Survey of Current Institutional Practices in the Use of High-Flow Nasal Cannula for Pediatric Patients.

OBJECTIVES: High-flow nasal cannula (HFNC) is an oxygen delivery device that provides heated humidified air with higher flow rates. The purpose of this survey is to look at institutional practice patterns of HFNC initiation, weaning, and disposition for pediatric patients across the United States. METHODS: Survey was sent via electronic listservs to pediatric physicians in emergency medicine, hospital medicine, critical care, and urgent care. The questionnaire was divided into demographics and HFNC practices (initiation, management, and weaning). One response per institution was included in the analysis. RESULTS: Two hundred twenty-four responses were included in the analysis, composed of 40% pediatric emergency medicine physicians, 46% pediatric hospitalists, 13% pediatric intensive care unit (PICU) physicians, and 1% pediatric urgent care physicians. Ninety-eight percent of the participants have HFNC at their institution. Thirty-seven percent of the respondents had a formal guideline for HFNC initiation. Nearly all guideline and nonguideline institutions report HFNC use in bronchiolitis. Guideline cohort is more likely to have exclusion criteria for HFNC (42% in the guideline cohort vs 17% in the nonguideline cohort; P < 0.001) and less frequently mandates PICU admissions once on HFNC (11% in the guideline cohort vs 56% in the nonguideline cohort; P < 0.001). Forty-six percent of guideline cohort had an objective scoring system to help determine the need for HFNC, and 73% had a weaning guideline. CONCLUSIONS: Although there is general agreement to use HFNC in bronchiolitis, great practice variation remains in the initiation, management, and weaning of HFNC across the United States. There is also a discordance on PICU use when a patient is using HFNC.

Fostering diversity work as a process of lifelong learning: A partnership case study with an immigrant services organisation.

Diversity work is an area of growing interest for organisations in both the private and public sectors. In a nutshell, the term refers to the work conducted within an organisation that promotes inclusive and equitable engagement with people and communities across social differences such as gender, race, ethnicity, sexuality and religion. Related research has generated relatively more knowledge about the challenges and problems of diversity initiatives than about effective practices that genuinely foster social equity and inclusion. This article contributes to the latter with a partnership case study involving the United Chinese Community Enrichment Services Society (S.U.C.C.E.S.S.), a large non-profit immigrant services organisation headquartered in Vancouver, Canada. Specifically, the study presented here focuses on the organisational practices that are constitutive of frontline workers' engagement with diversity work and learning. It shows that (1) building a diverse and inclusive organisation, (2) supporting continuous learning opportunities at work, and (3) providing diversity training, both directive and generative, form the organisation's diversity "curriculum". This study also demonstrates that the strength of this workplace curriculum is that it has the potential to challenge the boundary between instrumentalism (harnessing diversity work to business success) and equity activism (prioritising diversity work in its own right), and that it creates space for collective reflection in the presence of others. Conceptually drawing on the practice turn in social sciences, particularly Steven Billet and Jennifer Newton's learning practice, and what David Boud terms "the reflective turn", this article positions diversity work as a reflective and iterative process of lifelong learning for both organisations and individual workers.

Encourager le travail de diversité en tant que processus d'apprentissage tout au long de la vie : étude de cas en partenariat avec une organisation de services aux immigrants ­ Le travail de diversité (diversity work en anglais) est un domaine qui suscite un intérêt croissant tant dans le secteur privé que dans le secteur public. Pour faire court, cette expression renvoie au travail mené au sein d'une organisation qui promeut un engagement inclusif et équitable auprès de personnes et de communautés en dépassant les différences sociales comme le genre, la race, l'ethnicité, la sexualité et la religion. Les recherches liées à cela ont produit relativement plus de connaissances concernant les défis et problèmes des projets sur la diversité que sur les pratiques efficaces qui favorisent réellement l'équité sociale et l'inclusion. Cet article contribue à ces dernières en présentant une étude de cas en partenariat avec la United Chinese Community Enrichment Services Society (S.U.C.C.E.S.S.), grande organisation à but non lucratif de services aux immigrants, dont le siège se situe au Canada, à Vancouver. L'étude présentée ici est axée en particulier sur les pratiques organisationnelles constitutives de l'engagement des travailleurs sur le terrain en matière du travail de diversité et d'apprentissage. Elle montre que (1) créer une organisation diverse et inclusive, (2) soutenir des possibilités d'apprentissage continu au travail et (3) proposer une formation à la diversité, tant directive que générative, façonne le « curriculum ¼ de l'organisation en matière de diversité. Cette étude démontre également que la puissance de ce curriculum sur le lieu de travail réside dans ses possibilités de repousser les limites entre l'instrumentalisme (qui exploite le travail de diversité pour la réussite de l'entreprise) et l'activisme en matière d'équité (qui priorise le travail de diversité à part entière). S'appuyant sur le plan conceptuel sur le tournant pratique dans les sciences sociales (practice turn en anglais), notamment sur la pratique de l'apprentissage de Steven Billet et Jennifer Newton, et sur ce que David Boud appelle « le tournant réflexif ¼ (the reflexive turn), cet article positionne le travail de diversité en tant que processus réflexif et itératif d'apprentissage tout au long de la vie, tant pour les organisations que pour les travailleurs individuels.

Effect of tildrakizumab (MK-3222), a high affinity, selective anti-IL23p19 monoclonal antibody, on cytochrome P450 metabolism in subjects with moderate to severe psoriasis.

AIMS: Tildrakizumab, an interleukin (IL)-23 inhibitor, is indicated for the treatment of moderate to severe chronic plaque psoriasis. Although tildrakizumab is not metabolized by, and does not alter, cytochrome P450 (CYP) expression in vitro, clinically significant pharmacokinetic effects through changes in systemic inflammation, which alters CYP metabolism, have been well documented. At the time of study conduct, the effect of modulation of inflammation/cytokines, including IL-23 inhibition with tildrakizumab, on CYP metabolism, and therefore the potential for disease-drug interactions, in psoriasis patients was unknown. We therefore assessed whether tildrakizumab alters CYP metabolism in subjects with moderate to severe psoriasis. METHODS: This was an open-label, fixed-sequence, two-period trial. In Period 1 (Day 1), subjects received an oral CYP probe cocktail of up to five drugs (midazolam 2 mg [3A4], caffeine 200 mg [1A2], warfarin 10 mg [2C9], omeprazole 40 mg [2C19] and dextromethorphan 30 mg [2D6]), followed by a 7-day washout. In Period 2, subjects received tildrakizumab 200 mg subcutaneously on Days 1 and 29 and a second CYP probe cocktail on Day 57. Substrate or metabolite pharmacokinetics, safety and changes in Psoriasis Severity Area Index (PASI), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP), were assessed. RESULTS: Twenty subjects (13 men, 7 women) were enrolled. Tildrakizumab had no clinically relevant effect on the pharmacokinetics of any of the probe substrates tested. On Day 57 of Period 2, the median percentage decrease from baseline in PASI score following tildrakizumab was ~93%. There were no clinically relevant changes in IL-6 or hs-CRP. Treatment with tildrakizumab was generally well tolerated. CONCLUSION: In subjects with moderate to severe psoriasis, tildrakizumab 200 mg did not have a discernible effect on CYP metabolism. The potential for clinically significant drug-drug interactions (DDIs) with tildrakizumab in patients with psoriasis is low. The difference in the occurrence of DDIs seen with anti-inflammatory agents in rheumatoid arthritis patients compared with psoriasis patients may be due to the much greater extent of systemic inflammation in rheumatoid arthritis as compared to psoriasis.

Patients' Perspectives on Outcomes of Care After Discharge From the Emergency Department: A Qualitative Study.

STUDY OBJECTIVE: Much effort has been expended to understand what care experiences patients value in the emergency department (ED), yet little is known about which outcomes patients value after ED care. Our goal is to define outcomes of ED care that are valued by patients discharged from the ED, with the goal of informing the development of a patient-reported outcome measure for ED care. METHODS: We conducted qualitative semistructured interviews with patients recruited during their care at 1 of 2 EDs and interviewed in either English or French 1 to 9 days after their visit. Patients who were hospitalized were excluded. Interviews focused on perceived outcomes of care since the ED visit and expectations of care before the ED visit. We identified themes with standard descriptive content analysis techniques and a modified version of the constant comparative method, drawing on grounded theory methods. RESULTS: We interviewed 46 patients in English (n=38) or French (n=8). Participants with diverse reasons for seeking care appeared to value common outcomes from ED care that centered around 4 themes: understanding the cause and expected trajectory of their symptoms; reassurance; symptom relief; and having a plan to manage their symptoms, resolve their issue, or pursue further medical care. These themes were also reflected in the expectations participants recalled having when they decided to seek care in the ED. CONCLUSION: The 4 outcomes defined constitute areas for improvement and will inform the development of an ED patient-reported outcome questionnaire. Consideration should be given to measuring patient-reported outcomes separately from patient experience.

Effect of a Multi-Diagnosis Observation Unit on Emergency Department Length of Stay and Inpatient Admission Rate at Two Canadian Hospitals.

BACKGROUND: Observation units (OUs) have been shown to reduce emergency department (ED) lengths of stay (LOS) and admissions. Most published studies have been on OUs managing single complaints. OBJECTIVE: Our aim was to determine whether an OU reduces ED LOS and hospital admission rates for adults with a variety of presenting complaints. METHODS: We comparatively evaluated two hospitals in British Columbia, Canada (hereafter ED A and ED B) using a pre-post design. Data were extracted from administrative databases. The post-OU cohort included all adults presenting 6 months after OU implementation. The pre-OU cohort included all adults presenting in the same 6-month period 1 year before OU implementation. RESULTS: There were 109,625 patient visits during the study period. Of the 56,832 visits during the post-OU period (27,512 to ED A and 29,318 to ED B), 1.9% were managed in the OU in ED A and 1.4% in ED B. Implementation was associated with an increase in the median ED LOS at ED A (179.0 min pre vs. 192.0 min post [+13.0 min]; p < 0.001; mean difference -12.5 min, 95% confidence interval [CI] -15.2 to -9.9 min), but no change at ED B (182.0 min pre vs. 182.0 min post; p = 0.55; mean difference +2.0 min, 95% CI -0.7 to +4.7 min). Implementation significantly decreased the hospital admission rate for ED A (17.8% pre to 17.0% post [-0.8%], 95% CI -0.18% to 0.15%; p < 0.05) and did not significantly change the hospital admission rate at ED B (18.9% pre to 18.3% post [-0.6%], 95% CI -1.19% to -0.09%; p = 0.09). CONCLUSIONS: A multi-diagnosis OU can reduce hospital admission rate in a site-specific manner. In contrast to previous studies, we did not find that an OU reduced ED LOS. Further research is needed to determine whether OUs can reduce ED overcrowding.

Conducting Effective Physician Performance Feedback: A Primer for Healthcare Leaders.

Physician performance feedback (PPF) can help physicians gain insight into their practice, to identify areas for improvement, and to implement changes to improve care. There is increasing interest in the use of PPF in Canada. However, little is known about the different types of PPF methods and whether PPF can lead to improved physician performance and patient outcomes. We provide a primer for healthcare leaders interested in doing PPF by reviewing common PPF methods. We then describe our institution's experience with physician multi-source feedback and provide strategies to conduct meaningful PPF.

Ethnicity and health literacy: a survey on hypertension knowledge among Canadian ethnic populations.

OBJECTIVES: With an increase and diversity in ethnic populations in Westernized countries, understanding the differences in levels of knowledge surrounding hypertension is important in planning appropriate prevention strategies. The purpose of our study was to assess levels of hypertension knowledge in Chinese, Indian and White populations in a large metropolitan Canadian city. DESIGN: A telephone survey was conducted in English, Chinese (Cantonese and Mandarin) and Indian languages (Hindi, Punjabi and Urdu). Hypertension knowledge was assessed through a 10-item validated instrument; respondents received 1 point for each correct answer. Logistic regression was used to test differences in hypertension knowledge among these three populations. RESULTS: Survey response rates were 68.7% (301) for Chinese, 61.3% (248) for Indian and 69.7% (254) for White populations. The average hypertension knowledge score for Chinese respondents was 7.23 out of 10, 7.11 for Indian respondents and 7.28 for White respondents. Compared to White respondents, Chinese respondents were less likely than White respondents to know high blood pressure can cause heart attacks (adjusted odds ratio [aOR]: .43, 95% confidence interval [CI]: .19-.96] and Indian respondents were less likely to know losing weight usually decreases blood pressure (aOR: .38, 95% CI: .21-.68). CONCLUSIONS: Hypertension knowledge levels among these three ethnic/racial populations were similar and relatively high and varied by content. Low levels of knowledge for Chinese and Indian ethnic populations were on hypertension risk factors, long-term consequences of hypertension and anti-hypertensive medication adherence. Specifically, females, recent immigrants to Canada and Chinese seniors were identified as sub-groups who should be targeted for hypertension knowledge promotion.

Derivation and transcriptional reprogramming of border-forming wound repair astrocytes after spinal cord injury or stroke in mice.

Central nervous system (CNS) lesions become surrounded by neuroprotective borders of newly proliferated reactive astrocytes; however, fundamental features of these cells are poorly understood. Here we show that following spinal cord injury or stroke, 90% and 10% of border-forming astrocytes derive, respectively, from proliferating local astrocytes and oligodendrocyte progenitor cells in adult mice of both sexes. Temporal transcriptome analysis, single-nucleus RNA sequencing and immunohistochemistry show that after focal CNS injury, local mature astrocytes dedifferentiate, proliferate and become transcriptionally reprogrammed to permanently altered new states, with persisting downregulation of molecules associated with astrocyte-neuron interactions and upregulation of molecules associated with wound healing, microbial defense and interactions with stromal and immune cells. These wound repair astrocytes share morphologic and transcriptional features with perimeningeal limitans astrocytes and are the predominant source of neuroprotective borders that re-establish CNS integrity around lesions by separating neural parenchyma from stromal and immune cells as occurs throughout the healthy CNS.

Evaluation of endo- and exo-aryl-substitutions and central scaffold modifications on diphenyl substituted alkanes as 5-lipoxygenase activating protein inhibitors.

A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.

Amplification of CCND1 in Urothelial Carcinoma.

OBJECTIVES: Urothelial carcinoma (UC) is the most prevalent form of bladder cancer and a significant cause of mortality in the world each year. As molecular genetic techniques improve, researchers and medical professionals are turning toward finding potential biomarkers to diagnose and characterize UC, guide treatment decisions, and use as therapeutic targets. Located on chromosome 11q13.2, the CCND1 gene encodes Cyclin D1, a CDK-regulating protein that plays a critical role in cell cycle progression. Amplification of CCND1 is seen in about 10% of all bladder cancer patients and has been a target of research due to its potential as a prognostic biomarker and a therapeutic target. However, existing literature on CCND1 amplification and Cyclin D1 expression report conflicting information about their clinical significance and association with disease staging, pointing to the need for more research to determine mechanistic pathways. Additionally, while there are currently no approved therapies or drugs that directly target CCND1 or Cyclin D1 in UC, several clinical trials with drugs targeting CDK4/CDK6 in the Cyclin D1 pathway are already underway. This paper aims to provide an update on the amplification of CCND1 in urothelial carcinoma, including an overview of recent research on elucidated pathways, clinical significance, relevant therapies under development, and directions for future research.

Differential subcellular distribution renders HAI-2 a less effective protease inhibitor than HAI-1 in the control of extracellular matriptase proteolytic activity.

The integral membrane, Kunitz-type serine protease inhibitors HAI-1 and HAI-2, can suppress the proteolytic activity of the type 2 transmembrane serine protease matriptase with high specificity and potency. High levels of extracellular matriptase proteolytic activity have, however, been observed in some neoplastic B-cells with high levels of endogenous HAI-2, indicating that HAI-2 may be an ineffective matriptase inhibitor at the cellular level. The different effectiveness of the HAIs in the control of extracellular matriptase proteolytic activity is examined here. Upon inducing matriptase zymogen activation in the HAI Teton Daudi Burkitt lymphoma cells, which naturally express matriptase with very low levels of HAI-2 and no HAI-1, nascent active matriptase was rapidly inhibited or shed as an enzymatically active enzyme. With increasing HAI-1 expression, cellular matriptase-HAI-1 complex increased, and extracellular active matriptase decreased proportionally. Increasing HAI-2 expression, however, resulted in cellular matriptase-HAI-2 complex levels reaching a plateau, while extracellular active matriptase remained high. In contrast to this differential effect, both HAI-1 and HAI-2, even at very low levels, were shown to promote the expression and cell-surface translocation of endogenous matriptase. The difference in the suppression of extracellular active matriptase by the two closely related serine protease inhibitors could result from the primarily cell surface expression of HAI-1 compared to the mainly intracellular localization of HAI-2. The HAIs, therefore, resemble one another with respect to promoting matriptase expression and surface translocation but differ in their effectiveness in the control of extracellular matriptase enzymatic activity.

The PET tracer [11C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease.

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [11C]MK-6884 from rhesus monkeys to patients with Alzheimer's disease (AD). [3H]MK-6884/[11C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [11C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [11C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BPND) of [11C]MK-6884. These results suggest that [11C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD.

Additive renoprotective effects of B2-kinin receptor blocker and PPAR-γ agonist in uninephrectomized db/db mice.

We recently showed that the bradykinin B2 receptor (B2R) blocker icatibant (Icat) and the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (Ros) exerted anti-inflammatory effects in renal tubular cells exposed to a diabetic milieu. This study aims to explore whether these effects can be translated to an experimental model of type 2 diabetic nephropathy (DN). db/db mice and their nondiabetic db/m littermates underwent sham operation or uninephrectomy (Unx) at 10 weeks and received vehicle (Veh), metformin (Met), Icat, Ros, or Icat plus Ros for 8 weeks before killing. Among the db/db group with Unx, mice that received Icat or Ros had significantly lower serum creatinine and albuminuria, which was further reduced when Icat and Ros were given in combination. These beneficial effects were not observed in the Met group that achieved similar glycemic control as Ros-treated animals. Likewise, the severity of reactive glomerular and proximal tubular hypertrophy, glomerulosclerosis, interstitial injury, cortical F4/80 and α-smooth muscle actin immunostaining, and CCL-2, ICAM-1 and TGF-ß overexpression were all attenuated by Icat and Ros, and these effects were enhanced when both agents were combined. Immunohistochemical staining confirmed the proximal tubular expression of CCL-2 (inflammation) and TGF-ß (fibrosis). Treatment with Icat was associated with decreased B2R, but increased, B1R expression, which was exaggerated in Unx animals. At the signaling level, Icat and Ros reduced extracellular signal-regulated kinase 1/2 and STAT1 activation, respectively. Our results suggest a deleterious role of the kallikrein-kinin system in murine-accelerated DN, which can be ameliorated by the B2R blocker Icat and enhanced by the addition of Ros. This calls for further evaluation of this novel therapeutic approach in more animal models of diabetic nephropathy.

Differential effects of advanced glycation end-products on renal tubular cell inflammation.

AIM: The authors recently showed that advanced glycation end-products (AGE) in the form of glycated albumin (GA) upregulated renal tubular expression of interleukin (IL)-8 and soluble intercellular adhesion molecule-1 (sICAM-1), but not other important cytokines known to mediate diabetic nephropathy. This implies that other molecules such as the carbonyl intermediates of AGE or other modified protein lysine-albumin may participate in diabetic tubular injury. METHODS: Human proximal tubular epithelial cells (PTEC) were growth-arrested and exposed to methylglyoxal (MG), MG-bovine serum albumin (BSA)-AGE, carboxymethyllysine (CML)-BSA, AGE-BSA or BSA with or without prior addition of rosiglitazone that was previously shown to attenuate the pro-inflammatory effect of GA alone. RESULTS: MG-BSA-AGE and AGE-BSA upregulated tubular expression of connective tissue growth factor (CTGF), transforming growth factor (TGF)-ß, and vascular endothelial growth factor (VEGF), whereas CML-BSA stimulated expression of IL-6, CCL-2, CTGF, TGF-ß and VEGF. These AGE compounds also activated nuclear factor (NF)-κB and their effects were attenuated by pre-incubation with anti-RAGE antibody. MG and BSA did not affect the expression of any of these molecules. Rosiglitazone did not affect the in vitro biological effects of MG, MG-BSA-AGE, AGE-BSA or CML-BSA on PTEC. CONCLUSION: AGE exhibit differential inflammatory and fibrotic effects on PTEC via RAGE activation and NF-κB signal transduction. Rosiglitazone had no effect on these responses. Further investigations on compounds that nullify the downstream effects of these AGE are warranted.

c-MYC Amplification in AML.

OBJECTIVES: Acute myeloid leukemia (AML) is a clonal disorder of myeloid lineage precursors. Identification of cytogenetic aberrations is essential for classification and risk stratification of AML, with many demonstrating unique associations with various clinicopathologic features. One such abnormality is MYC amplification, a rare occurrence identified in less than 1% of AML patients. MYC is most commonly amplified in the form of double minutes, but may also occur via ring and marker chromosomes or homogeneously staining regions. Amplification of MYC often involves various chromosomal aberrations, including trisomies 4 and 6 and aneusomy of the sex chromosomes. In many cases, the presence of MYC amplicons is also associated with other negative prognostic factors, including complex karyotype and advanced age. Although MYC has been extensively investigated as a therapeutic target in various cancers, there are few studies examining the clinical significance of MYC amplification in AML. In this review, we explore recurrent cytogenetic abnormalities and demographic characteristics associated with amplification of MYC in patients with AML and discuss their diagnostic and therapeutic implications.

Experimental Medicine Study to Measure Immune Checkpoint Receptors PD-1 and GITR Turnover Rates In Vivo in Humans.

Development of monoclonal antibodies (mAbs) targeting immune-checkpoint receptors (IMRs) for the treatment of cancer is one of the most active areas of investment in the biopharmaceutical industry. A key decision in the clinical development of anti-IMR mAbs is dose selection. Dose selection can be challenging because the traditional oncology paradigm of administering the maximum tolerated dose is not applicable to anti-IMR mAbs. Instead, dose selection should be informed by the pharmacology of immune signaling. Engaging an IMR is a key initial step to triggering pharmacologic effects, and turnover (i.e., the rate of protein synthesis) of the IMR is a key property to determining the dose level needed to engage the IMR. Here, we applied the stable isotope labeling mass spectrometry technique using 13 C6 -leucine to measure the in vivo turnover rates of IMRs in humans. The 13 C6 -leucine was administered to 10 study participants over 15 hours to measure 13 C6 -leucine enrichment kinetics in 2 IMR targets that have been clinically pursued in oncology: GITR and PD-1. We report the first measurements of GITR and PD-1 median half-lives associated with turnover to be 55.6 and ≥ 49.5 hours, respectively. The approach outlined here can be applied to other IMRs and, more generally, to protein targets.

Cellphone enabled point-of-care assessment of breast tumor cytology and molecular HER2 expression from fine-needle aspirates.

Management of breast cancer in limited-resource settings is hindered by a lack of low-cost, logistically sustainable approaches toward molecular and cellular diagnostic pathology services that are needed to guide therapy. To address these limitations, we have developed a multimodal cellphone-based platform-the EpiView-D4-that can evaluate both cellular morphology and molecular expression of clinically relevant biomarkers directly from fine-needle aspiration (FNA) of breast tissue specimens within 1 h. The EpiView-D4 is comprised of two components: (1) an immunodiagnostic chip built upon a "non-fouling" polymer brush-coating (the "D4") which quantifies expression of protein biomarkers directly from crude cell lysates, and (2) a custom cellphone-based optical microscope ("EpiView") designed for imaging cytology preparations and D4 assay readout. As a proof-of-concept, we used the EpiView-D4 for assessment of human epidermal growth factor receptor-2 (HER2) expression and validated the performance using cancer cell lines, animal models, and human tissue specimens. We found that FNA cytology specimens (prepared in less than 5 min with rapid staining kits) imaged by the EpiView-D4 were adequate for assessment of lesional cellularity and tumor content. We also found our device could reliably distinguish between HER2 expression levels across multiple different cell lines and animal xenografts. In a pilot study with human tissue (n = 19), we were able to accurately categorize HER2-negative and HER2-positve tumors from FNA specimens. Taken together, the EpiView-D4 offers a promising alternative to invasive-and often unavailable-pathology services and may enable the democratization of effective breast cancer management in limited-resource settings.

Renoprotection by rosiglitazone in accelerated type 2 diabetic nephropathy: Role of STAT1 inhibition and nephrin restoration.

BACKGROUND: Rosiglitazone (Ros) has been shown to attenuate CXCL8 and ICAM-1 overexpression in renal tubular cells exposed to glycated albumin. The present study explores whether this can be translated into renoprotection in vivo. Uninephrectomized (Unx) type 2 diabetic db/db mice were chosen as a model of accelerated diabetic nephropathy. METHODS: Uninephrectomy was performed in 10-week-old db/db mice. They were then treated with vehicle, metformin or Ros for 8 weeks. RESULTS: Unx-db/db mice treated with Ros had lower serum creatinine and albuminuria, less severe glomerulosclerosis, tubulointerstitial injury, fewer infiltrating macrophages, and less proliferating nuclear antigen-positive tubular cells compared with mice treated with metformin that had a similar level of glycemic control and insulin resistance. In addition, Ros but not metformin attenuated renal cortical expression of CCL2, MIP-2, and ICAM-1 and inhibited p-STAT1 signal activation. Ros also increased glomerular nephrin expression. CONCLUSIONS: Our results delineated the biochemical and histologic characteristics of Unx-db/db mice and demonstrated the in vivo glucose-independent anti-inflammatory mechanisms of Ros in nephropathy of accelerated murine type 2 diabetes.

Bradykinin and high glucose promote renal tubular inflammation.

BACKGROUND: The role of the kallikrein-kinin system in diabetic nephropathy remains controversial. METHODS AND RESULTS: High-glucose (HG) super-induced interleukin (IL)-6, CCL-2, transforming growth factor (TGF)-beta, vascular endothelial growth factor (VEGF) and B(2)K receptor (B(2)KR) mRNA in cultured proximal tubular epithelial cells (PTEC), whereas bradykinin (BK) upregulated IL-6, CCL-2 and TGF-beta mRNA. HG activated mitogen-activated protein kinase (MAPK) p42/p44 and protein kinase C (PKC) signals, whereas BK only activated MAPK. Tubular expression of these mediators and tissue kallikrein 1 (KLK1) was confirmed in human diabetic kidney biopsies. Inhibition of MAPK p42/p44 by PD98059 partially reduced HG and BK induction of IL-6, CCL-2 and TGF-beta, whereas inhibition of PKC by staurosporine partially reduced HG- but not BK-induced overexpression of these cytokines and that of VEGF. Staurosporine and PD98059 synergistically reduced the effect of HG on IL-6, CCL-2 and TGF-beta expression. The B(2)KR blocker, icatibant, downregulated BK- and HG-induced MAPK p42/p44 but not HG-induced PKC activation and partially reduced both HG- and BK-induced IL-6, CCL-2 and TGF-beta secretion. HG stimulated expression of KLK1 and low-molecular-weight kininogen (LMWK) and its downstream effects were attenuated by aprotinin (tissue kallikrein inhibitor). The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, attenuated HG-induced PKC but not HG- or BK- induced MAPK p42/44 activation and reduced HG-stimulated VEGF, along with IL-6, CCL-2 and TGF-beta secretion. Rosiglitazone plus icatibant further reduced these effects of HG. CONCLUSIONS: In conclusion, HG stimulates tubular proinflammatory, profibrotic and angiogenic signals, which is partly mediated through BK via MAPK signalling and partly through PKC independent of BK. The potential therapeutic role of complementary B(2)KR blockade and PPAR-gamma activation deserves clinical investigation.

Consensus survey on pre-procedural safety practices in radiological examinations: a multicenter study in seven Asian regions.

OBJECTIVE: To understand the status of pre-procedural safety practices in radiological examinations at radiology residency training institutions in various Asian regions. METHODS: A questionnaire based on the Joint Commission International Accreditation Standards was electronically sent to 3 institutions each in 10 geographical regions across 9 Asian countries. Questions addressing 45 practices were divided into 3 categories. A five-tier scale with numerical scores was used to evaluate safety practices in each institution. Responses obtained from three institutions in the United States were used to validate the execution rate of each surveyed safety practice. RESULTS: The institutional response rate was 70.0% (7 Asian regions, 21 institutions). 44 practices (all those surveyed except for the application of wrist tags for identifying patients with fall risks) were validated using the US participants. Overall, the Asian participants reached a consensus on 89% of the safety practices. Comparatively, most Asian participants did not routinely perform three pre-procedural practices in the examination appropriateness topic. CONCLUSION: Based on the responses from 21 participating Asian institutions, most routinely perform standard practices during radiological examinations except when it comes to examination appropriateness. This study can provide direction for safety policymakers scrutinizing and improving regional standards of care. ADVANCES IN KNOWLEDGE: This is the first multicenter survey study to elucidate pre-procedural safety practices in radiological examinations in seven Asian regions.