience reduced or lack of flow during summer and autumn. In this study, the influence of stream permanence on stonefly assemblage composition and spatial distribution at Mammoth Cave National Park, Kentucky, USA, was addressed, based on a 14 month sampling regime from the fullest range of stream sizes and habitable flow regions available. Adult stoneflies were collected monthly from 43 sites at the Park plus an additional two sites at the near-adjacent Western Kentucky University Green River Preserve. Collections were done from December 2018–November 2019 using a standard timed protocol with beating sheets for adults and once in December 2019–January 2020 for larvae. Stream sites were assigned one of five category types: perennial spring runs, perennial spring seeps, upland perennial streams, perennial riverine and summer dry runs. In total, 34 species were collected. The most prominent difference in stonefly community structure was between spring runs, spring seeps and summer dry streams vs. upland perennial streams. Approximately 88% of species collected had univoltine-fast life cycles and 79% likely had an extended period of egg or larval diapause. Due to the predominance of small upland perennial and summer dry streams, species commonly typically found in larger lotic systems are fundamentally filtered out of the region due to the lack of available habitats. Species able to survive in intermittent habitats do so by life history adaptations including to survive desiccation as larvae or eggs.

Purpose: Proton therapy precisely delivers radiation to cancers to cause damaging strand breaks to cellular DNA, kill malignant cells, and stop tumor growth. Therapeutic protons also generate short-lived activated nuclei of carbon, oxygen, and nitrogen atoms in patients as a result of atomic transmutations that are imaged by positron emission tomography (PET). We hypothesized that the transition of 18Oto 18Fin an 18O-substituted nucleoside irradiated with therapeutic protons may result in the potential for combined diagnosis and treatment for cancer with proton therapy. Materials and Methods: Reported here is a feasibility study with a therapeutic proton beam used to irradiate H218O to a dose of 10 Gy produced by an 85 MeV pristine Bragg peak. PET imaging initiated >45 minutes later showed an 18F decay signal with T1/2 of ~111 minutes. Results: The 18Oto 18F transmutation effect on cell survival was tested by exposing SQ20B squamous carcinoma cells to physiologic 18O-thymidine concentrations of 5 μM for 48 hours followed by 1- to 9-Gy graded doses of proton radiation given 24 hours later. Survival analyses show radiation sensitization with a dose modification factor (DMF) of 1.2. Conclusions: These data support the idea of therapeutic transmutation in vitro as a biochemical consequence of proton activation of 18Oto 18F in substituted thymidine enabling proton radiation enhancement in a cancer cell. 18O-substituted molecules that incorporate into cancer targets may hold promise for improving the therapeutic window of protons and can be evaluated further for postproton therapy PET imaging.

For decades, mathematical models of disease transmission have provided researchers and public health officials with critical insights into the progression, control, and prevention of disease spread. Of these models, one of the most fundamental is the SIR differential equation model. However, this ubiquitous model has one significant and rarely acknowledged shortcoming: it is unable to account for a disease's true infectious period distribution. As the misspecification of such a biological characteristic is known to significantly affect model behavior, there is a need to develop new modeling approaches that capture such information. Therefore, we illustrate an innovative take on compartmental models, derived from their general formulation as systems of nonlinear Volterra integral equations, to capture a broader range of infectious period distributions, yet maintain the desirable formulation as systems of differential equations. Our work illustrates a compartmental model that captures any Erlang distributed duration of infection with only 3 differential equations, instead of the typical inflated model sizes required by traditional differential equation compartmental models, and a compartmental model that captures any mean, standard deviation, skewness, and kurtosis of an infectious period distribution with 4 differential equations. The significance of our work is that it opens up a new class of easy-to-use compartmental models to predict disease outbreaks that do not require a complete overhaul of existing theory, and thus provides a starting point for multiple research avenues of investigation under the contexts of mathematics, public health, and evolutionary biology.

Percutaneous biopsy can be used for tissue diagnosis of bladder tumors when cystoscopy with transurethral resection is not possible. The largest known case series includes 15 patients with no reported complications and good concordance with surgical pathology. However, concern remains regarding exposure of nonurothelial surfaces to tumor cells, as there are rare documented cases of tumor seeding along nephrostomy and biopsy tracts in upper tract urothelial carcinoma (UC). We present the first documented human case of bladder cancer involvement of the omentum and peritoneum along a biopsy tract and review the use of percutaneous access for upper and lower tract UC.

Abstract Background Profiling immune responses induced by either infection or vaccination can provide insight into identification of correlates of protection. Furthermore, profiling of serological responses can be used to identify biomarkers indicative of exposure to pathogens. Conducting such immune surveillance requires readout methods that are high-throughput, robust, and require small sample volumes. While the enzyme-linked immunosorbent assay (ELISA) is the classical readout method for assessing serological responses, the advent of multiplex assays has significantly increased the throughput and capacity for immunoprofiling. This report describes the development and assay performance (sensitivity, linearity of detection, requirement for multiple dilutions for each sample, intra- and inter-assay variability) of an electro-chemiluminescence (ECLIA)-based multiplex assay. Methods The current study describes the development of a multiplex ECLIA-based assay and characterizes the sensitivity, linear range, and inter- and intra-assay variability of the ECLIA platform and its agreement with the traditional ELISA. Special emphasis was placed on potential antigenic competition when testing closely related antigens in the multiplex format. Results Multiplexing of antigens in ECLIA provides significant practical benefits in terms of reducing sample volume requirements and experimental time. Beyond the practical advantages of multiplexing, the ECLIA provides superior assay performance when compared to the ELISA. Not only does ECLIA show good agreement with the ELISA assay, but the linear range of ECLIA is also sufficiently wide to permit single-dilution measurements of concentration without the need to do serial dilutions. The lack of antigenic competition allows the simultaneous testing of closely related antigens, such as plate antigens representing different alleles of the same protein, which can inform about cross-reactivities—or lack thereof—of serological responses. Conclusion The advantages of the newly developed tool for assessing the antigen profiles of serological responses may ultimately lead to the identification of biomarkers associated with various disease stages and or protection against disease.