Implementation of patient priorities-aligned care in a home-based primary care program.

BACKGROUND: Older adults may be limited in their ability to access care that meets their health goals owing to disease burden, financial instability, and psychosocial barriers. A home-based primary care (HBPC) program established in 2020 within a large family medicine practice uses the Patient Priorities Care (PPC) approach to identify and address patients' health priorities. When incorporated as part of the HBPC model of care, the PPC approach has the potential to enhance person-centered care for older adults in a way that best supports their health goals. OBJECTIVE: The objective of this study is to summarize common recommendations for alignment of care with patients' health outcome goals after implementation of the PPC approach in an HBPC population. METHODS: This retrospective study was exempt from review by an institutional review board. After enrollment in the HBPC program, patients participated in a PPC priorities identification conversation to identify their health outcome goals and care preferences. Through chart review, 2 researchers independently categorized these goals based on the set of values they most reflect: connecting, managing health, enjoying life, and functioning. Aspects of care in place before enrollment in HBPC were considered to determine any adjustments that needed to be made to align care with patients' identified priorities. RESULTS: The most common value associated with patients' most desired health outcome goal was functioning (n = 33, 66%). For secondary and tertiary health outcome goals, the most common value identified was managing health (secondary, n = 28, 56%; tertiary, n = 22, 44%). Common recommendations made to align care with patients' identified priorities included stopping potentially harmful medications, starting medications for untreated conditions, starting physical or occupational therapy, and adjusting medications. CONCLUSION: Through the PPC approach, patients' values were identified and care was assessed to aid in attainment of individualized health outcome goals and tailor care to What Matters most.

Guiding Post-Hospital Recovery by 'What Matters:' Implementation of Patient Priorities Identification in a VA Community Living Center.

BACKGROUND: Patient priorities care (PPC) is an effective age-friendly health systems (AFHS) approach to aligning care with goals derived from 'what matters'. The purpose of this quality improvement program was to evaluate the fidelity and feasibility of the health priorities identification (HPI) process in VA Community Living Centers (CLC). METHODS: PPC experts worked with local CLC staff to guide the integration of HPI into the CLC and utilized a Plan-Do-Study-Act (PDSA) model for this quality improvement project. PPC experts reviewed health priorities identification (HPI) encounters and interdisciplinary team (IDT) meetings for fidelity to the HPI process of PPC. Qualitative interviews with local CLC staff determined the appropriateness of the health priorities identification process in the CLC. RESULTS: Over 8 months, nine facilitators completed twenty HPI encounters. Development of a Patient Health Priorities note template, staff education and PPC facilitator training improved fidelity and documentation of HPI encounters in the electronic health record. Facilitator interviews suggested that PPC is appropriate in this setting, not burdensome to staff and fostered a person-centered approach to AFHS. CONCLUSIONS: The HPI process is an acceptable and feasible approach to ask the 'what matters' component of AFHS in a CLC setting.

Improving the study of RNA dynamics through advances in RNA-seq with metabolic labeling and nucleotide-recoding chemistry.

RNA metabolic labeling using 4-thiouridine (s4U) captures the dynamics of RNA synthesis and decay. The power of this approach is dependent on appropriate quantification of labeled and unlabeled sequencing reads, which can be compromised by the apparent loss of s4U-labeled reads in a process we refer to as dropout. Here we show that s4U-containing transcripts can be selectively lost when RNA samples are handled under sub-optimal conditions, but that this loss can be minimized using an optimized protocol. We demonstrate a second cause of dropout in nucleotide recoding and RNA sequencing (NR-seq) experiments that is computational and downstream of library preparation. NR-seq experiments involve chemically converting s4U from a uridine analog to a cytidine analog and using the apparent T-to-C mutations to identify the populations of newly synthesized RNA. We show that high levels of T-to-C mutations can prevent read alignment with some computational pipelines, but that this bias can be overcome using improved alignment pipelines. Importantly, kinetic parameter estimates are affected by dropout independent of the NR chemistry employed, and all chemistries are practically indistinguishable in bulk, short-read RNA-seq experiments. Dropout is an avoidable problem that can be identified by including unlabeled controls, and mitigated through improved sample handing and read alignment that together improve the robustness and reproducibility of NR-seq experiments.

Positive Basophil Tests Are Linked to High Disease Activity and Other Features of Autoimmune Chronic Spontaneous Urticaria: A Systematic Review.

BACKGROUND: Chronic spontaneous urticaria (CSU) is believed to be Autoimmune (aiCSU) (type IIb CSU) in at least 8% of patients, associated with mast cell-activating IgG autoantibodies. Basophil tests such as the basophil activation test (BAT) and basophil histamine release assay (BHRA) are considered the best single tests for an aiCSU diagnosis. To date, the strength of associations among a positive BAT and/or BHRA (BAT/BHRA+) and CSU features, patient demographics, and response to treatment remains poorly characterized. OBJECTIVE: To evaluate the strength of current evidence on basophil tests as parameters for CSU characteristics. METHODS: We performed a systematic literature search and review to assess the relationship between BAT/BHRA+ and clinical and laboratory parameters of CSU. Of 1,058 records found in the search, 94 studies were reviewed by experts in urticaria and 42 were included in the analysis. RESULTS: In CSU patients, BAT/BHRA+ showed a strong level of evidence for an association with high disease activity and low levels of total IgE. A weak level of evidence was shown for the association of BAT/BHRA+ and the presence of angioedema, and basopenia. CONCLUSIONS: Our results suggest that aiCSU defined by BAT/BHRA+ is more active or severe and is linked to other aiCSU markers such as low total IgE/basopenia. Basophil tests should be standardized and implemented in routine clinical care to improve the diagnosis and treatment of patients with aiCSU.

WAPL functions as a rheostat of Protocadherin isoform diversity that controls neural wiring.

Neural type-specific expression of clustered Protocadherin (Pcdh) proteins is essential for the establishment of connectivity patterns during brain development. In mammals, deterministic expression of the same Pcdh isoform promotes minimal overlap of tiled projections of serotonergic neuron axons throughout the brain, while stochastic expression of Pcdh genes allows for convergence of tightly packed, overlapping olfactory sensory neuron axons into targeted structures. How can the same gene locus generate opposite transcriptional programs that orchestrate distinct spatial arrangements of axonal patterns? Here, we reveal that cell type-specific Pcdh expression and axonal behavior depend on the activity of cohesin and its unloader, WAPL (wings apart-like protein homolog). While cohesin erases genomic-distance biases in Pcdh choice, WAPL functions as a rheostat of cohesin processivity that determines Pcdh isoform diversity.

Anti-KIT antibody, barzolvolimab, reduces skin mast cells and disease activity in chronic inducible urticaria.

BACKGROUND: Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)-mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX-0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose-dependent plasma tryptase suppression indicative of systemic mast cell ablation. METHODS: This is an open-label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12-week follow-up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI). RESULTS: Analysis populations were safety (n = 21) and pharmacodynamics/clinical activity (n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (

Using Wearable Sensors to Measure Goal Achievement in Older Veterans with Dementia.

Aligning treatment with patients' self-determined goals and health priorities is challenging in dementia care. Wearable-based remote health monitoring may facilitate determining the active participation of individuals with dementia towards achieving the determined goals. The present study aimed to demonstrate the feasibility of using wearables to assess healthcare goals set by older adults with cognitive impairment. We present four specific cases that assess (1) the feasibility of using wearables to monitor healthcare goals, (2) differences in function after goal-setting visits, and (3) goal achievement. Older veterans (n = 17) with cognitive impairment completed self-report assessments of mobility, then had an audio-recorded encounter with a geriatrician and wore a pendant sensor for 48 h. Follow-up was conducted at 4-6 months. Data obtained by wearables augments self-reported data and assessed function over time. Four patient cases illustrate the utility of combining sensors, self-report, notes from electronic health records, and visit transcripts at baseline and follow-up to assess goal achievement. Using data from multiple sources, we showed that the use of wearable devices could support clinical communication, mainly when patients, clinicians, and caregivers work to align care with the patient's priorities.

Pharmacist Identification of Older Patients' Priorities in a Home-Based Primary Care Program.

Background Patient Priorities Care (PPC) aims to identify and integrate patient goals and preferences into health care decision-making to provide more personalized care for multimorbid older individuals. Home-based primary care (HBPC) is a model of care delivery that supports aging in place. HBPC-integrated pharmacists can identify patient priorities and communicate with the team to ensure care is aligned with what matters most. Objectives Evaluate patients' perceptions of having priorities identification conversations with the pharmacist; identify the value domains represented by patients' health outcome goals. Setting HBPC program at a large family medicine practice where pharmacists are core members of the interdisciplinary team. Intervention Pharmacists led priorities identification conversations for patients newly enrolled in HBPC. Care preferences and health outcome goals were documented in the medical record and communicated during HBPC team meetings. Design This was a prospective, observational study of HBPC enrollees. After the priorities identification conversation, a three-question survey was administered to identify patients' perceptions of the conversation and interaction with the pharmacist. Health outcome goals and care preference statements were reviewed to determine with which value domain(s) they most aligned. Descriptive statistics were used for results analysis. Results Pharmacists led conversations with 30 participants. Average overall satisfaction with the conversation was 4.6 on a 5-point Likert scale (1 = least, 5 = most satisfied). Ninety-three percent of patients felt it was appropriate to have a pharmacist lead these conversations. Ninety-seven percent believed it was important/very important to discuss their values and goals with their health care team. The predominant value domains represented were Managing Health (43%) and Functioning (40%). Conclusion Patients were mostly satisfied with having PPC conversations and felt it was appropriate for a pharmacist to lead these conversations. Managing health conditions and preserving function were the most frequent value domains associated with patients' goals and care preferences.

Evidence for histamine release in chronic inducible urticaria - A systematic review.

Background: Chronic inducible urticaria (CIndU) constitutes a group of nine different CIndUs in which pruritic wheals and/or angioedema occur after exposure to specific and definite triggers. Histamine released from activated and degranulating skin mast cells is held to play a key role in the pathogenesis of CIndU, but evidence to support this has, as of yet, not been reviewed systematically or in detail. We aim to characterize the role and relevance of histamine in CIndU. Methods: We systematically searched 3 electronic databases (PubMed, Scopus, and Embase) for studies that reported increased serum or skin histamine concentration (direct evidence) or in vitro or ex vivo histamine release (indirect evidence) following trigger exposure. Results: An initial total of 3,882 articles was narrowed down to 107 relevant studies of which 52 were in cold urticaria, 19 in cholinergic urticaria, 14 in heat urticaria, 10 in contact urticaria, 7 each in solar urticaria and vibratory angioedema, 4 each in symptomatic dermographism and aquagenic urticaria, and 3 in delayed pressure urticaria. The results of our review support that histamine has a key pathogenic role in the pathogenesis of all CIndUs, but it is not the sole mediator as evidenced by the often poor relationship between the level of histamine and severity of symptoms and the variable clinical efficacy of H1-antihistamines. Conclusions: Histamine released from skin mast cells is a key driver of the development of signs and symptoms and a promising therapeutic target in CIndU.

Internally controlled RNA sequencing comparisons using nucleoside recoding chemistry.

Quantitative comparisons of RNA levels from different samples can lead to new biological understanding if they are able to distinguish biological variation from variable sample preparation. These challenges are pronounced in comparisons that require complex biochemical manipulations (e.g. isolating polysomes to study translation). Here, we present Transcript Regulation Identified by Labeling with Nucleoside Analogues in Cell Culture (TILAC), an internally controlled approach for quantitative comparisons of RNA content. TILAC uses two metabolic labels, 4-thiouridine (s4U) and 6-thioguanosine (s6G), to differentially label RNAs in cells, allowing experimental and control samples to be pooled prior to downstream biochemical manipulations. TILAC leverages nucleoside recoding chemistry to generate characteristic sequencing signatures for each label and uses statistical modeling to compare the abundance of RNA transcripts between samples. We verified the performance of TILAC in transcriptome-scale experiments involving RNA polymerase II inhibition and heat shock. We then applied TILAC to quantify changes in mRNA association with actively translating ribosomes during sodium arsenite stress and discovered a set of transcripts that are translationally upregulated, including MCM2 and DDX5. TILAC is broadly applicable to uncover differences between samples leading to improved biological insights.

Comparison of Collaborative Goal Setting With Enhanced Education for Managing Diabetes-Associated Distress and Hemoglobin A1c Levels: A Randomized Clinical Trial.

Importance: Type 2 diabetes is a prevalent and morbid condition. Poor engagement with self-management can contribute to diabetes-associated distress and hinder diabetes control. Objective: To evaluate the implementation and effectiveness of Empowering Patients in Chronic Care (EPICC), an evidence-based intervention to improve diabetes-associated distress and hemoglobin A1c (HbA1c) levels after the intervention and after 6-month maintenance. Design, Setting, and Participants: This hybrid (implementation-effectiveness) randomized clinical trial was performed in Veterans Affairs clinics across Illinois, Indiana, and Texas from July 1, 2015, to June 30, 2017. Participants included adults with uncontrolled type 2 diabetes (HbA1c level >8.0%) who received primary care during the prior year in participating clinics. Data collection was completed on November 30, 2018, and data analysis was completed on June 30, 2020. All analyses were based on intention to treat. Interventions: Participants in EPICC attended 6 group sessions based on a collaborative goal-setting theory led by health care professionals. Clinicians conducted individual motivational interviewing sessions after each group. Usual care was enhanced (EUC) with diabetes education. Main Outcomes and Measures: The primary outcome consisted of changes in HbA1c levels after the intervention and during maintenance. Secondary outcomes included the Diabetes Distress Scale (DDS), Morisky Medication Adherence Scale, and Lorig Self-efficacy Scale. Secondary implementation outcomes included reach, adoption, and implementation (number of sessions attended per patient). Results: A total of 280 participants with type 2 diabetes (mean [SD] age, 67.2 [8.4] years; 264 men [94.3]; 134 non-Hispanic White individuals [47.9%]) were equally randomized to EPICC or EUC. Participants receiving EPICC had significant postintervention improvements in HbA1c levels (F1, 252 = 9.12, Cohen d = 0.36 [95% CI, 0.12-0.59]; P = .003) and DDS (F1, 245 = 9.06, Cohen d = 0.37 [95% CI, 0.13-0.60]; P = .003) compared with EUC. During maintenance, differences between the EUC and EPICC groups remained significant for DDS score (F1, 245 = 8.94, Cohen d = 0.36 [95% CI, 0.12-0.59]; P = .003) but not for HbA1c levels (F1, 252 = 0.29, Cohen d = 0.06 [95% CI, -0.17 to 0.30]; P = .60). Improvements in DDS scores were modest. There were no differences between EPICC and EUC in improvements after intervention or maintenance for either adherence or self-efficacy. Among all 4002 eligible patients, 280 (7.0%) enrolled in the study (reach). Each clinic conducted all planned EPICC sessions and cohorts (100% adoption). The EPICC group participants attended a mean (SD) of 4.34 (1.98) sessions, with 54 (38.6%) receiving all 6 sessions. Conclusions and Relevance: A patient-empowerment approach using longitudinal collaborative goal setting and motivational interviewing is feasible in primary care. Improvements in HbA1c levels after the intervention were not sustained after maintenance. Modest improvements in diabetes-associated distress after the intervention were sustained after maintenance. Innovations to expand reach (eg, telemedicine-enabled shared appointments) and sustainability are needed. Trial Registration: ClinicalTrials.gov Identifier: NCT01876485.

Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies.

Splicing factor mutations are common among cancers, recently emerging as drivers of myeloid malignancies. U2AF1 carries hotspot mutations in its RNA-binding motifs; however, how they affect splicing and promote cancer remain unclear. The U2AF1/U2AF2 heterodimer is critical for 3' splice site (3'SS) definition. To specifically unmask changes in U2AF1 function in vivo, we developed a crosslinking and immunoprecipitation procedure that detects contacts between U2AF1 and the 3'SS AG at single-nucleotide resolution. Our data reveal that the U2AF1 S34F and Q157R mutants establish new 3'SS contacts at -3 and +1 nucleotides, respectively. These effects compromise U2AF2-RNA interactions, resulting predominantly in intron retention and exon exclusion. Integrating RNA binding, splicing, and turnover data, we predicted that U2AF1 mutations directly affect stress granule components, which was corroborated by single-cell RNA-seq. Remarkably, U2AF1-mutant cell lines and patient-derived MDS/AML blasts displayed a heightened stress granule response, pointing to a novel role for biomolecular condensates in adaptive oncogenic strategies.

Measuring Adoption of Patient Priorities-Aligned Care Using Natural Language Processing of Electronic Health Records: Development and Validation of the Model.

BACKGROUND: Patient Priorities Care (PPC) is a model of care that aligns health care recommendations with priorities of older adults who have multiple chronic conditions. Following identification of patient priorities, this information is documented in the patient's electronic health record (EHR). OBJECTIVE: Our goal is to develop and validate a natural language processing (NLP) model that reliably documents when clinicians identify patient priorities (ie, values, outcome goals, and care preferences) within the EHR as a measure of PPC adoption. METHODS: This is a retrospective analysis of unstructured National Veteran Health Administration EHR free-text notes using an NLP model. The data were sourced from 778 patient notes of 658 patients from encounters with 144 social workers in the primary care setting. Each patient's free-text clinical note was reviewed by 2 independent reviewers for the presence of PPC language such as priorities, values, and goals. We developed an NLP model that utilized statistical machine learning approaches. The performance of the NLP model in training and validation with 10-fold cross-validation is reported via accuracy, recall, and precision in comparison to the chart review. RESULTS: Of 778 notes, 589 (75.7%) were identified as containing PPC language (kappa=0.82, P<.001). The NLP model in the training stage had an accuracy of 0.98 (95% CI 0.98-0.99), a recall of 0.98 (95% CI 0.98-0.99), and precision of 0.98 (95% CI 0.97-1.00). The NLP model in the validation stage had an accuracy of 0.92 (95% CI 0.90-0.94), recall of 0.84 (95% CI 0.79-0.89), and precision of 0.84 (95% CI 0.77-0.91). In contrast, an approach using simple search terms for PPC only had a precision of 0.757. CONCLUSIONS: An automated NLP model can reliably measure with high precision, recall, and accuracy when clinicians document patient priorities as a key step in the adoption of PPC.

Author Correction: Enhanced nucleotide chemistry and toehold nanotechnology reveals lncRNA spreading on chromatin.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Enhanced nucleotide chemistry and toehold nanotechnology reveals lncRNA spreading on chromatin.

Understanding the targeting and spreading patterns of long non-coding RNAs (lncRNAs) on chromatin requires a technique that can detect both high-intensity binding sites and reveal genome-wide changes in spreading patterns with high precision and confidence. Here we determine lncRNA localization using biotinylated locked nucleic acid (LNA)-containing oligonucleotides with toehold architecture capable of hybridizing to target RNA through strand-exchange reaction. During hybridization, a protecting strand competitively displaces contaminating species, leading to highly specific RNA capture of individual RNAs. Analysis of Drosophila roX2 lncRNA using this approach revealed that heat shock, unlike the unfolded protein response, leads to reduced spreading of roX2 on the X chromosome, but surprisingly also to relocalization to sites on autosomes. Our results demonstrate that this improved hybridization capture approach can reveal previously uncharacterized changes in the targeting and spreading of lncRNAs on chromatin.

Empowering patients in chronic care to improve diabetes distress and glycaemic control: Protocol for a hybrid implementation-effectiveness clinical trial.

OBJECTIVES: To evaluate the effectiveness of a collaborative goal-setting intervention (Empowering Patients in Chronic Care [EPIC]) to improve glycaemic control and diabetesrelated distress, and implementation into routine care across multiple primary care clinics. DESIGN: Randomized controlled trial comparing the effectiveness of the EPIC intervention with enhanced usual care (EUC) at five clinic sites located in the greater Chicago and Houston areas. We will measure differences in haemoglobin A1c (HbA1c) and diabetes distress scale scores among study arms at post-intervention and maintenance (6 months post-intervention). We will evaluate implementation of the intervention across sites using the RE-AIM framework. We will evaluate reach by comparing the per cent and characteristics of enrolled study participants among all potentially eligible participants in the given clinic population. Adoption is reflected by the characteristics of the involved providers and the number of intervention sessions conducted. Implementation of EPIC will be evaluated by number of sessions delivered, participants' evaluation of group sessions, and evaluation of quality of goal-setting. PATIENTS: We randomized 280 participants with equal allocation to EPIC and enhanced usual care (EUC). RESULTS: At baseline, the groups were similar with the exception that EUC participants were more likely to have prior diabetes education. At baseline, participants were predominately older men who have poorly controlled diabetes (mean HbA1c = 76 mmol/mol [9.1%]) and moderate levels of diabetes distress (mean DDS = 2.43). CONCLUSIONS: This hybrid effectiveness-implementation protocol is designed to accelerate the translation of a patient-centred diabetes care intervention from research to clinical practice.

Expanding the Nucleoside Recoding Toolkit: Revealing RNA Population Dynamics with 6-Thioguanosine.

RNA-sequencing (RNA-seq) measures RNA abundance in a biological sample but does not provide temporal information about the sequenced RNAs. Metabolic labeling can be used to distinguish newly made RNAs from pre-existing RNAs. Mutations induced from chemical recoding of the hydrogen bonding pattern of the metabolic label can reveal which RNAs are new in the context of a sequencing experiment. These nucleotide recoding strategies have been developed for a single uridine analogue, 4-thiouridine (s4U), limiting the scope of these experiments. Here we report the first use of nucleoside recoding with a guanosine analogue, 6-thioguanosine (s6G). Using TimeLapse sequencing (TimeLapse-seq), s6G can be recoded under RNA-friendly oxidative nucleophilic-aromatic substitution conditions to produce adenine analogues (substituted 2-aminoadenosines). We demonstrate the first use of s6G recoding experiments to reveal transcriptome-wide RNA population dynamics.