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In patients with suspected acute coronary syndrome (ACS), troponin testing is effective for diagnosis and prognosis. Troponin testing has now expanded to include patients without suspected ACS. This nonselective troponin testing has unknown consequences for resource utilization and outcome. Therefore, we examined selective versus nonselective troponin testing with respect to patient characteristics, resource utilization, and outcome. This retrospective 1-year study included all patients with troponin testing at a U.S. emergency department. Testing was classified as selective (ACS) or nonselective (non-ACS) based on admission ICD-9 codes. Troponin upper reference limit (URL) was ≥99th percentile. Among 47,053 patients, troponin was measured in 9109 (19%) of whom 5764 were hospitalized. Admission diagnosis was non-ACS in 4427 (77%) and ACS in 1337 (23%). Non-ACS patients were older, 71±17 versus 65±16 years, with longer hospital stay, 77 versus 32 h, and greater 1-year mortality 22% versus 6.7%; P<.001. In patients with troponin ≥URL, revascularization was performed in 64 (4.7%) of non-ACS versus 213 (48%) of ACS; P<.001. In patients with troponin 80% of the non-ACS population Contemporary troponin testing is frequently nonselective. The non-ACS and ACS populations differ significantly regarding clinical characteristics, revascularization rates, and outcomes. Troponin elevation is a powerful predictor of 1-year mortality in non-ACS, this association reveals an opportunity for risk stratification and targeted therapy. In patients with suspected acute coronary syndrome (ACS), troponin testing is effective for diagnosis and prognosis. However, troponin testing has now expanded to include patients without suspected ACS. This nonselective troponin testing has unknown consequences for hospital resource utilization and patient outcome. Our findings demonstrate contemporary troponin testing is largely nonselective (77% of testing was performed in patients without acute coronary syndrome). In comparison to patients with acute coronary syndrome, those with non-acute coronary syndrome are older, with longer hospital stay, lower revascularization rates, and greater 1-year mortality. Troponin elevation identifies a high-risk population in both acute coronary syndrome and non-acute coronary syndrome populations, yet effective treatment for the latter is lacking.

Background Digital, or eHealth, interventions are highly promising approaches to help adolescents improve their health behaviours and reduce their risk of chronic disease. However, they often have low uptake and retention. There is also a paucity of high-quality research into the predictors of eHealth engagement, and a lack of studies that have systematically evaluated existing engagement strategies in adolescent populations. This paper describes the protocol for a randomised controlled trial which primarily aims to assess the effectiveness of different strategies in increasing engagement with a healthy lifestyles app, Health4Life. Associations between the engagement strategies and improvements in adolescent health behaviours (healthy eating, physical activity, sleep, recreational screen time, smoking, alcohol use) will also be examined, along with potential predictors of adolescents’ intentions to use health apps and their use of the Health4Life app. Methods The current study will aim to recruit 336 adolescent and parent/guardian dyads (total sample N  = 672) primarily through Australia wide online advertising. All adolescent participants will have access to the Health4Life app (a multiple health behaviour change, self-monitoring mobile app). The trial will employ a 2 4 factorial design, where participants will be randomly allocated to receive 1 of 16 different combinations of the four engagement strategies to be evaluated: text messages, access to a health coach, access to additional gamified app content, and provision of parent/guardian information resources. Adolescents and parents/guardians will both complete consent processes, baseline assessments, and a follow-up assessment after 3 months. All participants will also be invited to complete a qualitative interview shortly after follow-up. The primary outcome, app engagement, will be assessed via an App Engagement Index (Ei) using data collected in the Health4Life app and the Mobile App Rating Scale – User version. Discussion This research will contribute significantly to building our understanding of the types of strategies that are most effective in increasing adolescents’ engagement with health apps and which factors may predict adolescents’ use of health apps. Trial registration The trial is registered at the Australian New Zealand Clinical Trials Registry (ACTRN12623000399695). Date registered: 19/04/2023.

General circulation models' (GCMs) estimates of the liquid water path adjustment to anthropogenic aerosol emissions differ in sign from other lines of evidence. This reduces confidence in estimates of the effective radiative forcing of the climate by aerosol–cloud interactions (ERFaci). The discrepancy is thought to stem in part from GCMs' inability to represent the turbulence–microphysics interactions in cloud-top entrainment, a mechanism that leads to a reduction in liquid water in response to an anthropogenic increase in aerosols. In the real atmosphere, enhanced cloud-top entrainment is thought to be the dominant adjustment mechanism for liquid water path, weakening the overall ERFaci. We show that the latest generation of GCMs includes models that produce a negative correlation between the present-day cloud droplet number and liquid water path, a key piece of observational evidence supporting liquid water path reduction by anthropogenic aerosols and one that earlier-generation GCMs could not reproduce. However, even in GCMs with this negative correlation, the increase in anthropogenic aerosols from preindustrial to present-day values still leads to an increase in the simulated liquid water path due to the parameterized precipitation suppression mechanism. This adds to the evidence that correlations in the present-day climate are not necessarily causal. We investigate sources of confounding to explain the noncausal correlation between liquid water path and droplet number. These results are a reminder that assessments of climate parameters based on multiple lines of evidence must carefully consider the complementary strengths of different lines when the lines disagree.

Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R/V mutant histone H3.3. H3.3-G34R/V mutants are common in tumors with mutations in p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, and mutants show partial transcriptional overlap with set2 deletions. H3-G34R mutants exhibit genomic instability and increased replication stress, including slowed replication fork restart, although DNA replication checkpoints are functional. H3-G34R mutants are defective for DNA damage repair by homologous recombination (HR), and have altered HR protein dynamics in both damaged and untreated cells. These data suggest H3-G34R slows resolution of HR-mediated repair and that unresolved replication intermediates impair chromosome segregation. This analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma. Children suffering from a brain cancer called high-grade glioma rarely recover because there are no therapies that can effectively target this disease. Recently, mutations in a gene that encodes a protein called histone H3 were found in children’s glioma cells. Histone proteins bind to DNA to help package it into cells. They help to protect the DNA from damage, control when genes are switched on or off, and influence how the DNA is copied when cells are preparing to divide to produce two daughter cells. However, little was known about why one of the histone H3 mutations is associated with high-grade gliomas. Humans and other animals have many different versions of the histone H3 protein, which makes it difficult to study a mutation that only affects one particular version. Therefore Yadav et al. used fission yeast – which they engineered to only contain one form of histone H3 – to study what effect the mutation has on cells. The experiments show that fission yeast cells with the mutant form of histone H3 took longer to replicate their DNA and were more likely to die when exposed to chemicals that interfere with DNA duplication. Furthermore, the mutant cells were slower at repairing certain types of damage to DNA and were more likely to go on to divide before DNA duplication and repair were completed. As a result, the daughter cells produced were more likely to have gained or lost whole chunks of their DNA. This phenomenon is known as chromosomal instability and is often seen in cases of high-grade glioma in children. The findings of Yadav et al. give new insight into how a specific mutation affecting the histone H3 protein may act in cells. Future experiments will need to confirm whether this mutation also has a similar effect on children’s glioma cells, which may help to provide new options for treating this cancer.

Hospital outbreaks of COVID19 result in considerable mortality and disruption to healthcare services and yet little is known about transmission within this setting. We characterise within hospital transmission by combining viral genomic and epidemiological data using Bayesian modelling amongst 2181 patients and healthcare workers from a large UK NHS Trust. Transmission events were compared between Wave 1 (1st March to 25th J'uly 2020) and Wave 2 (30th November 2020 to 24th January 2021). We show that staff-to-staff transmissions reduced from 31.6% to 12.9% of all infections. Patient-to-patient transmissions increased from 27.1% to 52.1%. 40%-50% of hospital-onset patient cases resulted in onward transmission compared to 4% of community-acquired cases. Control measures introduced during the pandemic likely reduced transmissions between healthcare workers but were insufficient to prevent increasing numbers of patient-to-patient transmissions. As hospital-acquired cases drive most onward transmission, earlier identification of nosocomial cases will be required to break hospital transmission chains.

Studies of paediatric cancers have shown a high frequency of mutation across epigenetic regulators. Here we sequence 633 genes, encoding the majority of known epigenetic regulatory proteins, in over 1,000 paediatric tumours to define the landscape of somatic mutations in epigenetic regulators in paediatric cancer. Our results demonstrate a marked variation in the frequency of gene mutations across 21 different paediatric cancer subtypes, with the highest frequency of mutations detected in high-grade gliomas, T-lineage acute lymphoblastic leukaemia and medulloblastoma, and a paucity of mutations in low-grade glioma and retinoblastoma. The most frequently mutated genes are H3F3A , PHF6 , ATRX , KDM6A , SMARCA4 , ASXL2 , CREBBP , EZH2 , MLL2 , USP7 , ASXL1 , NSD2 , SETD2 , SMC1A and ZMYM3 . We identify novel loss-of-function mutations in the ubiquitin-specific processing protease 7 (USP7) in paediatric leukaemia, which result in decreased deubiquitination activity. Collectively, our results help to define the landscape of mutations in epigenetic regulatory genes in paediatric cancer and yield a valuable new database for investigating the role of epigenetic dysregulations in cancer. Proteins involved in epigenetic regulation are frequently mutated in several paediatric cancers. Here, Huether et al. characterize the somatic mutation frequency across 21 paediatric cancer subtypes by sequencing 633 epigenetic genes in over 1,000 tumours; generating a rich data set for investigating epigenetic dysregulation.

Warmer temperatures are expected to increase the incidence of Lyme disease through enhanced tick maturation rates and a longer season of transmission. In addition, there could be an increased risk of disease export because of infected mobile hosts, usually birds. A temperature-driven seasonal model of Borrelia burgdorferi (Lyme disease) transmission among four host types is constructed as a system of nonlinear ordinary differential equations. The model is developed and parametrized based on a collection of lab and field studies. The model is shown to produce biologically reasonable results for both the tick vector (Ixodes scapularis) and the hosts when compared to a different set of studies. The model is used to predict the response of Lyme disease risk to a mean annual temperature increase, based on current temperature cycles in Hanover, NH. Many of the risk measures suggested by the literature are shown to change with increased mean annual temperature. The most straightforward measure of disease risk is the abundance of infected questing ticks, averaged over a year. Compared to this measure, which is difficult and resource-intensive to track in the field, all other risk measures considered underestimate the rise of risk with rise in mean annual temperature. The measure coming closest was “degree days above zero.” Disease prevalence in ticks and hosts showed less increase with rising temperature. Single field measurements at the height of transmission season did not show much change at all with rising temperature.

Development of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) to monoclonal antibodies may adversely impact pharmacokinetics, efficacy, and/or safety. To describe incidence, titer, and persistence of dupilumab ADAs and NAbs, and their effects on pharmacokinetics, efficacy, and safety in patients with atopic dermatitis (AD). This analysis included seven phase 3 randomized, placebo-controlled (N=2,992) and two long-term open-label extension (N=2,287) trials of subcutaneous dupilumab in adults and pediatric patients with moderate-to-severe AD. ADA, NAb, and dupilumab concentration in serum were assessed using validated immunoassays. ADA impacts on efficacy (EASI) and safety were assessed. Treatment-emergent ADAs were observed in up to 8.6% (aged ≥18 years), 16.0% (12-17 years), 5.3% (6-11 years), and 2.0% (6 months to 5 years) dupilumab-treated patients. Among dupilumab-treated patients, ≤3.7% had persistent responses, <1% had high titers (≥10,000), and ≤5.1% were NAb-positive. NAbs were more common in patients with moderate- and high-titer ADA responses. High-titer ADAs, while infrequent, were the variable most associated with lower dupilumab concentrations in serum and loss of efficacy, independent of NAb status. Efficacy was generally similar in ADA-positive and -negative patients. For most patients with high- or moderate-titer ADAs, titers decreased and efficacy improved over time with continued dupilumab treatment. ADA-positive and -negative patients had similar incidences of treatment-emergent and serious treatment-emergent adverse events. One patient with high-titer ADAs developed serum sickness. In patients with AD, ADAs and NAbs had minimal impact on dupilumab concentration, efficacy, and safety, except for high-titer ADAs in a small number of patients. ClinicalTrials.gov, identifiers (NCT02277743, NCT02277769, NCT02260986, NCT02395133, NCT01949311, NCT03054428, NCT03345914, NCT02612454, and NCT03346434).

The prevalence of Lyme disease and other tick-borne diseases is dramatically increasing across the United States. While the rapid rise in Lyme disease is clear, the causes of it are not. Modeling Ixodes scapularis Say (Acari: Ixodidae), the primary Lyme disease vector in the eastern United States, presents an opportunity to disentangle the drivers of increasing Lyme disease, including climate, land cover, and host populations. We improved upon a recently developed compartment model of ordinary differential equations that simulates I. scapularis growth, abundance, and infection with Borrelia burgdorferi (Spirochaetales: Spirochaetaceae) by adding land cover effects on host populations, refining the representation of growth stages, and evaluating output against observed data. We then applied this model to analyze the sensitivity of simulated I. scapularis dynamics across temperature and land cover in the northeastern United States. Specifically, we ran an ensemble of 232 simulations with temperature from Hanover, New Hampshire and Storrs, Connecticut, and land cover from Hanover and Cardigan in New Hampshire, and Windsor and Danielson in Connecticut. Consistent with observations, simulations of I. scapularis abundance are sensitive to temperature, with the warmer Storrs climate significantly increasing the number of questing I. scapularis at all growth stages. While there is some variation in modeled populations of I. scapularis infected with B. burgdorferi among land cover distributions, our analysis of I. scapularis response to land cover is limited by a lack of observations describing host populations, the proportion of hosts competent to serve as B. burgdorferi reservoirs, and I. scapularis abundance.

FoxO transcription factors, inhibited by insulin/insulin‐like growth factor signalling (IIS), are crucial players in numerous organismal processes including lifespan. Using genomic tools, we uncover over 700 direct dFOXO targets in adult female Drosophila . dFOXO is directly required for transcription of several IIS components and interacting pathways, such as TOR , in the wild‐type fly. The genomic locations occupied by dFOXO in adults are different from those observed in larvae or cultured cells. These locations remain unchanged upon activation by stresses or reduced IIS, but the binding is increased and additional targets activated upon genetic reduction in IIS. We identify the part of the IIS transcriptional response directly controlled by dFOXO and the indirect effects and show that parts of the transcriptional response to IIS reduction do not require dfoxo . Promoter analyses revealed GATA and other forkhead factors as candidate mediators of the indirect and dfoxo ‐independent effects. We demonstrate genome‐wide evolutionary conservation of dFOXO targets between the fly and the worm Caenorhabditis elegans , enriched for a second tier of regulators including the dHR96 / daf‐12 nuclear hormone receptor. Synopsis Forkhead Box‐O (FoxO) transcription factors are crucial players in numerous cellular and organismal processes including metabolism, stress protection, cellular differentiation, cell‐cycle arrest, apoptosis and lifespan. FoxOs are regulated by a number of signalling pathways, including negative regulation by insulin/insulin‐like growth factor signalling (IIS) (Partridge and Bruning, 2008 ; Salih and Brunet, 2008 ). The fruit fly Drosophila melanogaster has a single FoxO orthologue—dFOXO. dFOXO is capable of extending fly lifespan, as well as being required for lifespan extension in response to downregulation of IIS (Giannakou et al , 2004 ; Hwangbo et al , 2004 ; Slack et al , 2011 ). To further our understanding of dFOXO biology, we uncover over 700 direct dFOXO targets in the adult female fly, both in the wild‐type fly and in a mutant with reduced IIS activity. dFOXO is directly required for transcription of several components of IIS and interacting pathways, such as the gene encoding the target of rapamycin (TOR) kinase, in the wild‐type fly. Indeed, the removal of dFOXO results in reduced signal through these pathways. The genomic locations occupied by dFOXO in adults are different from those observed by others in larvae or cultured cells (Puig et al , 2003 ; Teleman et al , 2008 ), indicating that dFOXO binding is influenced by developmental stage and/or cell type. These locations remain unchanged upon activation of dFOXO by stresses or reduced IIS in the adult, but the binding of dFOXO to the same sites is increased. Genetically induced reduction in IIS results in activation/repression of a greater number of direct dFOXO targets than observed in the wild‐type fly. To determine the relationship between dFOXO and IIS in the adult fly, we identify the part of the IIS transcriptional response that is controlled by dFOXO, both directly and indirectly. We observe that aspects of the transcriptional response to changes in IIS can take place in the absence of dFOXO, indicating that other transcriptional regulators must be involved. This is different to the situation in the worm Caenorhabditis elegans where the worm FoxO, encoded by the daf‐16 gene, is required for all the effects of a reduction in IIS (Kenyon et al , 1993 ; Gems et al , 1998 ; Murphy et al , 2003 ). On the other hand, the existence of dFOXO‐independent effects is in accordance with genetic experiments in the fly where lifespan extension and xenobiotic resistance caused by a reduction in IIS are dependent on dFOXO, while lowered fecundity and body size, delayed development and resistance to paraquat are not (Slack et al , 2011 ). Promoter analyses revealed GATA and other forkhead factors as candidate mediators of the dFOXO‐independent effects in the fly. Despite the different topology of the transcriptomic response to IIS changes in the two organisms, there is genome‐wide evolutionary conservation of dFOXO targets between the fly and the worm (Figure 9 ), enriched for a second tier of regulators including the dHR96 / daf‐12 nuclear hormone receptor. More than 700 direct transcriptional targets of dFOXO were determined in the adult Drosophila female, in the wild‐type or an insulin‐signalling mutant. dFOXO has an important role in the wild‐type fly and is important for transcription of numerous signalling components including TOR and Sos. While dFOXO is an important effector of the insulin signalling pathway, it is required for only a portion of the transcriptional changes that occur in response to alterations in the pathway in the fly, and in many cases indirectly. There is strong evolutionary conservation of dFOXO‐bound genes between the worm and the fly, specifically enriched in regulatory genes.