Many bacteria and archaea contain clustered regularly interspaced short palindromic repeats (CRISPRs) that confer resistance to invasive genetic elements. Central to this immune system is the ...production of CRISPR-derived RNAs (crRNAs) after transcription of the CRISPR locus. Here, we identify the endoribonuclease (Csy4) responsible for CRISPR transcript (pre-crRNA) processing in Pseudomonas aeruginosa. A 1.8 angstrom crystal structure of Csy4 bound to its cognate RNA reveals that Csy4 makes sequence-specific interactions in the major groove of the crRNA repeat stem-loop. Together with electrostatic contacts to the phosphate backbone, these enable Csy4 to bind selectively and cleave pre-crRNAs using phylogenetically conserved serine and histidine residues in the active site. The RNA recognition mechanism identified here explains sequence- and structure-specific processing by a large family of CRISPR-specific endoribonucleases.
To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients ...with advanced urothelial bladder cancer (UBC).
A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1-positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1.
A total of 61 patients (40 PD-L1-positive, 21 PD-L1-negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1-positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1-negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks).
Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, many of whom were heavily pretreated.
Advances in imaging and early cancer detection have increased interest in magnetic resonance (MR) guided focused ultrasound (MRgFUS) technologies for cancer treatment. MRgFUS ablation treatments ...could reduce surgical risks, preserve organ tissue and function, and improve patient quality of life. However, surgical resection and histological analysis remain the gold standard to assess cancer treatment response. For non-invasive ablation therapies such as MRgFUS, the treatment response must be determined through MR imaging biomarkers. However, current MR biomarkers are inconclusive and have not been rigorously evaluated against histology via accurate registration. Existing registration methods rely on anatomical features to directly register in vivo MR and histology. For MRgFUS applications in anatomies such as liver, kidney, or breast, anatomical features that are not caused by the treatment are often insufficient to drive direct registration. We present a novel MR to histology registration workflow that utilizes intermediate imaging and does not rely on anatomical MR features being visible in histology. The presented workflow yields an overall registration accuracy of 1.00 ± 0.13 mm. The developed registration pipeline is used to evaluate a common MRgFUS treatment assessment biomarker against histology. Evaluating MR biomarkers against histology using this registration pipeline will facilitate validating novel MRgFUS biomarkers to improve treatment assessment without surgical intervention. While the presented registration technique has been evaluated in a MRgFUS ablation treatment model, this technique could be potentially applied in any tissue to evaluate a variety of therapeutic options.
Food parenting practices (FPPs) are important in shaping children's dietary behaviors. However, existing FPP knowledge is largely based on research with mothers.
This study (1) identified fathers' ...FPPs; (2) described differences in FPP use by fathers' education and residential status.
Semi-structured interviews were conducted with 40 fathers (39 ± 9.1 years; 37.5% non-residential; 40% ≥college education). Interviews were audio-recorded and transcribed. NVivo 10 was used for theme detection, categorization and classification using inductive and deductive approaches. FPPs were identified and their relative distribution was examined across education and residential status.
Twenty FPPs were identified - 13 responsive practices and 7 unresponsive practices. Having food rules was the most common responsive FPP (81.5%), followed by feeding on schedule (60%) and making healthy food accessible (60%). Common unresponsive FPPs were letting child dictate preferences (70%), incentivizing food consumption (60%) and pressuring the child to eat (35%). Compared to fathers with a college education, more fathers without a college education reported letting child dictate preferences (92% vs. 37%), educating their children about food (37% vs 12%), fewer reported feeding on schedule (50% vs. 75%), modeling healthy practices (29% vs. 50%), and using distraction to feed (4% vs. 37%). Compared to residential fathers, more non-residential fathers monitored (60% vs. 40%) or encouraged (60% vs. 36%) child food intake and let child dictate preferences (87% vs. 60%).
Fathers used an extensive variety of FPPs, similar to those identified in mothers. Further study on the influence of fathers' education and residential status on FPP use is warranted.
People with chronic pain tend to interpret ambiguous information as health-related, more so than people without. In this study, we aimed to investigate whether people with rheumatoid arthritis (RA) ...exhibit this interpretation bias and whether it is associated with fear of disease progression (FoP). The interpretation biases of people with RA (n = 164) were compared with an age- and gender-matched control group. We hypothesized that (1) people with RA would have larger interpretation biases than people without; (2) those who scored in the clinical range for FoP would have larger interpretation bias than those who did not; (3) interpretation bias would moderate the relationship between pain severity and FoP; and (4) interpretation bias would explain variance in FoP above and beyond other established predictors. Our results confirmed that people with RA were more likely to interpret ambiguous information as health-related compared with people without RA. This effect was more pronounced for the RA subgroup with clinically significant FoP than those scoring in the normal range. We did not find evidence to suggest interpretation bias moderated the relationship between pain and FoP or that FoP added to the variance of other known predictors. Our results indicate that interpretation bias is common amongst people with RA and is associated with FoP. Further research is required to illuminate the exact nature of this relationship.
People with rheumatoid arthritis (RA) have higher levels of fear of disease progression (FOP) than cancer survivors. In cancer, FOP is inextricably linked with existential concerns. However, this has ...not been investigated in people with RA.
We recruited 165 people with RA (96%F) who volunteered for a treatment trial of psychological intervention. Participants completed the Existential Concerns Questionnaire (ECQ) and questionnaires measuring constructs associated with FOP in cancer. We created groups of people with RA, with and without clinically significant levels of FOP (clinical and control groups) and compared their existential concerns. We hypothesized that existential concerns would add to the variance in FOP over and above pain, psychopathology, and disability.
Nearly two-thirds of people with RA scored in the clinical range for FOP. The clinical group had higher levels of all existential concerns than the control group. When subscales of the ECQ were entered into a multiple regression with FOP as the dependent variable, death anxiety, meaninglessness and guilt domains accounted for significant variance in FOP. Moreover, when added to a regression equation controlling all other variables, existential concerns continued to account for unique variance in FOP (t = 2.712, p = 0.007).
Existential concerns were strongly associated with FOP. While this cross-sectional study cannot determine whether existential concerns underlie FOP in RA, these results show robust relationships that warrant future investigation.
•Fears of illness progression were prevalent in those with rheumatoid arthritis.•Existential concerns were strongly associated with fears of progression.•Existential concerns contributed unique variance over and above other predictors.
Innate lymphoid cells (ILC) promote lung inflammation in asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators, although less is known about ...RBPs in ILC biology. Here, we demonstrate that RNA-binding motif 3 (RBM3) is highly expressed in lung ILCs and is further induced by alarmins TSLP and IL-33. Rbm3
and Rbm3
Rag2
mice exposed to asthma-associated Alternaria allergen develop enhanced eosinophilic lung inflammation and ILC activation. IL-33 stimulation studies in vivo and in vitro show that RBM3 suppressed lung ILC responses. Further, Rbm3
ILCs from bone marrow chimeric mice display increased ILC cytokine production suggesting an ILC-intrinsic suppressive function of RBM3. RNA-sequencing of Rbm3
lung ILCs demonstrates increased expression of type 2/17 cytokines and cysteinyl leukotriene 1 receptor (CysLT1R). Finally, Rbm3
Cyslt1r
mice show dependence on CysLT1R for accumulation of ST2
IL-17
ILCs. Thus, RBM3 intrinsically regulates lung ILCs during allergen-induced type 2 inflammation that is partially dependent on CysLT1R.
IMPORTANCE: Patients with advanced chronic kidney disease (CKD) have the best chance for a longer and healthier life if they receive a kidney transplant. However, many barriers prevent patients from ...receiving a transplant. OBJECTIVES: To evaluate the effect of a multicomponent intervention designed to target several barriers that prevent eligible patients from completing key steps toward receiving a kidney transplant. DESIGN, SETTING, AND PARTICIPANTS: This pragmatic, 2-arm, parallel-group, open-label, registry-based, superiority, cluster randomized clinical trial included all 26 CKD programs in Ontario, Canada, from November 1, 2017, to December 31, 2021. These programs provide care for patients with advanced CKD (patients approaching the need for dialysis or receiving maintenance dialysis). INTERVENTIONS: Using stratified, covariate-constrained randomization, allocation of the CKD programs at a 1:1 ratio was used to compare the multicomponent intervention vs usual care for 4.2 years. The intervention had 4 main components, (1) administrative support to establish local quality improvement teams; (2) transplant educational resources; (3) an initiative for transplant recipients and living donors to share stories and experiences; and (4) program-level performance reports and oversight by administrative leaders. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate of steps completed toward receiving a kidney transplant. Each patient could complete up to 4 steps: step 1, referred to a transplant center for evaluation; step 2, had a potential living donor contact a transplant center for evaluation; step 3, added to the deceased donor waitlist; and step 4, received a transplant from a living or deceased donor. RESULTS: The 26 CKD programs (13 intervention, 13 usual care) during the trial period included 20 375 potentially transplant-eligible patients with advanced CKD (intervention group n = 9780 patients, usual-care group n = 10 595 patients). Despite evidence of intervention uptake, the step completion rate did not significantly differ between the intervention vs usual-care groups: 5334 vs 5638 steps; 24.8 vs 24.1 steps per 100 patient-years; adjusted hazard ratio, 1.00 (95% CI, 0.87-1.15). CONCLUSIONS AND RELEVANCE: This novel multicomponent intervention did not significantly increase the rate of completed steps toward receiving a kidney transplant. Improving access to transplantation remains a global priority that requires substantial effort. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03329521
To determine the utility of blood symmetric dimethylarginine (SDMA) concentration measurement as a diagnostic tool for chronic kidney disease (CKD) in tigers (Panthera tigris) by comparing results ...for SDMA with those for traditional renal biomarkers and investigating correlations between these biomarkers and histopathologic kidney changes in tigers with CKD.
Blood, urine, and kidney samples from 35 tigers with CKD from 2 sanctuaries.
Blood (serum or plasma) and urine samples were collected antemortem. Necropsy, including gross and histologic assessment, was performed for tigers that died or were euthanized for quality-of-life reasons. Results for CKD biomarkers in blood (BUN, creatinine, phosphorus, and SDMA concentrations) and urine (protein concentration, urine protein-to-creatinine ratio, and urine specific gravity) were evaluated for correlation with histologic kidney damage scored with an objective grading scale defined by percentage of inflammation, fibrosis, and tubular atrophy.
Symmetric dimethylarginine had the strongest significant correlation (ρ = 0.667) with histologic kidney damage score, followed by urine specific gravity (ρ = -0.639), blood creatinine concentration (ρ = 0.624), and BUN (ρ = 0.588). No significant correlation with kidney score was identified for blood phosphorus concentration, urine protein concentration, or the urine protein-to-creatinine ratio.
We recommend SDMA be prioritized as a renal biomarker in tigers, with SDMA results considered in addition to those of other traditional renal biomarkers when assessing kidney function in tigers. Additionally, the grading scale we developed could be replicated across patients and pathologists for more consistent postmortem assessment of CKD in tigers.
Despite agreement that snacks contribute significant energy to children's diets, evidence of the effects of snacks on health, especially in children, is weak. Some of the lack of consistent evidence ...may be due to a non-standardized definition of snacks. Understanding how caregivers of preschool-aged children conceptualize and define child snacks could provide valuable insights on epidemiological findings, targets for anticipatory guidance, and prevention efforts. Participants were 59 ethnically-diverse (White, Hispanic, and African American), low-income urban caregivers of children age 3–5 years. Each caregiver completed a 60–90 min semi-structured in-depth interview to elicit their definitions of child snacks. Data were coded by two trained coders using theoretically-guided emergent coding techniques to derive key dimensions of caregivers' child snack definitions. Five interrelated dimensions of a child snack definition were identified: (1) types of food, (2) portion size, (3) time, (4) location, and (5) purpose. Based on these dimensions, an empirically-derived definition of caregivers' perceptions of child snacks is offered: A small portion of food that is given in-between meals, frequently with an intention of reducing or preventing hunger until the next mealtime. These findings suggest interrelated dimensions that capture the types of foods and eating episodes that are defined as snacks. Child nutrition studies and interventions that include a focus on child snacks should consider using an a priori multi-dimensional definition of child snacks.
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