Effect of a Telephone Health Coaching Intervention on Hypertension Control in Young Adults: The MyHEART Randomized Clinical Trial.

Importance: Uncontrolled hypertension (ie, a 24-hour ambulatory systolic blood pressure of ≥130 mm Hg and diastolic blood pressure of ≥80 mm Hg or clinic systolic blood pressure of ≥140 mm Hg and diastolic blood pressure of ≥90 mm Hg) in young adults is a US public health burden. Objective: To evaluate the effect of a telephone coaching and blood pressure self-monitoring intervention compared with usual care on changes in systolic and diastolic blood pressures and behaviors at 6 and 12 months. Design, Setting, and Participants: This randomized clinical trial included male and female participants aged 18 to 39 years with uncontrolled hypertension confirmed by 24-hour ambulatory blood pressure testing. This was a geographically diverse, multicentered study within 2 large, Midwestern health care systems. Data were collected from October 2017 to February 2022 and analyzed from February to June 2022. Interventions: The My Hypertension Education and Reaching Target (MyHEART) intervention consisted of telephone coaching every 2 weeks for 6 months, with home blood pressure monitoring. Control participants received routine hypertension care. Main Outcomes and Measures: The co-primary clinical outcomes were changes in 24-hour ambulatory and clinic systolic and diastolic blood pressure at 6 and 12 months. The secondary outcomes were hypertension control (defined as ambulatory systolic blood pressure <130 mm Hg and diastolic blood pressure <80 mm Hg or clinic systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg) and changes in hypertension self-management behavior. Results: A total of 316 participants were randomized (159 to the control group and 157 to the intervention group) from October 2017 to December 2020. The median (IQR) age was 35 (31-37) years, 145 of 311 participants (46.6%) were female, and 166 (53.4%) were male; 72 (22.8%) were Black, and 222 (70.3%) were White. There were no differences in baseline characteristics between groups. There was no significant difference between control and intervention groups for mean 24-hour ambulatory systolic or diastolic blood pressure or clinic systolic or diastolic blood pressure at 6 or 12 months. However, there was appreciable clinical reduction in blood pressures in both study groups (eg, mean [SD] change in systolic blood pressure in intervention group at 6 months, -4.19 [9.77] mm Hg; P < .001). Hypertension control did not differ between study groups. Participants in the intervention group demonstrated a significant increase in home blood pressure monitoring at 6 and 12 months (eg, 13 of 152 participants [8.6%] checked blood pressure at home at least once a week at baseline vs 30 of 86 [34.9%] at 12 months; P < .001). There was a significant increase in physical activity, defined as active by the Godin-Shephard Leisure-Time Physical Activity Questionnaire, in the intervention group at 6 months (69 of 100 [69.0%] vs 51 of 104 [49.0%]; P = .004) but not at 12 months (49 of 86 [57.0%] vs 49 of 90 [54.4%]; P = .76). There was a significant reduction in mean (SD) sodium intake among intervention participants at 6 months (3968.20 [1725.17] mg vs 3354.72 [1365.75] mg; P = .003) but not 12 months. There were no significant differences in other dietary measures. Conclusions and Relevance: The MyHEART intervention did not demonstrate a significant change in systolic or diastolic blood pressures at 6 or 12 months between study groups; however, both study groups had an appreciable reduction in blood pressure. Intervention participants had a significant reduction in dietary sodium intake, increased physical activity, and increased home blood pressure monitoring compared with control participants. These findings suggest that the MyHEART intervention could support behavioral changes in young adults with uncontrolled hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT03158051.

Delays in discharge in a tertiary care pediatric hospital.

BACKGROUND: Delays in discharges affect both efficiency and timeliness of care; 2 measures of quality of inpatient care. OBJECTIVE: Describe number, length, and type of delays in hospital discharges. Characterize impact of delays on overall length of stay (LOS) and costs. DESIGN: Prospective observational cohort study. SETTING: Tertiary-care children's hospital. PATIENTS: All children on 2 medical teams during August 2004. INTERVENTION: Two research assistants presented detailed data of patient care (from daily rounds) to 2 physicians who identified delays and classified the delay type. Discharge was identified as delayed if there was no medical reason for the patient to be in the hospital on a given day. MEASUREMENTS: Delays were classified using a validated and reliable instrument, the Delay Tool. LOS and costs were extracted from an administrative database. RESULTS: Two teams cared for 171 patients. Mean LOS and costs were 7.3 days (standard deviation [SD] 14.3) and $15,197 (SD 38,395), respectively: 22.8% of patients experienced at least 1 delay, accounting for 82 delay-related hospital days (9% of total hospital days) and $170,000 in costs (8.9% of hospital costs); 42.3% of the delays resulted from physician behavior, 21.8% were related to discharge planning, 14.1% were related to consultation, and 12.8% were related to test scheduling. CONCLUSIONS: Almost one-fourth of patients in this 1-month period could have been discharged sooner than they were. Impact of delays on LOS and costs are substantial. Interventions will need to address variations in physician criteria for discharge, more efficient discharge planning, and timely scheduling of consultation and diagnostic testing.

Structure of the central RNA recognition motif of human TIA-1 at 1.95A resolution.

T-cell-restricted intracellular antigen-1 (TIA-1) regulates alternative pre-mRNA splicing in the nucleus, and mRNA translation in the cytoplasm, by recognizing uridine-rich sequences of RNAs. As a step towards understanding RNA recognition by this regulatory factor, the X-ray structure of the central RNA recognition motif (RRM2) of human TIA-1 is presented at 1.95A resolution. Comparison with structurally homologous RRM-RNA complexes identifies residues at the RNA interfaces that are conserved in TIA-1-RRM2. The versatile capability of RNP motifs to interact with either proteins or RNA is reinforced by symmetry-related protein-protein interactions mediated by the RNP motifs of TIA-1-RRM2. Importantly, the TIA-1-RRM2 structure reveals the locations of mutations responsible for inhibiting nuclear import. In contrast with previous assumptions, the mutated residues are buried within the hydrophobic interior of the domain, where they would be likely to destabilize the RRM fold rather than directly inhibit RNA binding.

Structure of a DNA repair substrate containing an alkyl interstrand cross-link at 1.65 A resolution.

Chemotherapeutic alkylating agents, such as bifunctional nitrogen mustards and cisplatins, generate interstrand DNA cross-links that inhibit cell proliferation by arresting DNA transcription and replication. A synthetic N4C-ethyl-N4C interstrand cross-link between opposing cytidines mimics the DNA damage produced by this class of clinically important compounds and can be synthesized in large quantities to study the repair, physical properties, and structures of these DNA adducts. The X-ray structure of a DNA duplex d(CCAAC*GTTGG)2 containing a synthetic N4C-ethyl-N4C interstrand cross-link between the cytosines of the central CpG step (*) has been determined at 1.65 A resolution. This structure reveals that the ethyl cross-link in the CpG major groove does not significantly disrupt the B-form DNA helix. Comparison of the N4C-ethyl-N4C cross-linked structure with the structure of an un-cross-linked oligonucleotide of the same sequence reveals that the cross-link selectively stabilizes a preexisting alternative conformation. The conformation preferred by the cross-linked DNA is constrained by the geometry of the ethyl group bridging the cytosine amines. Characteristics of the cross-linked CpG step include subtle differences in the roll of the base pairs, optimized Watson-Crick hydrogen bonds, and loss of a divalent cation binding site. Given that the N4C-ethyl-N4C cross-link stabilizes a preexisting conformation of the CpG step, this synthetically accessible substrate presents an ideal model system for studying the genomic effects of covalently coupling the DNA strands, independent of gross alterations in DNA structure.

Major phosphorylation of SF1 on adjacent Ser-Pro motifs enhances interaction with U2AF65.

Protein phosphorylation ensures the accurate and controlled expression of the genome, for instance by regulating the activities of pre-mRNA splicing factors. Here we report that splicing factor 1 (SF1), which is involved in an early step of intronic sequence recognition, is highly phosphorylated in mammalian cells on two serines within an SPSP motif at the junction between its U2AF65 and RNA binding domains. We show that SF1 interacts in vitro with the protein kinase KIS, which possesses a 'U2AF homology motif' (UHM) domain. The UHM domain of KIS is required for KIS and SF1 to interact, and for KIS to efficiently phosphorylate SF1 on the SPSP motif. Importantly, SPSP phosphorylation by KIS increases binding of SF1 to U2AF65, and enhances formation of the ternary SF1-U2AF65-RNA complex. These results further suggest that this phosphorylation event has an important role for the function of SF1, and possibly for the structural rearrangements associated with spliceosome assembly and function.

Multiple U2AF65 binding sites within SF3b155: thermodynamic and spectroscopic characterization of protein-protein interactions among pre-mRNA splicing factors.

Essential, protein-protein complexes between the large subunit of the U2 small nuclear RNA auxiliary factor (U2AF65) with the splicing factor 1 (SF1) or the spliceosomal component SF3b155 are exchanged during a critical, ATP-dependent step of pre-mRNA splicing. Both SF1 and the N-terminal domain of SF3b155 interact with a U2AF homology motif (UHM) of U2AF65. SF3b155 contains seven tryptophan-containing sites with sequence similarity to the previously characterized U2AF65-binding domain of SF1. We show that the SF3b155 domain lacks detectable secondary structure using circular dichroism spectroscopy, and demonstrate that five of the tryptophan-containing SF3b155 sites are recognized by the U2AF65-UHM using intrinsic tryptophan fluorescence experiments with SF3b155 variants. When compared with SF1, similar spectral shifts and sequence requirements indicate that U2AF65 interactions with each of the SF3b155 sites are similar to the minimal SF1 site. However, thermodynamic comparison of SF1 or SF3b155 proteins with minimal peptides demonstrates that formation the SF1/U2AF65 complex is likely to affect regions of SF1 beyond the previously identified, linear interaction site, in a remarkably distinct manner from the local U2AF65 binding mode of SF3b155. Furthermore, the complex of the SF1/U2AF65 interacting domains is stabilized by 3.3 kcal mol-1 relative to the complex of the SF3b155/U2AF65 interacting domains, consistent with the need for ATP hydrolysis to drive exchange of these partners during pre-mRNA splicing. We propose that the multiple U2AF65 binding sites within SF3b155 regulate conformational rearrangements during spliceosome assembly. Comparison of the SF3b155 sites defines an (R/K)nXRW(DE) consensus sequence for predicting U2AF65-UHM ligands from genomic sequences, where parentheses denote residues that contribute to, but are not required for binding.