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Abstract We analyzed genomic data from the prostate cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CHD1-deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. Subclonal deletion of CHD1 was nearly three times as frequent in prostate tumors of African American than in European American men and it associates with rapid disease progression. CHD1 deletion was not associated with HR deficiency associated mutational signatures or HR deficiency as detected by RAD51 foci formation. This was consistent with the moderate increase of olaparib and talazoparib sensitivity with several CHD1 deficient cell lines showing talazoparib sensitivity in the clinically relevant concentration range. CHD1 loss may contribute to worse disease outcome in African American men.

Abstract Tinnitus is a common sensorineural complication that can occur de novo or after cancer treatments involving cisplatin or radiotherapy. Considering the heterogeneous etiology and pathophysiology of tinnitus, the extent to which shared genetic risk factors contribute to de novo tinnitus and cancer treatment-induced tinnitus is not clear. Here we report a GWAS for de novo tinnitus using the UK Biobank cohort with nine loci showing significantly associated variants (p

Abstract Throughout development, complex networks of cell signaling pathways drive cellular decision-making across different tissues and contexts. The transforming growth factor β (TGF-β) pathways, including the BMP/Smad pathway, play crucial roles in determining cellular responses. However, as the Smad pathway is used reiteratively throughout the life cycle of all animals, its systems-level behavior varies from one context to another, despite the pathway connectivity remaining nearly constant. For instance, some cellular systems require a rapid response, while others require high noise filtering. In this paper, we examine how the BMP-Smad pathway balances trade-offs among three such systems-level behaviors, or “Performance Objectives (POs)”: response speed, noise amplification, and the sensitivity of pathway output to receptor input. Using a Smad pathway model fit to human cell data, we show that varying non-conserved parameters (NCPs) such as protein concentrations, the Smad pathway can be tuned to emphasize any of the three POs and that the concentration of nuclear phosphatase has the greatest effect on tuning the POs. However, due to competition among the POs, the pathway cannot simultaneously optimize all three, but at best must balance trade-offs among the POs. We applied the multi-objective optimization concept of the Pareto Front, a widely used concept in economics to identify optimal trade-offs among various requirements. We show that the BMP pathway efficiently balances competing POs across species and is largely Pareto optimal. Our findings reveal that varying the concentration of NCPs allows the Smad signaling pathway to generate a diverse range of POs. This insight identifies how signaling pathways can be optimally tuned for each context.

Benign adrenal cysts are relatively uncommon variants of all adrenal incidentalomas. When identified, most benign adrenal cysts are asymptomatic, which differentiates them from other functional adrenal lesions. There are various types of adrenal cysts, although the most common being an endothelial cyst. Ultimately, evaluation and management approaches are aimed at ruling out a functional adrenal mass and management of symptoms if present. We present a unique presentation of an otherwise healthy male with a large incidental adrenal cyst, later identified as a benign endothelial cyst, who presented with classic symptoms of catecholamine excess. The patient had a negative hormonal evaluation, and his episodic symptoms were resolved with surgical removal of the adrenal mass. This case report and brief review provides valuable insight into the evaluation and management of a unique clinical scenario, where a benign cystic mass led to compression-related symptoms of catecholamine excess that were resolved after removal of the nonfunctional, cystic, mass.

Abstract Sex differences and age-related changes in the human heart at the tissue, cell, and molecular level have been well-documented and many may be relevant for cardiovascular disease. However, how molecular programs within individual cell types vary across individuals by age and sex remains poorly characterized. To better understand this variation, we performed single-nucleus combinatorial indexing (sci) ATAC- and RNA-Seq in human heart samples from nine donors. We identify hundreds of differentially expressed genes by age and sex and find epigenetic signatures of variation in ATAC-Seq data in this discovery cohort. We then scale up our single-cell RNA-Seq analysis by combining our data with five recently published single nucleus RNA-Seq datasets of healthy adult hearts. We find variation such as metabolic alterations by sex and immune changes by age in differential expression tests, as well as alterations in abundance of cardiomyocytes by sex and neurons with age. In addition, we compare our adult-derived ATAC-Seq profiles to analogous fetal cell types to identify putative developmental-stage-specific regulatory factors. Finally, we train predictive models of cell-type-specific RNA expression levels utilizing ATAC-Seq profiles to link distal regulatory sequences to promoters, quantifying the predictive value of a simple TF-to-expression regulatory grammar and identifying cell-type-specific TFs. Our analysis represents the largest single-cell analysis of cardiac variation by age and sex to date and provides a resource for further study of healthy cardiac variation and transcriptional regulation at single-cell resolution.

Abstract Background Subsequent short‐latency leukemias are well‐described among survivors of childhood cancer. However, late (5–14.9 years from diagnosis, LL) and very late (≥15 years from diagnosis, VLL) subsequent leukemias have not been well studied. We assessed risk factors, prevalence, and outcomes for LL and VLL in the Childhood Cancer Survivor Study cohort. Methods Subsequent leukemias, among 25,656 five‐year survivors, were self‐reported and confirmed by pathology review. Standardized incidence ratios (SIR) and cumulative incidences were calculated, and relative risks (RR) were estimated using Cox regression for exposures. Results Seventy‐seven survivors developed subsequent leukemia, 49 survivors with LL (median time from diagnosis 7.8 years, range 5.0–14.5 years) and 28 with VLL (median time from diagnosis 25.4 years, range 15.9–42.8 years), with a cumulative incidence of 0.23% (95% CI 0.18%–0.30%) 20 years from diagnosis for all subsequent leukemias. The most common leukemia subtypes were acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. Compared to the general population, survivors were at increased risk, for developing LL (SIR 9.3, 95% CI 7.0–12.1) and VLL (SIR 5.9, 95% CI 3.9–8.4). In multivariable relative risk analyses, cumulative epipodophyllotoxin dose >4000 mg/m2 was associated with increased risk for LL and VLL (RR 4.5, 95% CI 2.0–9.9). Conclusions In this large series of late subsequent leukemias, survivors of childhood cancer are at increased risk, with no evidence of plateau over time. We observed most risk among survivors who received high cumulative doses of epipodophyllotoxins. Ongoing consideration for this late effect should continue beyond 10 years.

The Nix-TB clinical trial evaluated a new 6 month regimen containing three oral drugs; bedaquiline (B), pretomanid (Pa), and linezolid (L) (BPaL regimen) for the treatment of tuberculosis (TB). This regimen achieved remarkable results as almost 90% of the multidrug-resistant or extensively drug-resistant TB participants were cured but many patients also developed severe adverse events (AEs). The AEs were associated with the long-term administration of the protein synthesis inhibitor linezolid. Spectinamide 1599 is also a protein synthesis inhibitor of Mycobacterium tuberculosis with an excellent safety profile, but it lacks oral bioavailability. Here, we propose to replace L in the BPaL regimen with spectinamide (S) administered via inhalation and we demonstrate that inhaled spectinamide 1599, combined with BPa ––BPaS regimen––has similar efficacy to that of the BPaL regimen while simultaneously avoiding the L-associated AEs. The BPaL and BPaS regimens were compared in the BALB/c and C3HeB/FeJ murine chronic TB efficacy models. After 4-weeks of treatment, both regimens promoted equivalent bactericidal effects in both TB murine models. However, treatment with BPaL resulted in significant weight loss and the complete blood count suggested the development of anemia. These effects were not similarly observed in mice treated with BPaS. BPaL and BPa, but not the BPaS treatment, also decreased myeloid to erythroid ratio suggesting the S in the BPaS regimen was able to recover this effect. Moreover, the BPaL also increased concentration of proinflammatory cytokines in bone marrow compared to mice receiving BPaS regimen. These combined data suggest that inhaled spectinamide 1599 combined with BPa is an effective TB regimen without L-associated AEs.

Abstract Background & Methods In this study, a novel restriction enzyme (RE) digestion-based droplet digital polymerase chain reaction (ddPCR) assay was designed for cg005575921 within the AHRR gene body and compared with matching results obtained by bisulfite conversion (BIS) ddPCR and Illumina DNA methylation array. Results The RE ddPCR cg05575921 assay appeared concordant with BIS ddPCR (r 2 = 0.94, P

Abstract Effective science instruction and associated student learning is reliant upon a strong foundation of teacher content knowledge. This study of the Praxis Ⓡ General Science Content Knowledge Test from May 2006 to June 2016 investigates content knowledge of 28,688 general science teacher candidates. Examinees performed well on Life Science topics while Earth & Space Science was identified as an area in need of support. Analysis of the assessment revealed differences in achievement associated with undergraduate major, gender, and ethnicity. Test-takers with STEM majors demonstrated stronger content knowledge than their out-of-field counterparts, that men outperformed women in the study, and White test-takers lost fewer scaled points than Black and Hispanic candidates. To strengthen recruitment and retention efforts, recommendations include reviewing our findings for alignment with state standards. This will facilitate development of comprehensive content knowledge professional learning experiences that will be used as an anchor for focused support on those topics where test-takers tend to demonstrate lowest proficiency.

The chemokine CCL28 is highly expressed in mucosal tissues, but its role during infection is not well understood. Here, we show that CCL28 promotes neutrophil accumulation in the gut of mice infected with Salmonella and in the lung of mice infected with Acinetobacter. Neutrophils isolated from the infected mucosa expressed the CCL28 receptors CCR3 and, to a lesser extent, CCR10, on their surface. The functional consequences of CCL28 deficiency varied between the two infections: Ccl28−/− mice were highly susceptible to Salmonella gut infection but highly resistant to otherwise lethal Acinetobacter lung infection. In vitro, unstimulated neutrophils harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following phagocytosis or inflammatory stimuli. Moreover, CCL28 stimulation enhanced neutrophil antimicrobial activity, production of reactive oxygen species, and formation of extracellular traps, all processes largely dependent on CCR3. Consistent with the different outcomes in the two infection models, neutrophil stimulation with CCL28 boosted the killing of Salmonella but not Acinetobacter. CCL28 thus plays a critical role in the immune response to mucosal pathogens by increasing neutrophil accumulation and activation, which can enhance pathogen clearance but also exacerbate disease depending on the mucosal site and the infectious agent.

BackgroundMedulloblastoma is the most common malignant brain tumor in children. Most cases are sporadic, but well characterized germline alterations in APC, ELP1, GPR161, PTCH1, SUFU, and TP53 predispose to medulloblastoma. However, knowledge about pathogenic/likely pathogenic (P/LP) variants that predispose to medulloblastoma vary based on genes evaluated, patient demographics, and pathogenicity definitions.MethodsGermline exome sequencing was conducted on 160 childhood survivors of medulloblastoma. Analyses focused on rare variants in 239 known cancer susceptibility genes (CSGs). P/LP variants were identified using ClinVar and InterVar. Variants of unknown significance in known medulloblastoma predisposing genes (APC, ELP1, GPR161, PTCH1, SUFU, TP53) were further classified for loss of function variants. We compared the frequency of P/LP variants in cases to that in 1,259 cancer-free adult controls.ResultsTwenty cases (12.5%) had a P/LP variant in an autosomal dominant CSG versus 5% in controls (p=1.0 x10-3), and 10 (6.3%) of these were P/LP variants in a known medulloblastoma gene, significantly greater than 0.2% observed in controls (p=1.4x10-8). The CSGs with the most P/LP variants in cases, and significantly higher than controls, were ELP1 (p=3.0x10-4) and SUFU (p=1.4x10-3).ConclusionApproximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma.

Abstract Purpose The aim of this study was to examine demographic and surgical factors that influence patient‐reported knee function in patients who undergo anterior crucial ligament reconstruction (ACLR) with concurrent bucket‐handle meniscal tear (BHMT) procedures. We hypothesized that repair of BHMT in the setting of concomitant ACLR and shorter time from injury to surgery would lead to improved patient‐reported outcomes. Methods Forty‐one patients (mean age: 28.0 ± 9.8 years, 72% male) with BHMT at the time of ACLR completed the International Knee Documentation Committee Subjective Knee Form (IKDC‐SKF) via online survey at an average of 15.2 months postop. Patient demographics and surgical characteristics, including time from injury to surgery, were compared between repair (n = 22) and meniscectomy (n = 19) groups using one‐way analysis of variances; distributions of sex, graft source, BHMT compartment and zone were compared between groups using χ2 tests. The association between IKDC‐SKF score, demographics and surgical characteristics was evaluated using multivariable linear regression. A priori alpha level was p

Abstract Background Survivors of childhood central nervous system (CNS) tumors can develop motor and sensory impairment from their cancer and treatment history. We estimated the prevalence of motor and sensory impairment in survivors compared with controls through clinical assessment and identified associated treatment exposures and functional, quality of life (QOL), and social outcomes. Methods Survivors of childhood CNS tumors from the St. Jude Lifetime Cohort (n = 378, median [range] age 24.0 [18.0–53.0] years, 43.4% female) ≥5 years from diagnosis and controls (n = 445, median [range] age 34.0 [18.0–70.0] years, 55.7% female) completed in‐person evaluation for motor and sensory impairment using the modified Total Neuropathy Score. Impairment was graded by modified Common Terminology Criteria for Adverse Events. Multivariable models estimated associations between grade ≥2 motor/sensory impairment, individual/treatment characteristics, and secondary outcomes (function by Physical Performance Test, fitness by physiologic cost index, QOL by Medical Outcomes Survey Short Form‐36 physical/mental summary scores, social attainment). Results Grade ≥2 motor or sensory impairment was more prevalent in survivors (24.1%, 95% Confidence Interval [CI] 19.8%–29.4%) than controls (2.9%, CI 1.4–4.5%). Among survivors, in multivariable models, motor impairment was associated with vinca exposure 2036 mg/m2 versus none (OR 12.61, CI 2.19–72.72). Sensory impairment was associated with older age at diagnosis (OR 1.09, CI 1.01–1.16) and craniospinal irradiation versus none (OR 4.39, CI 1.68–11.50). There were lower odds of motor/sensory impairment in survivors treated in the year 2000 or later versus before 1990 (Motor: OR 0.29, CI 0.10–0.84, Sensory: OR 0.35, CI 0.13–0.96). Motor impairment was associated with impaired physical QOL (OR 2.64, CI 1.22–5.72). Conclusions In survivors of childhood CNS tumors, motor and sensory impairment is prevalent by clinical assessment, especially after exposure to etoposide, vinca, or craniospinal radiation. Treating motor impairment may improve survivors' QOL.

Introduction A substantial proportion of patients with inflammatory bowel disease (IBD) on intravenous infliximab require dose intensification. Accessing additional intravenous infliximab is labour-intensive and expensive, depending on insurance and pharmaceutical reimbursement. Observational data suggest that subcutaneous infliximab may offer a convenient and safe alternative to maintain disease remission in patients requiring dose-intensified infliximab. A prospective, controlled trial is required to confirm that subcutaneous infliximab is as effective as dose-intensified intravenous infliximab, to identify predictors of disease flare and to establish the role of subcutaneous infliximab therapeutic drug monitoring.Methods and analysis The DISCUS-IBD trial is an investigator-initiated, prospective, multicentre, randomised, open-label non-inferiority study comparing the rate of disease flares in participants randomised to continue dose-intensified intravenous infliximab to those switched to subcutaneous infliximab after 48 weeks. Participants are adult patients with IBD in sustained corticosteroid-free remission on any regimen of dose-intensified infliximab up to a maximum of 10 mg/kg 4-weekly intravenously. Participants allocated to intravenous infliximab will continue infliximab at the same dose-intensified regimen they were receiving at study enrolment. Subcutaneous infliximab dosing will be stratified by prior intravenous infliximab dosing. Clinical (Harvey-Bradshaw Index, partial Mayo score), biochemical (C reactive protein, faecal calprotectin), pharmacokinetic (drug-level±antidrug antibodies) and qualitative data are collected 12-weekly until study conclusion at week 48. 13 sites across Australia will participate in recruitment to reach a calculated sample size of 120 participants.Ethics and dissemination Multisite ethics approval was obtained from the Health District Human Research Ethics Committee (HREC) at The Alfred Hospital under a National Mutual Acceptance (NMA) agreement (HREC/90559/Alfred-2022; Local Reference: Project 618/22, version 1.6, 2 March 2023). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. DISCUS-IBD was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) prior to commencing recruitment.Trial registration number ACTRN12622001458729.

Abstract Background Germline cancer genetic testing has become a standard evidence-based practice, with established risk reduction and screening guidelines for genetic carriers. Access to genetic services is limited in many places, which leaves many genetic carriers unidentified and at risk for late diagnosis of cancers and poor outcomes. This poses a problem for childhood cancer survivors, as this is a population with an increased risk for subsequent malignant neoplasms (SMN) due to cancer therapy or inherited cancer predisposition. The ENGaging and Activating cancer survivors in Genetic services (ENGAGE) study evaluates the effectiveness of an in-home, collaborative PCP model of remote telegenetic services to increase uptake of cancer genetic testing in childhood cancer survivors compared to usual care options for genetic testing. Methods The ENGAGE study is a 3-arm randomized hybrid type 1 effectiveness and implementation study within the Childhood Cancer Survivor Study population which tests a clinical intervention while gathering information on its delivery during the effectiveness trial and its potential for future implementation among 360 participants. Participants are randomized into three arms. Those randomized to Arm A receive genetic services via videoconferencing, those in Arm B receive these services by phone, and those randomized to Arm C will receive usual care services. Discussion With many barriers to accessing genetic services, innovative delivery models are needed to address this gap and increase uptake of genetic services. The ENGAGE study evaluates the effectiveness of an adapted model of remote delivery of genetic services to increase the uptake of recommended genetic testing in childhood cancer survivors. This study assesses the uptake in remote genetic services and identify barriers to uptake to inform future recommendations and a theoretically-informed process evaluation which can inform modifications to enhance dissemination beyond this study population and to realize the benefits of precision medicine. Trial registration This protocol was registered at clinicaltrials.gov (NCT04455698) on July 2, 2020.

Abstract Objective To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)‐directed therapies. Methods A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS‐treated]; median age [range] = 25.5 years [18–48]; time since diagnosis = 17.7 years [6.8–30.2]) and 8039 without CNS‐directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal care needs, ability to work/attend school, attainment of driver's license, marital/partner status). Multivariable regression models, adjusted for age, sex, race/ethnicity, and chronic health conditions, estimated odds ratios (OR) or relative risks (RR) for associations between neurologic morbidity, functional independence, and emotional distress. Results Among CNS‐treated survivors, three classes of independence were identified: (1) moderately independent, never married, and non‐independent living (78.7%); (2) moderately independent, unable to drive (15.6%); and (3) non‐independent (5.7%). In contrast to 50% of non‐CNS‐treated survivors and 60% of siblings, a fourth fully independent class of CNS‐treated survivors was not identified. History of stroke (OR = 2.50, 95% CI: 1.70–3.68), seizure (OR = 9.70, 95% CI: 7.37–12.8), neurosensory deficits (OR = 2.67, 95% CI: 2.16–3.31), and focal neurologic dysfunction (OR = 3.05, 95% CI: 2.40–3.88) were associated with non‐independence among CNS‐treated survivors. Non‐independence was associated with emotional distress symptoms. Interpretation CNS‐treated survivors do not attain full independence comparable to non‐CNS‐treated survivors or siblings. Interventions to promote independence may be beneficial for survivors with treatment‐related neurological sequalae.

Background and Aims: We quantified hepatic functional impairment using quantitative function tests and linked severity of functional impairment to liver-related complications and outcome in primary sclerosing cholangitis. Methods: Forty-seven patients had baseline testing, and 40 were retested after 1 year. For each test, cholates labeled with cold, nonradioactive isotopes were administered orally (DuO, SHUNT tests) and intravenously (SHUNT test), and blood was analyzed at 20 and 60 minutes (DuO), or 0, 5, 20, 45, 60, and 90 minutes (SHUNT). Disease severity index (DSI), hepatic reserve (HR%), and portal-systemic shunting (SHUNT%) were calculated. Results: Three subgroups with low, moderate, and high disease severity were defined from the age-adjusted results for DSI, HR%, and SHUNT%. Standard laboratory tests, clinical scores, cytokine levels, and clinical outcome correlated with these subgroups. In univariate analysis of baseline tests, SHUNT% was a strong predictor of clinical outcome (n = 13 of 47; areas under the receiver operating characteristic curve, 0.84DuO, 0.90SHUNT). A model combining SHUNT%, DSI (or HR%), platelet count, and changes from baseline was most predictive of outcome (n = 10 of 40; areas under the receiver operating characteristic curve, 0.95DuO, 0.96SHUNT). Conclusion: DSI, HR%, and SHUNT% identified subgroups of primary sclerosing cholangitis based on the age-related severity of hepatic impairment that predicted risk for liver-related clinical outcome. Further study is warranted to confirm and validate these intriguing findings both in studies of natural progression of primary sclerosing cholangitis and in clinical trials. DuO enhances the utility of quantitative liver function testing.

This study emphasizes two variables as significant determinants of the number of individuals who choose self-employment. First, it is assumed that the opportunity cost of self-employment has a negative effect. This cost is measured as the income that would be earned in wage employment. Second, self-employment provides more opportunities for tax evasion and tax avoidance. The higher the corruption rate, the higher the self-employment rate. These two variables—wages and corruption scores—are used as potential determinants of the ratio of self-employed persons to the total labor force. Data from the twenty Eurozone countries are employed to test these hypotheses. Both hypotheses cannot be rejected based on the empirical evidence.

Background Patients receiving mechanical ventilation for more than 48 hours are at risk for developing ventilator-associated pneumonia (VAP). Methods We investigated aerosol flow in a ventilator circuit attached to test lungs to better understand how airflow dynamics in ventilator tubing can contribute to the pathogenesis of VAP. The ventilator was operated so that the lungs cyclically inflated and deflated. Aerosolized saline was used as a surrogate for bioaerosols and was generated in the circuit with an aerosol generator attached to the tubing below an endotracheal cuff that sealed an endotracheal tube at the opening of the lungs. We used a particle collector and analyzer attached to the circuit approximately two feet from the opening of the lungs to determine whether aerosols flowed into the tubing. Results We detected significant levels of aerosolized particles (P

Abstract Single-cell chromatin accessibility has emerged as a powerful means of understanding the epigenetic landscape of diverse tissues and cell types, but profiling cells from many independent specimens is challenging and costly. Here we describe a novel approach, sciPlex-ATAC-seq, which uses unmodified DNA oligos as sample-specific nuclear labels, enabling the concurrent profiling of chromatin accessibility within single nuclei from virtually unlimited specimens or experimental conditions. We first demonstrate our method with a chemical epigenomics screen, in which we identify drug-altered distal regulatory sites predictive of compound- and dose-dependent effects on transcription. We then analyze cell type-specific chromatin changes in PBMCs from multiple donors responding to synthetic and allogeneic immune stimulation. We quantify stimulation-altered immune cell compositions and isolate the unique effects of allogeneic stimulation on chromatin accessibility specific to T-lymphocytes. Finally, we observe that impaired global chromatin decondensation often coincides with chemical inhibition of allogeneic T-cell activation.

The saddle point (Van Hove singularity) exhibits a divergent density of states in two-dimensional systems, leading to fascinating phenomena such as strong correlations and unconventional superconductivity, yet it is seldom observed in three-dimensional (3D) systems. In this work we find two types of 3D higher-order saddle points (HOSPs) in emerging 3D kagome metals YbCo_{6}Ge_{6} and MgCo_{6}Ge_{6}. Both HOSPs exhibit a singularity in their density of states, which is significantly enhanced compared to the ordinary saddle point. The HOSP near the Fermi energy generates a flatband extending a large area in the Brillouin zone, potentially amplifying the correlation effect and fostering electronic instabilities. Two types of HOSPs exhibit distinct robustness upon element substitution and lattice distortions in these kagome compounds. Our work paves the way for engineering exotic band structures, such as saddle points and flatbands, and exploring interesting phenomena in Co-based kagome materials.

This paper aims to outline the effectiveness of modern universal gate quantum computers when utilizing different configurations to solve the B-SAT (Boolean satisfiability) problem. The quantum computing experiments were performed using Grover’s search algorithm to find a valid solution. The experiments were performed under different variations to demonstrate their effects on the results. Changing the number of shots, qubit mapping, and using a different quantum processor were all among the experimental variables. The study also branched into a dedicated experiment highlighting a peculiar behavior that IBM quantum processors exhibit when running circuits with a certain number of shots.

The highly variable ’leafscapes’ of plants across the world represent billions of square metres of mite habitat. The phytoseiid mites (Acari: Phytoseiidae), an extremely species-rich group of mostly generalist predators, are providers of ecosystem services for humanity worth many hundreds of millions of dollars annually by helping suppress phytophagous mites and insects in forests, agro-ecosystems, shade-houses and home gardens. In this study, the phytoseiid mite assemblages on the leaves of four species of common tree species, namely oak (Quercus cerris var. cerris), poplar (Populus deltoides, P. nigra) and walnut (Juglans regia), were compared. The three data sets used were generated in three independent seasonal studies in Samsun Province, Türkiye, between 2018 and 2022. In total, mite species in 18 families, including 15 families on walnut, were recorded. Nineteen phytoseiid species in 13 genera, Amblydromalus, Amblyseius, Euseius, Kampimodromus, Neoseiulella, Neoseiulus, Paraseiulus, Phytoseius, Transeius, Typhlodromina, Typhlodromips, Typhlodromus and Typhloseiulus, were collected. Only Eusieus amissibilis was collected from all three tree genera, whereas 14 species were collected from only one tree genus. Shannon diversity and Jaccard similarity indexes were calculated for mite families and phytoseiid genera and species. Potential reasons for the observed differences in the phytoseiid assemblages on the different host trees are explored in depth. In the ‘big picture’, global biodiversity, likely including many undescribed phytoseiid species, is threatened by widespread habitat degradation and destruction, especially in the tropics, and accelerating climate change, and rapidly stopping them is imperative.

Background: Health disparities are pervasive in surgical care. Particularly racial and socioeconomic inequalities have been demonstrated in emergency general surgery outcomes, but less so in elective abdominal wall reconstruction (AWR). The goal of this study was to evaluate the disparities in referrals to a tertiary hernia center.Methods: A prospectively maintained hernia database was queried for patients who underwent open ventral hernia (OVHR) or minimally invasive surgical (MISR) repair from 2011 to 2022 with complete insurance and address information. Patients were divided by home address into in-state (IS) and out-of-state (OOS) referrals as well as by operative technique. Demographic data and outcomes were compared. Standard and inferential statistical analyses were performed.Results: Of 554 patients, most were IS (59.0%); 334 underwent OVHR, and 220 underwent MISR. IS patients were more likely to undergo MISR (OVHR: 45.6% vs. 81.5%, laparoscopic: 38.2% vs. 14.1%, robotic: 16.2% vs. 4.4%; p < 0.001) when compared to OOS referrals. Of OVHR patients, 44.6% were IS and 55.4% were OOS. Patients’ average age and BMI, sex, ASA score, and insurance payer were similar between IS and OOS groups. IS patients were more often Black (White: 77.9% vs. 93.5%, Black: 16.8% vs. 4.3%; p < 0.001). IS patients had more smokers (12.1% vs. 3.2%; p = 0.001), fewer recurrent hernias (45.0% vs. 69.7%; p < 0.001), and smaller defects (155.7 ± 142.2 vs. 256.4 ± 202.9 cm2; p < 0.001). Wound class, mesh type, and rate of fascial closure were similar, but IS patients underwent fewer panniculectomies (13.4% vs. 34.1%; p < 0.001), component separations (26.2% vs. 51.4%; p < 0.001), received smaller mesh (744.2 ± 495.6 vs. 975.7 ± 442.3 cm2; p < 0.001), and had shorter length-of-stay (4.8 ± 2.0 vs. 7.0 ± 5.5 days; p < 0.001). There was no difference in wound breakdown, seroma requiring intervention, hematoma, mesh infection, or recurrence; however, IS patients had decreased wound infections (2.0% vs. 8.6%; p = 0.009), overall wound complications (11.4% vs. 21.1%; p = 0.016), readmissions (2.7% vs. 13.0%; p = 0.001), and reoperations (3.4% vs. 11.4%; p = 0.007). Of MISR patients, 80.9% were IS and 19.1% were OOS. In contrast to OVHR, MISR IS and OOS patients had similar demographics, preoperative characteristics, intraoperative details, and postoperative outcomes.Conclusion: Although there were no differences in referred patients for MISR, this study demonstrates the racial disparities that exist among our IS and OOS complex, open AWR patients. Awareness of these disparities can help clinicians work towards equitable access to care and equal referrals to tertiary hernia centers.

IntroductionCancer therapies predispose childhood cancer survivors to various treatment-related late effects, which contribute to a higher symptom burden, chronic health conditions (CHCs), and premature mortality. Regular monitoring of symptoms between clinic visits is useful for timely medical consultation and interventions that can improve quality of life (QOL). The Health Share Study aims to utilize mHealth to collect patient-generated health data (PGHD; daily symptoms, momentary physical health status) and develop survivor-specific risk prediction scores for mitigating adverse health outcomes including poor QOL and emergency room admissions. These personalized risk scores will be integrated into the hospital-based electronic health record (EHR) system to facilitate clinician communications with survivors for timely management of late effects.MethodsThis prospective study will recruit 600 adult survivors of childhood cancer from the St. Jude Lifetime Cohort study. Data collection include 20 daily symptoms via a smartphone, objective physical health data (physical activity intensity, sleep performance, and biometric data including resting heart rate, heart rate variability, oxygen saturation, and physical stress) via a wearable activity monitor, patient-reported outcomes (poor QOL, unplanned healthcare utilization) via a smartphone, and clinically ascertained outcomes (physical performance deficits, onset of/worsening CHCs) assessed in the survivorship clinic. Participants will complete health surveys and physical/functional assessments in the clinic at baseline, 2) report daily symptoms, wear an activity monitor, measure blood pressure at home over 4 months, and 3) complete health surveys and physical/functional assessments in the clinic 1 and 2 years from the baseline. Socio-demographic and clinical data abstracted from the EHR will be included in the analysis. We will invite 20 cancer survivors to investigate suitable formats to display predicted risk information on a dashboard and 10 clinicians to suggest evidence-based risk management strategies for adverse health outcomes.AnalysisMachine and statistical learning will be used in prediction modeling. Both approaches can handle a large number of predictors, including longitudinal patterns of daily symptoms/other PGHD, along with cancer treatments and socio-demographics.ConclusionThe individualized risk prediction scores and added communications between providers and survivors have the potential to improve survivorship care and outcomes by identifying early clinical presentations of adverse events.

Abstract Current noninvasive liver tests measure fibrosis, inflammation, or steatosis and do not measure function. The HepQuant platform of noninvasive tests uniquely assesses both liver function and physiology through the hepatic uptake of stable isotopes of cholate. However, the prototypical HepQuant SHUNT test (SHUNT V1.0) is cumbersome to administer, requiring intravenous and oral administration of cholate and six peripheral venous blood samples over 90 min. To alleviate the burden of test administration, we explored whether an oral only (DuO) version, and other simplified versions, of the test could provide reproducible measurements of liver function. DuO requires only oral dosing and two blood samples over 60 min. The simplified SHUNT test versions were SHUNT V1.1 (oral and IV dosing but four blood samples) and SHUNT V2.0 (oral and IV dosing but only two blood samples over 60 min). In this paper, we describe the reproducibility of DuO and the simplified SHUNT tests relative to that of SHUNT V1.0; equivalency is described in a separate paper. Data from two studies comprising 236 SHUNT tests in 94 subjects were analyzed retrospectively by each method. All simplified methods were highly reproducible across test parameters with intraclass correlation coefficients >0.93 for test parameters Disease Severity Index (DSI) and Hepatic Reserve. DuO and SHUNT V2.0 improved reproducibility in measuring portal‐systemic shunting (SHUNT%). These simplified tests, particularly DuO and SHUNT V2.0, are easier to administer and less invasive, thus, having the potential to be more widely accepted by care providers administering the test and by patients receiving the test.

Abstract Life‐history theory predicts that reproductive investments are traded‐off against self‐maintenance. Telomeres, the protective caps on the ends of chromosomes, offer a promising avenue for assessing life‐history trade‐offs, as they shorten in response to stressors and are predictive of the remaining lifespan. In males, testosterone frequently mediates life‐history trade‐offs, in part, through its effects on sexual ornamentation, which is an important aspect of reproductive investment. However, studies of within‐individual associations between telomere dynamics and sexual ornamentation are limited in number and have produced mixed results. Furthermore, most such studies have been observational, making it difficult to discern the nature of any causal relationship. To address this, we used short‐acting testosterone implants in free‐living male superb fairy‐wrens (Malurus cyaneus) to stimulate the production of a sexual ornament: early moult into a costly blue breeding plumage. We found no evidence that elevated testosterone, and the consequent earlier moult into breeding plumage, accelerated telomere shortening. We therefore followed up with a systematic review and two meta‐analyses (28 studies, 54 effect sizes) exploring the associations between telomeres and (1) testosterone and (2) sexual ornamentation. In line with our experimental findings, neither meta‐analysis showed an overall correlation of testosterone or sexual ornamentation with telomere length or telomere dynamics. However, meta‐regression showed that experimental, compared to observational, studies reported greater evidence of trade‐offs. Our meta‐analyses highlight the need for further experimental studies to better understand potential responses of telomere length or telomere dynamics to testosterone or sexual ornamentation.

Abstract Background Oral squamous cell carcinoma (SCC) is associated with oral microbial dysbiosis. In this unique study, we compared pre- to post-treatment salivary microbiome in patients with SCC by 16S rRNA gene sequencing and examined how microbiome changes correlated with the expression of an anti-microbial protein. Results Treatment of SCC was associated with a reduction in overall bacterial richness and diversity. There were significant changes in the microbial community structure, including a decrease in the abundance of Porphyromonaceae and Prevotellaceae and an increase in Lactobacillaceae. There were also significant changes in the microbial community structure before and after treatment with chemoradiotherapy, but not with surgery alone. In patients treated with chemoradiotherapy alone, several bacterial populations were differentially abundant between responders and non-responders before and after therapy. Microbiome changes were associated with a change in the expression of DMBT1, an anti-microbial protein in human saliva. Additionally, we found that salivary DMBT1, which increases after treatment, could serve as a post-treatment salivary biomarker that links to microbial changes. Specifically, post-treatment increases in human salivary DMBT1 correlated with increased abundance of Gemella spp., Pasteurellaceae spp., Lactobacillus spp., and Oribacterium spp. This is the first longitudinal study to investigate treatment-associated changes (chemoradiotherapy and surgery) in the oral microbiome in patients with SCC along with changes in expression of an anti-microbial protein in saliva. Conclusions The composition of the oral microbiota may predict treatment responses; salivary DMBT1 may have a role in modulating the oral microbiome in patients with SCC. Graphical Abstract After completion of treatment, 6 months after diagnosis, patients had a less diverse and less rich oral microbiome. Leptotrichia was a highly prevalent bacteria genus associated with disease. Expression of DMBT1 was higher after treatment and associated with microbiome changes, the most prominent genus being Gemella Video Abstract

Abstract Due to a demonstrated lack of DNA repair deficiencies, clear cell renal cell carcinoma (ccRCC) has not benefitted from targeted synthetic lethality-based therapies. We investigated whether nucleotide excision repair (NER) deficiency is present in an identifiable subset of ccRCC cases that would render those tumors sensitive to therapy targeting this specific DNA repair pathway aberration. We used functional assays that detect UV-induced 6–4 pyrimidine-pyrimidone photoproducts to quantify NER deficiency in ccRCC cell lines. We also measured sensitivity to irofulven, an experimental cancer therapeutic agent that specifically targets cells with inactivated transcription-coupled nucleotide excision repair (TC-NER). In order to detect NER deficiency in clinical biopsies, we assessed whole exome sequencing data for the presence of an NER deficiency associated mutational signature previously identified in ERCC2 mutant bladder cancer. Functional assays showed NER deficiency in ccRCC cells. Some cell lines showed irofulven sensitivity at a concentration that is well tolerated by patients. Prostaglandin reductase 1 (PTGR1), which activates irofulven, was also associated with this sensitivity. Next generation sequencing data of the cell lines showed NER deficiency-associated mutational signatures. A significant subset of ccRCC patients had the same signature and high PTGR1 expression. ccRCC cell line-based analysis showed that NER deficiency is likely present in this cancer type. Approximately 10% of ccRCC patients in the TCGA cohort showed mutational signatures consistent with ERCC2 inactivation associated NER deficiency and also substantial levels of PTGR1 expression. These patients may be responsive to irofulven, a previously abandoned anticancer agent that has minimal activity in NER-proficient cells.

This paper is a first attempt to look at the Greek media coverage of the Russian-Belarus invasion of Ukraine. Three daily newspapers are used during the period of December 2021-February 2022 to measure the frequency of coverage of the issue during the pre-invasion phase and the first day of the invasion. In addition, a qualitative content analysis is employed to account for the three newspapers’ stance on the Russian-Belarus invasion. One conclusion that emerges, which to many would appear surprising, is that all newspapers unequivocally condemned the Russia-Belarus invasion without any strings attached to their position. Since these three newspapers cover a wide spectrum of the Greek political ideology, it appears that despite Greece’s long historical, economic, and cultural (religion included) ties with Russia, this invasion was considered unacceptable.

Abstract Background After childhood acute lymphoblastic leukemia (ALL), sequelae include overweight and obesity, yet with conflicting evidence. We compared the prevalence of overweight and obesity between ≥5‐year ALL survivors from the North American Childhood Cancer Survivor Study (CCSS) and the Swiss Childhood Cancer Survivor Study (SCCSS) and described risk factors. Methods We included adult childhood ALL survivors diagnosed between 1976 and 1999. We matched CCSS participants (3:1) to SCCSS participants by sex and attained age. We calculated body mass index (BMI) from self‐reported height and weight for 1287 CCSS and 429 SCCSS participants; we then compared those with siblings (2034) in North America and Switzerland (678) siblings. We assessed risk factors for overweight (BMI 25–29.9 kg/m2) and obesity (≥30 kg/m2) using multinomial regression. Results We found overweight and obesity significantly more common among survivors in North America when compared with survivors in Switzerland [overweight: 30%, 95% confidence interval (CI): 27–32 vs. 24%, 21–29; obesity: 29%, 27–32 vs. 7%, 5–10] and siblings (overweight: 30%, 27–32 vs. 25%, 22–29; obesity: 24%, 22–26 vs. 6%, 4–8). Survivors in North America [odds ratio (OR) = 1.24, 1.01–1.53] and Switzerland (1.27, 0.74–2.21) were slightly more often obese than siblings. Among survivors, risk factors for obesity included residency in North America (5.8, 3.7–9.0); male (1.7, 1.3–2.3); attained age (≥45 years: 5.1, 2.4–10.8); Non‐Hispanic Black (3.4, 1.6–7.0); low household income (2.3, 1.4–3.5); young age at diagnosis (1.6, 1.1–2.2). Cranial radiotherapy ≥18 Gray was only a risk factor for overweight (1.4, 1.0–1.8); steroids were not associated with overweight or obesity. Interaction tests found no evidence of difference in risk factors between cohorts. Conclusions Although treatment‐related risk for overweight and obesity were similar between regions, higher prevalence among survivors in North America identifies important sociodemographic drivers for informing health policy and targeted intervention trials.

Missing data is unavoidable in longitudinal clinical trials, and outcomes are not always normally distributed. In the presence of outliers or heavy-tailed distributions, the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect (ATE) based on the multivariate normal assumption may produce bias and power loss. Control-based imputation (CBI) is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those with an identical history in the control group. We develop a robust framework to handle non-normal outcomes under CBI without imposing any parametric modeling assumptions. Under the proposed framework, sequential weighted robust regressions are applied to protect the constructed imputation model against non-normality in the covariates and the response variables. Accompanied by the subsequent mean imputation and robust model analysis, the resulting ATE estimator has good theoretical properties in terms of consistency and asymptotic normality. Moreover, our proposed method guarantees the analysis model robustness of the ATE estimation in the sense that its asymptotic results remain intact even when the analysis model is misspecified. The superiority of the proposed robust method is demonstrated by comprehensive simulation studies and an AIDS clinical trial data application.

Estimating vital rates of avian species is important to understand population dynamics and develop potential conservation strategies that target rates for management. Avian species have reduced potential for high annual fecundity in alpine ecosystems due to a short breeding window and harsh weather conditions. We located nests from Southern White-tailed Ptarmigan ( Lagopus leucura altipetens ) across six study sites in the Southern Rocky Mountains of Colorado to estimate daily nest survival from 2013–2017. We used a known-fate hierarchical nest survival model and fit several covariates, including environmental conditions representing daily weather events and shrub cover, to describe variation in daily survival and derive estimates of nest success. We located and monitored 198 nests from 128 radio-marked ptarmigan hens. The mean nest success estimated as a derived parameter from daily nest survival was 45.6% (95% credible interval [CI]: 31.2–59.6%) and ranged from 40.3% to 50.3% across sites. Variation in daily nest survival was poorly described by the covariates we fit (95% CI of most slope coefficients overlapped 0), although there was some support for a negative effect of relative elevation (nests at lower elevations within a site survived at higher rates) and a positive effect of nest age (older nests survived at higher rates). We examined how variation in nest success was likely to influence the finite rate of population growth using a simple simulation with an age-transition matrix parameterized with previously reported fecundity and survival estimates. We found that the finite growth rate was predicted to increase 18.7% when evaluated from the lower to upper 95% CI estimated values of nest success, conditional on the other vital rates used in our simulation. We discuss the broader implications of these findings in the context of managing for nest survival of Southern White-tailed Ptarmigan.

Abstract Background Whether diet has beneficial effects on cardiovascular disease (CVD) in childhood cancer survivors as in the general population is unknown. Therefore, we examined associations between dietary patterns and risk of CVD in adult survivors of childhood cancer. Methods Childhood cancer survivors, 18–65 years old in the St Jude Lifetime Cohort (1882 men and 1634 women) were included in the analysis. Dietary patterns were defined by the adherence to the Healthy Eating Index (HEI)–2015, Dietary Approaches to Stop Hypertension (DASH), and alternate Mediterranean diet (aMED) based on a food frequency questionnaire at study entry. CVD cases (323 in men and 213 in women) were defined as participants with at least one grade 2 or higher CVD-related diagnosis at baseline. Multivariable logistic regression adjusted for confounders was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of CVD. Results Greater adherence to HEI-2015 (OR=0.88, 95% CI: 0.75–1.03, per 10 score increment), DASH (OR=0.85, 95% CI: 0.71–1.01, per 10 score increment), and aMED (OR=0.92, 95% CI: 0.84–1.00, each score increment) were, albeit trending towards significance, associated with a lower risk of CVD in women. HEI-2015 was associated with a non-significantly lower risk of CVD in men (ORQ5 vs. Q1=0.80, 95% CI: 0.50–1.28). These dietary patterns were also associated with a lower risk of CVD in survivors with high underlying CVD risk. Conclusions As recommended to the general population, a diet rich in plant foods and moderate in animal foods needs to be a part of CVD management and prevention in childhood cancer survivors.

Post-operative cognitive dysfunction (POCD) is an iatrogenic cognitive decline with unclear etiology. While current hypotheses include surgical and pharmacological-induced neuroinflammatory mechanisms, the growing prevalence, especially amongst the geriatric population, emphasizes the ambiguity of the dysfunction. Recent studies have highlighted the potential role of general and regional anesthesia in the pathogenesis of POCD; these pharmacological effects have been demonstrated to disrupt blood-brain barrier integrity, influence microglial polarization, and have been linked to worsening prognoses in cognitive decline. Moreover, mechanical stress from surgical intervention and reperfusion injury may exacerbate the generation of reactive oxygen species (ROS), thereby increasing oxidative stress to the brain synergistically with blood-brain barrier disruptions. In previous studies, factors for the variable incidence and various risk factors have been explored. In this review, we examine the pharmacological effects of local, regional, and general anesthesia on molecular and cellular glial response, along with its intercellular interactions and previously reported clinical outcomes.

Abstract Children with severe Group 1 pulmonary arterial hypertension (PAH) have an unpredictable response to subcutaneous treprostinil (TRE) therapy, which may be influenced by age, disease severity, or other unknown variables at time of initiation. In this retrospective single‐center cohort study, we hypothesized that younger age at TRE initiation, early hemodynamic response (a decrease in pulmonary vascular resistance by ≥30% at follow‐up catheterization), and less severe baseline hemodynamics (Rp:Rs < 1.1) would each be associated with better clinical outcomes. In 40 pediatric patients with Group I PAH aged 17 days−18 years treated with subcutaneous TRE, younger age (cut‐off of 6‐years of age, AUC 0.824) at TRE initiation was associated with superior 5‐year freedom from adverse events (94% vs. 39%, p = 0.002), better WHO functional class (I or II: 88% vs. 39% p = 0.003), and better echocardiographic indices of right ventricular function at most recent follow‐up. Neither early hemodynamic response nor less severe baseline hemodynamics were associated with better outcomes. Patients who did not have a significant early hemodynamic response to TRE by first follow‐up catheterization were unlikely to show subsequent improvement in PVRi (1/8, 13%). These findings may help clinicians counsel families and guide clinical decision making regarding the timing of advanced therapies.

Abstract Background Lifestyle is associated with meningioma risk in the general population. Aims We assessed longitudinal associations between lifestyle‐associated factors and subsequent meningiomas in childhood cancer survivors. Methods and results Childhood cancer survivors age ≥18 years in the St. Jude Lifetime Cohort Study were evaluated for body composition, self‐reported physical activity, cardiopulmonary fitness, muscle strength, smoking, and alcohol consumption at baseline. Time to first meningioma analyses were performed, adjusted for sex, age at diagnosis and baseline assessment, treatment decade, and childhood cancer treatment exposures. The study included 4,072 survivors (47% female; [mean (SD)] 9 (6) years at diagnosis; 30 (8.5) years at the start of follow‐up, with 7.0 (3.3) years of follow‐up). 30% of the participants were survivors of acute lymphoblastic leukemia and 29% of the participants had received cranial radiation. During follow‐up, 90 participants developed ≥1 meningioma, of whom 73% were survivors of acute lymphoblastic leukemia, with cranial radiation being the strongest risk factor (relative risk [RR] 29.7, 95% confidence interval [CI] 10.6‐83.2). Muscle strength assessed by knee extension was associated with a lower risk of developing a meningioma in the adjusted analyses (RR 0.5, 95% CI 0.2‐1.0, p = 0.04 for quartiles 3‐4 vs. 1). No other lifestyle‐associated variable was associated with subsequent meningioma. Conclusion Independent of cranial radiation, muscle strength was associated with a lower risk of developing a subsequent meningioma in childhood cancer survivors.

ABSTRACTTo address the ongoing global tuberculosis crisis, there is a need for shorter, more effective treatments. A major reason why tuberculosis requires prolonged treatment is that, following a short initial phase of rapid killing, the residual Mycobacterium tuberculosis withstands drug killing. Because existing methods lack sensitivity to quantify low-abundance mycobacterial RNA in drug-treated animals, cellular adaptations of drug-exposed bacterial phenotypes in vivo remain poorly understood. Here, we used a novel RNA-seq method called SEARCH-TB to elucidate the Mycobacterium tuberculosis transcriptome in mice treated for up to 28 days with standard doses of isoniazid, rifampin, pyrazinamide, and ethambutol. We compared murine results with in vitro SEARCH-TB results during exposure to the same regimen. Treatment suppressed genes associated with growth, transcription, translation, synthesis of rRNA proteins, and immunogenic secretory peptides. Bacteria that survived prolonged treatment appeared to transition from ATP-maximizing respiration toward lower-efficiency pathways and showed modification and recycling of cell wall components, large-scale regulatory reprogramming, and reconfiguration of efflux pump expression. Although the pre-treatment in vivo and in vitro transcriptomes differed profoundly, genes differentially expressed following treatment in vivo and in vitro were similar, with differences likely attributable to immunity and drug pharmacokinetics in mice. These results reveal cellular adaptations of Mycobacterium tuberculosis that withstand prolonged drug exposure in vivo, demonstrating proof of concept that SEARCH-TB is a highly granular pharmacodynamic readout. The surprising finding that differential expression is concordant in vivo and in vitro suggests that insights from transcriptional analyses in vitro may translate to the mouse.IMPORTANCEA major reason that curing tuberculosis requires prolonged treatment is that drug exposure changes bacterial phenotypes. The physiologic adaptations of Mycobacterium tuberculosis that survive drug exposure in vivo have been obscure due to low sensitivity of existing methods in drug-treated animals. Using the novel SEARCH-TB RNA-seq platform, we elucidated Mycobacterium tuberculosis phenotypes in mice treated for with the global standard 4-drug regimen and compared them with the effect of the same regimen in vitro. This first view of the transcriptome of the minority Mycobacterium tuberculosis population that withstands treatment in vivo reveals adaptation of a broad range of cellular processes, including a shift in metabolism and cell wall modification. Surprisingly, the change in gene expression induced by treatment in vivo and in vitro was largely similar. This apparent “portability” from in vitro to the mouse provides important new context for in vitro transcriptional analyses that may support early preclinical drug evaluation.

ABSTRACTDNA methylation (DNAm) epigenome-wide association studies (EWAS) have been performed on diverse ethnicities to discover novel biomarkers associated with various diseases, such as cancers, autoimmune diseases, and neurological disorders. However, genetic polymorphisms can influence DNAm levels resulting in methylation quantitative trait loci (meQTL). These can be either direct effects, by altering the sequence of the methylation (CpG) site itself, or, in the case of array-based measures, indirectly altering the detection probe-binding site interaction. Given that genetic variant frequencies associated with meQTL can differ between population groups, these have the potential to confound EWAS observations, particularly in multi-ethnic populations. In this study, we analysed publicly available DNA methylation profiles (450K array), consisting of 1342 individuals from 6 distinct ancestral groups. We investigate two distinct tools (GapHunter and MethylToSNP) specifically designed to identify CpG sites that may be influenced by genetic variation. Results from this aggregated trans-ancestral epigenome-wide dataset suggest that both tools fail to consistently identify not only rarer (MAF < 0.05) genetic variant effects but also more than half of sites predicted to be associated with variants with much higher allele frequencies (MAF >0.2). In addition, there is a relatively low concordance in the detection of polymorphic CpGs between GapHunter and MethylToSNP. Screening of CpG site associations from EWAS using either of these tools is unlikely to be a robust or comprehensive means of identifying all genetic variant confounding effects.

Abstract Promoter-proximal pausing by RNA Pol II is a rate-determining step in gene transcription that is hypothesized to be a prominent point at which regulatory factors act. The pausing factor NELF is known to induce and stabilize pausing, but not all kinds of pausing are NELF-mediated. Here, we find that NELF-depleted Drosophila melanogaster cells functionally recapitulate the NELF-independent pausing we previously observed in fission yeast (which lack NELF). Critically, only NELF-mediated pausing establishes a strict requirement for Cdk9 kinase activity for the release of paused Pol II into productive elongation. Upon inhibition of Cdk9, cells with NELF efficiently shutdown gene transcription, while in NELF-depleted cells, defective, non-productive transcription continues unabated. By introducing a strict checkpoint for Cdk9, the evolution of NELF was likely critical to enable increased regulation of Cdk9 in higher eukaryotes, as Cdk9 availability can be restricted to limit gene transcription without inducing wasteful, non-productive transcription.

This study deals with Hesiod’s most important economic contribution. He introduced and explicitly defined the concept of economic scarcity, relating it to the productivity of labor. The latter can be enhanced by an unbounded Prometheus (technology), which permits the exploitation of new materials such as iron. In this paper, a distinction is made between a static and a dynamic definition of scarcity. Related to scarcity is the debate on the etymology of the word “economics”. In Works and Days, the word itself is absent, but, nevertheless, the word “oikos” is mentioned many times to clearly mean family business, which needs economic management within the institutionally-determined peace and justice. Without these two pre-conditions, the economies cannot flourish (grow).

Abstract Background Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born

Abstract Background Retaining highly qualified science, technology, engineering, and mathematics (STEM) teachers is imperative for meeting demands of the twenty-first century STEM workforce. While multiple studies have revealed several factors that influence teacher retention, little work has examined how these factors interact with one another. This study explored the relationship between two critical factors that relate to teachers’ decisions to remain in the profession: teacher identity and communities of practice (CoP) networks. Results Drawing upon scholarship on science teacher identity, CoP, and social network theory, we demonstrate a quantitative relationship between perceived network bridging roles and career commitment, which is mediated through teacher identity. Conclusions The findings from this study have both implications for scholarship in teacher retention and science teacher identity development. Potential solutions for improving novice teachers’ self-image through providing opportunities to grow their professional networks both locally and regionally/nationally are suggested.

Recent data suggest that 3,4-methylenedioxypyrovalerone (MDPV) has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced by the co-use of these two stimulants. The current study investigated the degree to which self-administered MDPV or a mixture of MDPV+caffeine can produce deficits in recognition memory and alter neurochemistry relative to prototypical stimulants. Male Sprague Dawley rats were provided 90 min or 12 h access to MDPV, MDPV+caffeine, methamphetamine, cocaine, or saline for 6 weeks. Novel object recognition (NOR) memory was evaluated prior to any drug self-administration history and 3 weeks after the final self-administration session. Rats that had 12 h access to methamphetamine and those that had 90 min or 12 h access to MDPV+caffeine exhibited significant deficits in NOR, whereas no significant deficits were observed in rats that self-administered cocaine or MDPV. Striatal monoamine levels were not systematically affected. These data demonstrate synergism between MDPV and caffeine with regard to producing recognition memory deficits, highlighting the importance of recapitulating the manner in which drugs are used (e.g., in mixtures containing multiple stimulants, binge-like patterns of intake).

This paper examines the quality evaluations of the Greek Universities highlighting those which offer a full-fledged study program of primary education. There are eight principles-criteria according to which each university is evaluated. For each principle, scores may range from 1 (noncompliance with the principle) to 4 (fully compliance). I present and compare results of the Greek university evaluations completed by the Hellenic Quality Assurance and Accreditation Agency (HQA). Surprisingly, no university has been graded as non-compliant in any of the eight principles-criteria. These evaluations are performed by an alleged “external” and “independent” committee. For all practical purposes, they are, nevertheless, based on subjective and biased opinions of academics affiliated with international universities with links to Greece and its universities. Independent and evidence-based evaluations paint a different picture. Universities which get perfect scores in the quality evaluation processes perform badly in the pertinent international ranking systems. As a case study, their primary education departments have lower research performance with high variability between faculty members and departments. Given that one criterion of evaluating quality is research, then not all Greek universities can be evaluated as highly performing research institutions, either in absolute or relevant terms. This criterion of quality is not satisfied by the primary education departments of Greek universities. According to this evidence, using the HQA as an agency to assess and accredit quality is useless. It should be abolished. A new system should be based on objective criteria such as independent teaching evaluations and research performance. These do not require any committee to evaluate performance and can be constructed on evidence-based policy. The latter relies solely on rigorously established objective facts.

Background: Localized prostate cancer (PCa) treatment is associated with reduced health-related quality of life (HRQoL). Current literature is limited by short-term follow-up. Objective: To prospectively evaluate the 5-yr HRQoL outcomes in men undergoing radical prostatectomy (RP), external beam radiotherapy (EBRT), or active surveillance (AS). Design, setting, and participants: We prospectively evaluated HRQoL in patients with low-risk/favorable intermediate-risk PCa enrolled in the Center for Prostate Disease Research multicenter database between 2007 and 2017. Intervention: Of 1012 patients included in the study, 252 (24.9%) underwent AS, 557 (55.0%) RP, and 203 (20.0%) EBRT. Patients complete the Expanded Prostate Cancer Index Composite and the 36-item Medical Outcomes Study Short Form at baseline and thereafter each year up to 5 yr after treatment. Outcome measurements and statistical analysis: Temporal changes in HRQoL were compared between treatments and were modeled using linear regression models adjusted for baseline HRQoL, demographic, and clinical characteristics. Results and limitations: RP showed the least irritative symptoms and worse incontinence in comparison with AS (p