Thyroid hormone regulates abrupt skin morphogenesis during zebrafish postembryonic development.

Thyroid hormone is a key regulator of post-embryonic vertebrate development. Skin is a biomedically important thyroid hormone target organ, but the cellular and molecular mechanisms underlying skin pathologies associated with thyroid dysfunction remain obscure. The transparent skin of zebrafish is an accessible model system for studying vertebrate skin development. During post-embryonic development of the zebrafish, scales emerge in the skin from a hexagonally patterned array of dermal papillae, like other vertebrate skin appendages such as feathers and hair follicles. We show here that thyroid hormone regulates the rate of post-embryonic dermal development through interaction with nuclear hormone receptors. This couples skin development with body growth to generate a well ordered array of correctly proportioned scales. This work extends our knowledge of thyroid hormone actions on skin by providing in-vivo evidence that thyroid hormone regulates multiple aspects of dermal development.

Activation of platelet-adherent basophils in chronic rhinosinusitis with alcohol hypersensitivity.

BACKGROUND: Alcohol hypersensitivity (AH), an exacerbation of respiratory symptoms in response to alcohol consumption, is common in aspirin-exacerbated respiratory disease and other forms of chronic rhinosinusitis (CRS). We speculated that these reactions relate to the activation of innate immune cells including basophils and, in particular, platelet-adherent basophils by polyphenolic compounds contained within eliciting alcoholic beverages. OBJECTIVE: We investigated the absolute numbers of these cells in patients with AH and the ability of relevant polyphenolic compounds to cause cellular activation. METHODS: Data were collected from 412 consecutive adults presenting to a tertiary care sinonasal clinic in whom the presence of AH was elicited. The CRS phenotype was determined and results from complete blood cell count and differential were analyzed. A subset of patients was invited to donate blood samples that were used to explore the ability of relevant compounds associated with alcohol consumption to activate platelet-nonadherent and platelet-adherent basophils. Activation was quantified by flow cytometry as up-regulated expression of CD63 and as secretion of lipid metabolites. RESULTS: Of the 412 patients enrolled, 69 (16.7%) endorsed having AH. Significantly higher platelet counts were seen in patients reporting AH. Red wine extract and several polyphenolic compounds produced basophil activation and this was primarily observed among platelet-adherent basophils. Platelet activation was further established as the release of thromboxane B2. CONCLUSION: The presence of AH is associated with significantly higher platelet levels and compounds present in alcoholic beverages can directly mediate both their activation and the activation of platelet-adherent basophils.

Yardstick for the medical management of chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is an inflammatory condition of the paranasal sinuses defined by classic symptoms, imaging findings, or endoscopic findings. There are a growing number of emerging pharmacologic therapies being evaluated to treat patients with CRS, some of which have gained indication status in the United States. There have not been updated treatment guidelines published in the United States however since 2014. This document is meant to serve as an updated expert consensus document for the pharmacologic management of patients with CRS. We review available data focusing on prospective clinical trials on oral and intranasal corticosteroids, nasal irrigation, biologics, antibiotics, and allergy immunotherapy for CRS both with and without nasal polyposis, including specific therapies for aspirin-exacerbated respiratory disease-associated CRS and allergic fungal CRS. There are multiple options to treat CRS, and clinicians should be knowledgeable on the efficacy and risks of these available therapies. Allergists-immunologists now have various therapies available to treat patients with CRS.

Impact of type 2 targeting biologics on acute exacerbations of chronic rhinosinusitis.

Background: Acute exacerbations of chronic rhinosinusitis (AECRS) are associated with significant morbidity and decreased quality of life. There are sparse data assessing the real-world impact of biologics on AECRS. Objectives: We sought to determine the impact of type 2-targeting biologics on the frequency of medication use for AECRS episodes. Methods: Antibiotic and/or systemic corticosteroid courses for AECRS were identified in a retrospective study from November 2015 to February 2020, at a single academic health system. The estimated yearly rates for antibiotic and corticosteroid courses were evaluated before and after initiation of type 2 biologics. Results: One-hundred and sixty-five patients with chronic rhinosinusitis (CRS) had received either omalizumab (n = 12), mepolizumab (n = 42), benralizumab (n = 44), dupilumab (n = 61), or reslizumab (n = 6). Seventy percent had CRS with nasal polyps, and 30% had CRS without nasal polyps. All the patients had asthma. When all the biologics were combined, the estimated yearly rate for antibiotics for AECRS decreased from 1.34 (95% confidence interval [CI], 1.12-1.59) to 0.68 (95% CI, 0.52-0.88) with biologic use (49% reduction, p < 0.001). Those with frequent AECRS (three or more courses of antibiotics in the 1 year before biologic use) had a larger degree of reduction, with an estimated yearly rate of 4.15 (95% CI, 3.79-4.55) to 1.58 (95% CI, 1.06-2.35) with biologic use (n = 27; 62% reduction; p < 0.001). Within the total cohort, the estimated yearly rate for systemic corticosteroids for AECRS decreased from 1.69 (95% CI, 1.42-2.02) to 0.68 (95% CI, 0.53-0.88) with biologic use (60% reduction; p < 0.001). Conclusion: Type 2-targeting biologics reduced medication use for AECRS. This suggested that biologics may be a therapeutic option for patients with frequent AECRS.

Explaining discrepancies in assessment protocols: Trait relevance and functional equivalence.

Inconsistencies among independent sources of information about psychological constructs are widely documented, but not adequately explained. Measurement error as the primary explanation, though historically popular, is no longer tenable. Yet, even as assessors acknowledge that various measures of the same construct are not necessarily interchangeable, there are no agreed upon frameworks to discern the unique contribution of each measure in multiinformant and multimethod assessment protocols. In this study, we focus on the relevance of the target trait in its measured contexts and on the functional equivalence of the trait across its measures (similar self-regulatory requirements for trait expression) as driving relations between scores. These 2 considerations enabled prediction of informant differences in mean ratings and of patterns of divergences and convergences between parent and teacher ratings of kindergarteners' social competence (SC) and executive functioning (EF) and between informant-based and performance-based measures of executive functioning (N = 73). (PsycINFO Database Record

Development of a computerized monitoring program to identify narcotic diversion in a pediatric anesthesia practice.

PURPOSE: Development of an operational reporting dashboard designed to correlate data from multiple sources to help detect potential drug diversion by automated dispensing cabinet (ADC) users is described. METHODS: A commercial business intelligence platform was used to create a dashboard tool for rapid detection of unusual patterns of ADC transactions by anesthesia service providers at a large pediatric hospital. By linking information from the hospital's pharmacy information management system (PIMS) and anesthesia information management system (AIMS) in an associative data model, the "narcotic reconciliation dashboard" can generate various reports to help spot outlier activity associated with ADC dispensing of controlled substances and documentation of medication waste processing. RESULTS: The dashboard's utility was evaluated by "back-testing" the program with historical data on an actual episode of diversion by an anesthesia provider that had not been detected through traditional methods of PIMS and AIMS data monitoring. Dashboard-generated reports on key metrics (e.g., ADC transaction counts, discrepancies in dispensed versus reconciled amounts of narcotics, PIMS-AIMS documentation mismatches) over various time frames during the period of known diversion clearly indicated the diverter's outlier status relative to other authorized ADC users. CONCLUSION: A dashboard program for correlating ADC transaction data with pharmacy and patient care data may be an effective tool for detecting patterns of ADC use that suggest drug diversion.

Hyaluronan digestion controls DC migration from the skin.

The breakdown and release of hyaluronan (HA) from the extracellular matrix has been hypothesized to act as an endogenous signal of injury. To test this hypothesis, we generated mice that conditionally overexpressed human hyaluronidase 1 (HYAL1). Mice expressing HYAL1 in skin either during early development or by inducible transient expression exhibited extensive HA degradation, yet displayed no evidence of spontaneous inflammation. Further, HYAL1 expression activated migration and promoted loss of DCs from the skin. We subsequently determined that induction of HYAL1 expression prior to topical antigen application resulted in a lack of an antigenic response due to the depletion of DCs from the skin. In contrast, induction of HYAL1 expression concurrent with antigen exposure accelerated allergic sensitization. Administration of HA tetrasaccharides, before or simultaneously with antigen application, recapitulated phenotypes observed in HYAL1-expressing animals, suggesting that the generation of small HA fragments, rather than the loss of large HA molecules, promotes DC migration and subsequent modification of allergic responses. Furthermore, mice lacking TLR4 did not exhibit HA-associated phenotypes, indicating that TLR4 mediates these responses. This study provides direct evidence that HA breakdown controls the capacity of the skin to present antigen. These events may influence DC function in injury or disease and have potential to be exploited therapeutically for modification of allergic responses.

Hyaluronic acid oligosaccharides suppress TLR3-dependent cytokine expression in a TLR4-dependent manner.

The release of endogenous molecules from the skin after injury has been proposed to influence inflammation. Recent studies have found that pro-inflammatory signals can be generated by damaged endogenous self-RNA, and this event is detected by TLR3. Conversely, release of endogenous fragments of hyaluronic acid (HA) after injury has been proposed to inhibit LPS induced inflammation driven by TLR4. In this study we investigated if HA oligomers could also influence inflammation mediated by TLR3. A tetramer form of HA (oligo-HA) was added to MH-S cells (mouse alveolar macrophage cell line) that were then activated by poly(I:C). ELISA analysis of culture supernatants showed that the presence of oligo-HA suppressed the poly(I:C) induced release of IL-6 and TNFα. IL-6 mRNA expression was also suppressed as measured by quantitative RT-PCR. To determine the mechanism of action for oligo-HA to inhibit poly(I:C), macrophages derived from wild-type (WT), Tlr2-/- or Tlr4-/- mice were treated with oligo-HA and poly(I:C). Similar to WT cells, Tlr2-/- macrophages were inhibited by oligo-HA and retained suppression of cytokine release. In contrast, Tlr4-/- macrophages lost the capacity to be suppressed by oligo-HA. An increase in Traf1 (TLR negative regulator) mRNA was observed after oligo-HA treatment of WT but not in Tlr4-/- macrophages, and oligo-HA did not suppress cytokine responsiveness in Traf1-/- macrophages. These results show that oligo-HA acts through TLR4 and TRAF1 to inhibit TLR3-dependent inflammation. This observation illustrates the complex immunomodulatory action of endogenous products released after injury.

Value of peak exercise oxygen consumption combined with B-type natriuretic peptide levels for optimal timing of cardiac transplantation.

BACKGROUND: Peak exercise oxygen consumption (VO(2)) is widely used to select candidates for heart transplantation (HTx). However, the prognosis of patients with advanced heart failure and peak VO(2) of 10 to 14 mL/min per kg in the era of modern medical therapy for heart failure is not fully elucidated. B-type natriuretic peptide (BNP) is a useful prognostic marker in patients with heart failure. METHODS AND RESULTS: A total of 424 patients undergoing HTx evaluation were classified according to peak VO(2) during cardiopulmonary exercise testing (>14, 10-14, and <10 mL/min per kg). Survival after cardiopulmonary exercise testing without HTx or ventricular assist device (VAD) support was compared with survival of 743 de novo HTx recipients. Multivariable analysis revealed that high BNP and low peak VO(2) were independently associated with death, HTx, or VAD requirements (hazard ratio, 3.5 and 0.6; 95% CI, 1.24-9.23 and 0.03-0.71; P=0.02 and <0.0001, respectively). VAD-free or HTx-free survival of patients with peak VO(2) 10 to 14 mL/min per kg was identical to post-HTx survival. When patients with peak VO(2) 10 to 14 mL/min per kg were dichotomized by a cutoff value of BNP of 506 pg/mL, those with BNP<506 pg/mL was equivalent to post-HTx survival (1 year: 90.8% versus 87.2%; P=0.61), whereas those with BNP≥506 showed worse VAD-free or HTx-free survival (1 year: 79.7%; P<0.001 versus post-HTx). Patients with peak VO(2) <10 mL/min per kg showed worse survival compared with post-HTx survival, and there was a survival difference between those with BNP≥506 and <506 pg/mL (1 year: 77.2% versus 56.1%; P=0.01). CONCLUSIONS: Patients with peak VO(2) 10 to 14 mL/min per kg and low BNP levels have a VAD-free or HTx-free survival similar to post-HTx survival in heart recipients, whereas high BNP levels indicate worse outcome in this group of patients.

Hepatic dysfunction in ambulatory patients with heart failure: application of the MELD scoring system for outcome prediction.

OBJECTIVES: This study evaluated the Model for End-Stage Liver Disease (MELD) score and its modified versions, which are established measures of liver dysfunction, as a tool to assess heart transplantation (HTx) urgency in ambulatory patients with heart failure. BACKGROUND: Liver abnormalities have a prognostic impact on the outcome of patients with advanced heart failure. METHODS: We retrospectively evaluated 343 patients undergoing HTx evaluation between 2005 and 2009. The prognostic effectiveness of MELD and 2 modifications (MELDNa [includes serum sodium levels] and MELD-XI [does not include international normalized ratio]) for endpoint events, defined as death/HTx/ventricular assist device requirement, was evaluated in our cohort and in subgroups of patients on and off oral anticoagulation. RESULTS: The MELD and MELDNa scores were excellent predictors for 1-year endpoint events (areas under the curve: 0.71 and 0.73, respectively). High scores (>12) were strongly associated with poor survival at 1 year (MELD 69.3% vs. 90.4% [p < 0.0001]; MELDNa 70.4% vs. 96.9% [p < 0.0001]). Increased scores were associated with increased risk for HTx (hazard ratio: 1.10 [95% confidence interval: 1.06 to 1.14]; p < 0.0001 for both scores), which was independent of other known risk factors (MELD p = 0.0055; MELDNa p = 0.0083). Anticoagulant use was associated with poor survival at 1 year (73.7% vs. 86.4%; p = 0.0118), and the statistical significance of MELD/MELDNa was higher in patients not receiving oral anticoagulation therapy. MELD-XI was a fair but limited predictor of the endpoint events in patients receiving oral anticoagulation therapy. CONCLUSIONS: Assessment of liver dysfunction according to the MELD scoring system provides additional risk information in ambulatory patients with heart failure.