Patient and clinician perspectives of a remote monitoring program for COVID-19 and lessons for future programs.

COVID Watch is a remote patient monitoring program implemented during the pandemic to support home dwelling patients with COVID-19. The program conferred a large survival advantage. We conducted semi-structured interviews of 85 patients and clinicians using COVID Watch to understand how to design such programs even better. Patients and clinicians found COVID Watch to be comforting and beneficial, but both groups desired more clarity about the purpose and timing of enrollment and alternatives to text-messages to adapt to patients' preferences as these may have limited engagement and enrollment among marginalized patient populations. Because inclusiveness and equity are important elements of programmatic success, future programs will need flexible and multi-channel human-to-human communication pathways for complex clinical interactions or for patients who do not desire tech-first approaches.

An accelerated hospital observation pathway to reduce length of stay for patients with COVID-19.

OBJECTIVES: Strategies to maintain hospital capacity during the COVID-19 pandemic included reducing hospital length of stay (LOS) for infected patients. We sought to evaluate the association between LOS and enrollment in the COVID Accelerated Care Pathway, which consisted of a hospital observation protocol and postdischarge automated text message-based monitoring. STUDY DESIGN: Retrospective matched cohort study of patients hospitalized from December 14, 2020, to January 31, 2021. METHODS: Participants were patients who presented to the emergency department with acute infection due to COVID-19, required hospitalization, and met pathway inclusion criteria. Participants were compared with a propensity score-matched cohort of patients with COVID-19 admitted to the same hospital during the 7 weeks preceding and following pathway implementation. RESULTS: There were 44 patients in the intervention group and 83 patients in the propensity score-matched cohort. The mean (SD) hospital LOS for patients in the intervention group was 1.7 (2.6) days compared with 3.9 (2.3) days for patients in the matched cohort (difference, -2.2 days; 95% CI, -3.3 to -1.1). In the intervention group, 2 patients (5%; 95% CI, 0%-15%) were rehospitalized within 14 days compared with 8 (10%; 95% CI, 4%-17%) in the matched cohort. CONCLUSIONS: Patients with COVID-19 who were managed through an accelerated hospital observation protocol and postdischarge monitoring service had reduced hospital LOS compared with patients receiving standard care. Hospital preparedness for future public health emergencies may involve the design of pathways that reduce the time that patients spend in the hospital, lower cost, and ensure continued recovery upon discharge.

Comparative Effectiveness of an Automated Text Messaging Service for Monitoring COVID-19 at Home.

BACKGROUND: Although most patients with SARS-CoV-2 infection can be safely managed at home, the need for hospitalization can arise suddenly. OBJECTIVE: To determine whether enrollment in an automated remote monitoring service for community-dwelling adults with COVID-19 at home ("COVID Watch") was associated with improved mortality. DESIGN: Retrospective cohort analysis. SETTING: Mid-Atlantic academic health system in the United States. PARTICIPANTS: Outpatients who tested positive for SARS-CoV-2 between 23 March and 30 November 2020. INTERVENTION: The COVID Watch service consists of twice-daily, automated text message check-ins with an option to report worsening symptoms at any time. All escalations were managed 24 hours a day, 7 days a week by dedicated telemedicine clinicians. MEASUREMENTS: Thirty- and 60-day outcomes of patients enrolled in COVID Watch were compared with those of patients who were eligible to enroll but received usual care. The primary outcome was death at 30 days. Secondary outcomes included emergency department (ED) visits and hospitalizations. Treatment effects were estimated with propensity score-weighted risk adjustment models. RESULTS: A total of 3488 patients enrolled in COVID Watch and 4377 usual care control participants were compared with propensity score weighted models. At 30 days, COVID Watch patients had an odds ratio for death of 0.32 (95% CI, 0.12 to 0.72), with 1.8 fewer deaths per 1000 patients (CI, 0.5 to 3.1) (P = 0.005); at 60 days, the difference was 2.5 fewer deaths per 1000 patients (CI, 0.9 to 4.0) (P = 0.002). Patients in COVID Watch had more telemedicine encounters, ED visits, and hospitalizations and presented to the ED sooner (mean, 1.9 days sooner [CI, 0.9 to 2.9 days]; all P < 0.001). LIMITATION: Observational study with the potential for unobserved confounding. CONCLUSION: Enrollment of outpatients with COVID-19 in an automated remote monitoring service was associated with reduced mortality, potentially explained by more frequent telemedicine encounters and more frequent and earlier presentation to the ED. PRIMARY FUNDING SOURCE: Patient-Centered Outcomes Research Institute.

Does BRAF V600E mutation predict aggressive features in papillary thyroid cancer? Results from four endocrine surgery centers.

BACKGROUND: Existing evidence is controversial regarding the association between BRAF mutation status and aggressive features of papillary thyroid cancer (PTC). Specifically, no study has incorporated multiple surgical practices performing routine central lymph node dissection (CLND) and thus has patients who are truly evaluable for the presence or absence of central lymph node metastases (CLNMs). METHODS: Consecutive patients who underwent total thyroidectomy and routine CLND at 4 tertiary endocrine surgery centers were retrospectively reviewed. Descriptive and bivariable analyses examined demographic, patient, and tumor-related factors. Multivariable analyses examined the odds of CLNM associated with positive BRAF status. RESULTS: In patients with classical variant PTC, bivariate analysis found no significant associations between BRAF mutation and aggressive clinicopathologic features; multivariate analysis demonstrated that BRAF status was not an independent predictor of CLNM. When all patients with PTC were analyzed, including those with aggressive or follicular subtypes, bivariate analysis showed BRAF mutation to be associated with LNM, advanced American Joint Committee on Cancer (AJCC) stage, and histologic subtype. Multivariable analyses showed BRAF, age, size, and extrathyroidal extension to be associated with CLNM. CONCLUSION: Although BRAF mutation was found to be an independent predictor of central LNM in the overall cohort of patients with PTC, this relationship lost significance when only classical variant PTC was included in the analysis. The usefulness of BRAF in predicting the presence of LNM remains questionable. Prospective studies are needed before BRAF mutation can be considered a reliable factor to guide the treatment of patients with PTC, specifically whether to perform prophylactic CLND.

BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysis.

BACKGROUND: There is conflicting literature regarding the association of the BRAF V600E mutation and aggressive clinicopathological features of papillary thyroid cancer (PTC). Nevertheless, some propose that BRAF status be incorporated into the management of patients with PTC, specifically recommendations regarding lymph node dissection. We therefore performed a meta-analysis to examine the relationship between BRAF and clinicopathological features of PTC. METHODS: A literature search was performed within PubMed and EMBASE databases using the following Medical Subject Headings (MeSH) and keywords: "braf," "mutation," "thyroid," "neoplasm(s)," "tumor," "cancer," and "carcinoma." Individual study-specific odds ratios and confidence intervals were calculated, as were Mantel-Haenszel pooled odds ratios for the combined studies. RESULTS: Thirty-two studies including 6372 patients were reviewed. BRAF mutation was associated with lymph node metastases (LNM), advanced stage, extrathyroidal extension, tumor size, male gender, multifocality, absence of capsule, classic PTC, and tall-cell variant PTC. There was no association with age or vascular invasion. Only two studies were prospective; nine included consecutive patients, whereas one included randomly selected patients; and only two included patients who had undergone routine central lymph node dissection and were thus evaluable for the presence of LNM. CONCLUSION: Meta-analysis found that BRAF mutation is associated with LNM, stage, extrathyroidal extension, tumor size, male gender, multifocality, absence of capsule, classic PTC, and tall-cell variant PTC in PTC. However, almost all studies were retrospective and only two of 32 included patients who had undergone routine central lymph node dissection, emphasizing the need for well-designed studies to appropriately examine this association before making important clinical decisions.

Is BRAF mutation associated with lymph node metastasis in patients with papillary thyroid cancer?

BACKGROUND: Some have proposed using V600E BRAF mutation status to dictate the surgical management of patients with papillary thyroid cancer (PTC). However, well-designed studies examining BRAF association with aggressive clinicopathologic features of PTC, including the presence of lymph node metastases (LNM), in patients who have undergone routine central lymph node dissection (CLND), are lacking. METHODS: Under institutional review board approval, 63 patients diagnosed with PTC on fine-needle aspiration who underwent total thyroidectomy and CLND were included. BRAF mutation status was determined in fresh frozen or intraoperative fine-needle aspiration samples with a colorimetric assay. Associations between BRAF mutation status and clinicopathologic features of PTC were examined using Chi-square and multivariate logistic regression analyses. RESULTS: BRAF mutation was found to be significantly associated with race only on Chi-square analysis. BRAF mutation was not found to be significantly associated with the presence of LNM (P = .167). On multivariate analysis, only size and venous/lymphatic invasion were significantly associated with LNM. CONCLUSION: This small series underscores the prematurity in utilizing BRAF mutation status to determine the surgical management of patients with PTC, specifically whether or not to perform a CLND.

Purification of Escherichia coli RNA polymerase using a self-cleaving elastin-like polypeptide tag.

A self-cleaving elastin-like polypeptide (ELP) tag was used to purify the multisubunit Escherichia coli RNA polymerase (RNAP) via a simple, nonchromatographic method. To accomplish this, the RNAP alpha subunit was tagged with a self-cleaving ELP-intein tag and coexpressed with the beta, beta', and omega subunits. The assembled RNAP was purified with its associated subunits, and was active and acquired at reasonable yield and purity. To remove residual polynucleotides bound to the purified RNAP, two polymer precipitation methods were investigated: polyethyleneimine (PEI) and polyethylene (PEG) precipitation. The PEG procedure was shown to enhance purity and was compatible with downstream ELP-intein purification. Thus, this simple ELP-based method should be applicable for the nonchromatographic purification of other recombinant, in vivo-assembled multisubunit complexes in a single step. Further, the simplicity and low cost of this method will likely facilitate scale up for large-scale production of additional multimeric protein targets. Finally, this technique may have utility in isolating protein interaction partners that associate with a given target.

S100A7 (Psoriasin)--mechanism of antibacterial action in wounds.

S100A7, also called psoriasin, is a member of the S100 multigene family that is encoded in the epidermal differentiation complex on chromosome 1q21. S100A7 is highly expressed in epidermal hyperproliferative disease; however, its function is not well understood. These studies show high levels of monomer and covalently crosslinked high molecular weight S100A7 in human wound exudate and granulation tissue. Immunohistological studies suggest that this S100A7 is produced by keratinocytes surrounding the wound and is released into the wound exudate. S100A7 is also detected in keratinocyte-conditioned cell culture medium. Studies using recombinant S100A7 indicate that it adheres to and reduces E. coli survival. Mutation of the conserved carboxyl-terminal EF-hand calcium-binding motif or heat denaturation slightly reduces S100A7 antibacterial activity; however, the antibacterial activity is destroyed by protease treatment. Mutation of the zinc-binding motif, located at the C-terminus, reduces antibacterial activity; however, this reduction can be reversed by simultaneous removal of the amino terminus. This indicates the surprising finding that the central region of S100A7, including only amino acids 35-80, is sufficient for full antibacterial activity. These studies also indicate that reduced S100A7 association with bacteria is associated with reduced antibacterial activity.

S100A7 (Psoriasin): a story of mice and men.

S100 proteins are calcium-regulated proteins that regulate fundamental biological processes. S100A7 (psoriasin), functions as a transglutaminase substrate/cornified envelope precursor, signal transduction protein, chemokine, and antibacterial protein in normal epidermis. S100A7 is markedly increased in epidermal hyperproliferative disorders. The murine homolog of S100A7 and S10015 has been identified, providing a valuable tool for studying the regulation and function of this protein in epidermis.

Selective recognition of distinct classes of coactivators by a ligand-inducible activation domain.

How nuclear receptors (NRs) coordinate the sequential, ligand-dependent recruitment of multiple coactivator complexes (e.g., SRC complexes and Mediator) that share similar receptor binding determinants is unclear. We show that although the receptor binding subunits of these complexes (i.e., SRCs and Med220, respectively) share overlapping binding sites on estrogen receptor alpha (ERalpha), information contained in the receptor-coactivator interface allows the receptor to distinguish between them. In support of this conclusion, we have identified an ERalpha AF-2 point mutant (L540Q) that selectively binds and recruits Med220, but not SRCs, both in vitro and in vivo. In cells expressing this mutant, the recruitment of Med220 to the pS2 promoter is delayed, and the expression of the vast majority of estrogen target genes is impaired, suggesting a nearly global functional interdependence of these coactivators. Collectively, our results suggest that "facilitated recruitment," rather than competition, drives the sequential recruitment of SRC complexes and Mediator by NRs.

Transcriptional activation by thyroid hormone receptor-beta involves chromatin remodeling, histone acetylation, and synergistic stimulation by p300 and steroid receptor coactivators.

Transcriptional regulation by heterodimers of thyroid hormone receptor (TR) and the 9-cis retinoid X receptor (RXR) is a highly complex process involving a large number of accessory factors, as well as chromatin remodeling. We have used a biochemical approach, including an in vitro chromatin assembly and transcription system that accurately recapitulates ligand- and activation function (AF)-2-dependent transcriptional activation by TRbeta/RXRalpha heterodimers, as well as in vitro chromatin immunoprecipitation assays, to study the mechanisms of TRbeta-mediated transcription with chromatin templates. Using this approach, we show that chromatin is required for robust ligand-dependent activation by TRbeta. We also show that the binding of liganded TRbeta to chromatin induces promoter-proximal chromatin remodeling and histone acetylation, and that histone acetylation is correlated with increased TRbeta-dependent transcription. Additionally, we find that steroid receptor coactivators (SRCs) and p300 function synergistically to stimulate TRbeta-dependent transcription, with multiple functional domains of p300 contributing to its coactivator activity with TRbeta. A major conclusion from our experiments is that the primary role of the SRC proteins is to recruit p300/cAMP response element binding protein-binding protein to hormone-regulated promoters. Together, our results suggest a multiple step pathway for transcriptional regulation by liganded TRbeta, including chromatin remodeling, recruitment of coactivators, targeted histone acetylation, and recruitment of the RNA polymerase II transcriptional machinery. Our studies highlight the functional importance of chromatin in transcriptional control and further define the molecular mechanisms by which the SRC and p300 coactivators facilitate transcriptional activation by liganded TRbeta.