Digital guided self-help for eating disorders (GSH-ED) can reduce treatment disparities. Understanding program participants' interests throughout the program can help adapt programs to the service ...users' needs. Participants were 383 college students receiving a digital GSH-ED, who were each assigned a coach to help them better utilize the intervention through text correspondence. A thematic and affective analysis of the texts participants had sent found they primarily focused on: strategies for changing their ED-related cognitions, behaviors, and relationships; describing symptoms without expressing an active endeavor to change; and participants' relationship with their coach. Most texts also expressed affect, demonstrating emotional engagement with the intervention. Findings suggest that participants in GSH-ED demonstrate high involvement with the intervention, and discuss topics that are similar to those reported in clinician-facilitated interventions. The themes discussed by digital program participants can inform future iterations of GSH-ED, thereby increasing scalability and accessibility of digital evidence-based ED interventions.
Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. We generated isogenic CRISPR-Cas9 knockouts (Δ) of 43 genes in human induced pluripotent stem cells, ...cultured them in the absence of added DNA damage, and performed whole-genome sequencing of 173 subclones. Δ
Δ
Δ
Δ
Δ
Δ
Δ
Δ
and Δ
produced marked mutational signatures indicative of being critical mitigators of endogenous DNA modifications. Detailed analyses revealed mutational mechanistic insights, including how 8-oxo-dG elimination is sequence-context-specific while uracil clearance is sequence-context-independent. Mismatch repair (MMR) deficiency signatures are engendered by oxidative damage (C>A transversions), differential misincorporation by replicative polymerases (T>C and C>T transitions), and we propose a 'reverse template slippage' model for T>A transversions. Δ
Δ
and Δ
signatures were similar to each other but distinct from Δ
. Finally, we developed a classifier, MMRDetect, where application to 7,695 WGS cancers showed enhanced detection of MMR-deficient tumors, with implications for responsiveness to immunotherapies.
The Millennium Drought lasted more than a decade and is notable for causing persistent shifts in the relationship between rainfall and runoff in many southeastern Australian catchments. Research to ...date has successfully characterised where and when shifts occurred and explored relationships with potential drivers, but a convincing physical explanation for observed changes in catchment behaviour is still lacking. Originating from a large multi-disciplinary workshop, this paper presents and evaluates a range of hypothesised process explanations of flow response to the Millennium Drought. The hypotheses consider climatic forcing, vegetation, soil moisture dynamics, groundwater, and anthropogenic influence. The hypotheses are assessed against evidence both temporally (e.g. why was the Millennium Drought different to previous droughts?) and spatially (e.g. why did rainfall–runoff relationships shift in some catchments but not in others?). Thus, the strength of this work is a large-scale assessment of hydrologic changes and potential drivers. Of 24 hypotheses, 3 are considered plausible, 10 are considered inconsistent with evidence, and 11 are in a category in between, whereby they are plausible yet with reservations (e.g. applicable in some catchments but not others). The results point to the unprecedented length of the drought as the primary climatic driver, paired with interrelated groundwater processes, including declines in groundwater storage, altered recharge associated with vadose zone expansion, and reduced connection between subsurface and surface water
processes. Other causes include increased evaporative demand and harvesting
of runoff by small private dams. Finally, we discuss the need for long-term
field monitoring, particularly targeting internal catchment processes and
subsurface dynamics. We recommend continued investment in the understanding of hydrological shifts, particularly given their relevance to water planning under climate variability and change.
Local flexibility markets (LFM) for electricity are in their early stages, and most research has focused on their design aspects and aggregators, while little attention has been paid to providers and ...potential providers of flexibility resources. The present research aims to fill this gap by analysing data from 25 in-depth interviews with enrolled and potential flexibility service providers of two LFMs in Sweden. The primary goal of the analysis is to identify the drivers and barriers to participating in and providing flexibility to LFMs that are influencing these actors. Our findings show that monetary incentives were not as important as expected. The main drivers were as follows: an aggregator acting as a mediator between the buyer and the provider; a champion with personal engagement in the organisation; a wish to be a part of resolving congestion in the electricity grid; and gaining knowledge about flexibility as a resource. The main barriers identified were that LFM design was challenging to understand and that extensive knowledge about how the market functions was needed to participate. Other barriers were related to existing regulations, manual and time-consuming processes, participation not being profitable enough, perceived interference with the companies’ core businesses, and the risk of compromising customer relationships. For the future, it is essential to simplify participation, develop automation, and contribute to establishing aggregators who can support potential flexibility service providers.
•Interviews with enrolled and potential flexibility service providers of two local flexibility markets (LFM).•Identifying drivers of and barriers to providing flexibility.•Main drivers of participation include support from an aggregator and personal engagement.•Main barriers to participation are a lack of knowledge about how the market functions.•It is important to consider flexibility service providers' interests when developing future LFMs.
Although cardiac device infections (CDIs) are a devastating complication of permanent pacemakers or implantable cardioverter-defibrillators, the incidence of CDI in patients with bacteremia is not ...well defined. The objective of this study was to determine the incidence of CDI among patients with permanent pacemakers or implantable cardioverter-defibrillators who develop Staphylococcus aureus bacteremia (SAB).
A cohort of all adult patients with SAB and permanent pacemakers or implantable cardioverter-defibrillators over a 6-year period was evaluated prospectively. The overall incidence of confirmed CDI was 15 of 33 (45.4%). Confirmed CDI occurred in 9 of the 12 patients (75%) with early SAB (<1 year after device placement). Fifteen of 21 patients (71.5%) with late SAB (>/=1 year after device placement) had either confirmed (6 of 21, 28.5%) or possible (9 of 21, 43%) CDI. In 60% of the patients (9 of 15) with confirmed CDI, no local signs or symptoms suggesting generator pocket infection were noted.
The incidence of CDI among patients with SAB and cardiac devices is high. Neither physical examination nor echocardiography can exclude the possibility of CDI. In patients with early SAB, the device is usually involved, and approximately 40% of these patients have obvious clinical signs of cardiac device involvement. Conversely, in patients with late SAB, the cardiac device is rarely the initial source of bacteremia, and there is a paucity of local signs of device involvement. The cardiac device is involved, however, in >/=28% of these patients.
Purpose
In the lungs of cystic fibrosis patients, Pseudomonas aeruginosa is exposed to a myriad of antibiotics leading to alterations in antibiotic susceptibility. This study identifies mutations ...resulting in hypersusceptibility in isogenic mutants of a P. aeruginosa clinical isolate, PA34.
Methods
PA34 was exposed to subinhibitory concentrations of doripenem or meropenem during growth to mid‐log phase. Antibiotic susceptibility of surviving colonies was determined by agar dilution. Two carbapenem‐resistant colonies hypersusceptible to non‐carbapenem antibiotics were selected for further analysis. Antibiotic resistance gene expression was evaluated by RT‐rtPCR and OprD production by SDS‐PAGE. PA34 and isogenic mutants were evaluated with whole genome sequencing. Sequence variants were confirmed by Sanger sequencing, and cognate genes in eight carbapenem‐resistant clinical isolates hypersusceptible to non‐carbapenem antibiotics were sequenced. Lipopolysaccharide preparations of PA34 and hypersusceptible mutants were evaluated with ProQ‐Emerald stain.
Results
Isogenic mutants showed 4‐ to 8‐fold MIC increase for imipenem, meropenem, and doripenem. However, they were hypersusceptible (≥4‐fold MIC decrease) to aminoglycosides, fluoroquinolones, and non‐carbapenem β‐lactams. Expression of ampC or mex‐opr efflux pumps was unchanged, but OprD production was decreased. Mutations causing Q86H AlgU and G77C LptG amino acid substitutions and nonsense mutations within OprD were observed in both mutants. Lipopolysaccharide modifications were observed between isogenic mutants and PA34. Non‐synonymous mutations in LptF or LptG were observed in 6/8 hypersusceptible clinical isolates resistant to carbapenem antibiotics.
Conclusion
Evaluation of hypersusceptible mutants identified the association between lptG and a hypersusceptible phenotype. Modifications in lipopolysaccharide profiles suggests LptG modification interferes with lipopolysaccharide transport and contributes to hypersusceptibility.
This study identifies mutations resulting in hypersusceptibility in isogenic mutants and clinical isolates of Pseudomonas aeruginosa. Mutations in the gene encoding the LptG subunit of the LptFG heterodimer were found to alter lipopolysaccharide (LPS) profiles in isogenic mutants. Modifications in LPS profiles suggest LptG modification interferes with LPS transport and contributes to hypersusceptibility.
•A thin ideal measure was developed, the Perceived Benefits of Thinness Scale.•The scale assesses how people think thinness positively impacts their lives.•The scale exhibited good test-retest ...reliability and sensitivity to change.•Concurrent and discriminant validity were strengths of the measure.•Clinical eating disorder (ED) samples reported higher scores than non-ED samples.
Thin ideal internalization is a risk factor for disordered eating behaviors, poor body image, and eating disorders (EDs). This paper evaluated the psychometric properties of a novel measure, the Perceived Benefits of Thinness Scale (PBTS), which assesses how individuals feel being thinner would affect various aspects of their lives. Three separate studies with unique samples of college-aged women over 18 years were conducted to assess reliability and validity. In Study 1, exploratory and confirmatory factor analyses suggested all PBTS items loaded onto one factor that was distinct from a measure of weight and shape concerns. A large correlation between changes in PTBS scores and changes in ED psychopathology scores over 8 months (r = .57, p < .01) suggested sensitivity to change. Greater severity in ED pathology was also associated with higher scores on the PBTS. In Study 2, the PBTS showed good test-retest reliability (r = .84, p < .001) and, in Study 3, expected correlations with existing measures of thin ideal internalization (rs = .38–.60, ps < .001). Overall, the PBTS displayed good factor structure, reliability, concurrent validity, and sensitivity to change. By emphasizing social, emotional, and quality of life benefits, the PBTS may serve clinicians, researchers, and patients in understanding thin ideal internalization and associated ED risk.
The histologic evolution of the full spectrum of nonalcoholic fatty liver disease (NAFLD) and factors associated with progression or regression remain to be definitively established.
To evaluate the ...histologic evolution of NAFLD and the factors associated with changes in disease severity over time.
A prospective cohort substudy from the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database study, a noninterventional registry, was performed at 8 university medical research centers. Masked assessment of liver histologic specimens was performed, using a prespecified protocol to score individual biopsies. Participants included 446 adults with NAFLD enrolled in the NASH CRN Database studies between October 27, 2004, and September 13, 2013, who underwent 2 liver biopsies 1 or more year apart. Data analysis was performed from October 2016 to October 2018.
Progression and regression of fibrosis stage, using clinical, laboratory, and histologic findings, including the NAFLD activity score (NAS) (sum of scores for steatosis, lobular inflammation, and ballooning; range, 0-8, with 8 indicating more severe disease).
A total of 446 adults (mean SD age, 47 11 years; 294 65.9% women) with NAFLD (NAFL, 86 19.3%), borderline NASH (84 18.8%), and definite NASH (276 61.9%) were studied. Over a mean (SD) interval of 4.9 (2.8) years between biopsies, NAFL resolved in 11 patients (12.8%) and progressed to steatohepatitis in 36 patients (41.9%). Steatohepatitis resolved in 24 (28.6%) of the patients with borderline NASH and 61 (22.1%) of those with definite NASH. Fibrosis progression or regression by at least 1 stage occurred in 132 (30%) and 151 34% participants, respectively. Metabolic syndrome (20 95% vs 108 72%; P = .03), baseline NAS (mean SD, 5.0 1.4 vs 4.3 1.6; P = .005), and smaller reduction in NAS (-0.2 2 vs -0.9 2; P < .001) were associated with progression to advanced (stage 3-4) fibrosis vs those without progression to stage 3 to 4 fibrosis. Fibrosis regression was associated with lower baseline insulin level (20 vs 33 μU/mL; P = .02) and decrease in all NAS components (steatosis grade -0.8 0.1 vs -0.3 0.9; P < .001; lobular inflammation -0.5 0.8 vs -0.2 0.9; P < .001; ballooning -0.7 1.1 vs -0.1 0.9; P < .001). Only baseline aspartate aminotransferase (AST) levels were associated with fibrosis regression vs no change and progression vs no change on multivariable regression: baseline AST (regression: conditional odds ratio cOR, 0.6 per 10 U/L AST; 95% CI, 0.4-0.7; P < .001; progression: cOR, 1.3; 95% CI, 1.1-1.5; P = .002). Changes in the AST level, alanine aminotransferase (ALT) level, and NAS were also associated with fibrosis regression and progression (ΔAST level: regression, cOR, 0.9; 95% CI, 0.6-1.2; P = .47; progression, cOR, 1.3; 95% CI, 1.0-1.6; P = .02; ΔALT level: regression, cOR, 0.7 per 10 U/L AST; 95% CI, 0.5-0.9; P = .002; progression, cOR, 1.0 per 10 U/L AST; 95% CI, 0.9-1.2; P = .93; ΔNAS: regression, cOR, 0.7; 95% CI, 0.6-0.9; P = .001; progression, cOR, 1.3; 95% CI, 1.1-1.5; P = .01).
Improvement or worsening of disease activity may be associated with fibrosis regression or progression, respectively, in NAFLD.
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