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Background: The COVID-19 pandemic brought rapid changes to the work and personal lives of clinicians., Objective: To assess clinician burnout and well-being during the COVID-19 pandemic and guide healthcare system improvement efforts., Design: A survey asking about clinician burnout, well-being, and work experiences., Participants: Surveys distributed to 8141 clinicians from June to August 2020 in 9 medical groups and 17 hospitals at Sutter Health, a large healthcare system in Northern California., Main Measures: Burnout was the primary outcome, and other indicators of well-being and work experience were also measured. Descriptive statistics and multivariate logistic regression analyses were performed. All statistical inferences were based on weighted estimates adjusting for response bias., Key Results: A total of 3176 clinicians (39.0%) responded to the survey. Weighted results showed 29.2% reported burnout, and burnout was more common among women than among men (39.0% vs. 22.7%, p<0.01). In multivariate models, being a woman was associated with increased odds of reporting burnout (OR=2.19, 95% CI: 1.51-3.17) and being 55+ years old with lower odds (OR=0.54, 95% CI: 0.34-0.87). More women than men reported that childcare/caregiving was impacting work (32.9% vs. 19.0%, p<0.01). Even after controlling for age and gender, clinicians who reported childcare/caregiving responsibilities impacted their work had substantially higher odds of reporting burnout (OR=2.19, 95% CI: 1.54-3.11). Other factors associated with higher burnout included worrying about safety at work, being given additional work tasks, concern about losing one's job, and working in emergency medicine or radiology. Protective factors included believing one's concerns will be acted upon and feeling highly valued., Conclusions: This large survey found the pandemic disproportionally impacted women, younger clinicians, and those whose caregiving responsibilities impacted their work. These results highlight the need for a holistic and targeted strategy for improving clinician well-being that addresses the needs of women, younger clinicians, and those with caregiving responsibilities., (© 2021. The Author(s).)

During progression towards malignancy, many tumor cells display changes in their repertoire of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). The recent finding that many members of the MMPs are regulated by protooncogenes may explain the frequent observation of changes in MMP gene expression during progression of many tumor types. While studies involving enzymatic assays of MMPs are usually confined to one or a few MMPs, reverse transcription-PCR (RT-PCR) permitted the analysis of seven members of the MMP family and two members of the TIMP family in several normal and transformed cell lines. RT-PCR permitted us to confirm the observation that MMP-9 is activated following transformation and also to observe the previously unreported activation of MMP-7 in SV40-transformed cells. It has previously been found that MMP-1, -2, -3, -8, and -9 are upregulated by phorbol esters; we have found that MMP-10 is also upregulated by phorbol esters. The phorbol ester upregulation of MMP-1, -3, and -10 was found to be abolished in cells transformed by SV40 virus. Several studies have shown that MMP-1 is upregulated by an integrin-mediated signal transduction pathway. This study demonstrates that MMP-3 and MMP-10 are also regulated by integrin-mediated signal transduction and that upregulation by this pathway is abolished following SV40 transformation. In summary, the more global view of MMP expression afforded by RT-PCR indicates that MMP-1, -3, and -10 are regulated by both integrin-mediated signal transduction and phorbol esters. While fibroblasts and transformed bone cells express several members of the MMP gene family, several other cell types do not express MMPs.

Background: A multidisciplinary team of health scientists and educators at an academic medical center came together to consider the various factors that impact well-being among self-identified women working in healthcare and conducted a comprehensive literature review to identify the existing body of knowledge. Objectives: To examine how well-being is defined, what instruments are used to measure it, and correlation between professional and personal gender-specific factors that impact the well-being of women in healthcare occupations. Methods: A total of 71 studies published in 26 countries between 1979-2022 were extracted from PubMed. Studies enrolled adult women (18-74 y.o.) healthcare professionals including nurses, physicians, clinical social workers, and mental health providers. Well-being related phenomena such as quality of life (QOL), stress, burnout, resiliency, and wellness were investigated. In this review, women are broadly defined to include any individual who primarily identifies as a woman regardless of their sex assigned at birth. Results: The results of our analysis were consistent across the scope of the literature and indicated that women in healthcare occupations endure a significantly higher level of stress and burnout compared to their male counterparts. The following gender-specific factors were identified as having direct correlation to well-being: job satisfaction, psychological health, and work-life integration. Conclusions: The findings from this review indicate a need for evidence-based integrative interventions across healthcare enterprises to combat stress and burnout and strengthen the resiliency and well-being of women in healthcare. Using information from this review, our team will launch a comprehensive well-being assessment and a series of interventions to support resiliency and well-being at our academic medical center. [ABSTRACT FROM AUTHOR]

Purpose: Physical activity is associated with improved health outcomes for cancer survivors and their romantic partners, yet it is unclear if joint exercise programs for survivor-partner dyads are acceptable. This study examined demographic, relationship, exercise, and cancer history correlates of survivors' and their romantic partners' couples-based exercise beliefs and their preferences for program designs. Methods: All participants (survivors n=209, partners n=155, couples n=143) completed an online survey. Correlations and linear regression analyses were used to examine correlates of participants' importance of and interest in couples-based exercise and their likelihood of joining a couples-based exercise program. Intraclass correlations estimated shared variance at the couple level. Results: Most participants believed that couples-based exercise was highly important (51.8%) and were interested in a couples-based exercise program (61.5%), but fewer survivors believed their partner would be interested or would likely join a couples-based program. Across all outcomes, partner support for exercise was most strongly associated with participants' couples-based exercise beliefs (r = 0.19–0.54, p<.05), and couples were significantly aligned in their beliefs (ρ=0.20–0.31, p<.01). Participants were interested in exercise programs involving exercising together (67.3%) as well as exercising separately while sharing activity data on an app or website (48.0%). Conclusions: This novel understanding of couples-based exercise beliefs provides a strong foundation upon which future exercise programs may be designed for survivors and their romantic partners. Impact for Cancer Survivors: Survivors' adoption and maintenance of exercise may be enhanced by the inclusion of romantic partners in exercise programs, and partners' inclusion is appealing to couples. [ABSTRACT FROM AUTHOR]

Metalloproteinase activities of a disintegrin and metalloproteinases (ADAMs), matrix metalloproteinases (MMPs), and membrane type (MT-)MMPs are involved in many aspects of tumor biology. ADAMs are transmembrane proteins that cleave membrane-anchored proteins to release soluble factors, and thereby mediate important biological phenomena in tumors. The aim of this study was to analyze histopathology, expression and roles of metalloproteinases, especially ADAMs, in gastric gastrointestinal stromal tumor (GIST). Histopathology and immunohistochemical expression of ADAMs were examined in 89 gastric GISTs. In 11 GISTs, ADAM expression was examined at mRNA and protein levels by reverse transcription – polymerase chain reaction (RT-PCR) and immunoblotting, respectively. RT-PCR analysis showed frequent expression of ADAM9 (91%), ADAM10 (64%), ADAM17 (82%), MMP-2 (82%), and MT1-MMP (73%). However, ADAM17 and MMP-2 were the only metalloproteinases that were up-regulated in GISTs at the protein level compared with non-neoplastic gastric tissues. ADAM17 was immunohistochemically expressed in 93% of GIST versus 16% of normal gastric tissues. Furthermore, CD117-positive interstitial cells of Cajal in normal gastric tissues were all negative for ADAM17 with double immunostaining. Expressions of epidermal growth factor receptor (EGFR) and several EGFR ligands such as amphiregulin, heparin-binding epidermal growth factor (HB-EGF), betacellulin, and epiregulin were also demonstrated in GIST by RT-PCR. Protein expression of EGFR, phosphorylated EGFR, amphiregulin, and HB-EGF, both of which can be shed by ADAM17, was confirmed in tumors coexpressing ADAM17 by immunoblotting. Moreover, proteolytically cleaved soluble forms of amphiregulin were identified in tumor extracts. Considered together, the results suggest that ADAM17 may contribute to the progression and growth of GIST through shedding of EGFR ligands and consequent EGFR stimulation. ADAM17, as a major sheddase in GIST, could be potentially a suitable target in anticancer treatment of imatinib-resistant GISTs. ( Cancer Sci 2009; 100: 654–662) [ABSTRACT FROM AUTHOR]

In bronchial mucosa, T cells are in close association with fibroblasts. This cell contact raises the possibility of cross-talk between the two cell types through cytokines, such as interleukin-4 (IL-4). We postulated that IL-4 may modulate collagen synthesis and degradation in the fibroblasts of asthmatics. Bronchial fibroblasts from asthmatics (BAF) and normal controls (BNF) were stimulated with IL-4. Procollagen I gene expression and protein production were measured by real-time PCR, RT-PCR, and radioimmunoassay. The effect of IL-4 on the regulation of procollagen I (α1) promoter was studied through transient cell transfections. The implication of Sp1 and AP-1 in regulating IL-4-induced procollagen I (α1) production was determined. The effect of IL-4 on metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) production and gene expression was evaluated. Following IL-4 stimulation, there was a significant increase in the expression of mRNA of procollagen I (α1) by human bronchial fibroblasts of asthmatics and controls. IL-4 has a dose–response effect on mRNA, with a maximal effect at 5 ng/mL, as determined by real-time PCR. The maximal increase in procollagen I (α1) was observed at 6 h after IL-4 stimulation in both BNF and BAF. BAFs have a greater increase in the procollagen I (α1)/β2 microglobulin ratio after 6 h of IL-4 stimulation (4.1×10−2±0.03 to 20.8×10−2±0.1) compared with BNF (2.9×10−2±0.006 to 9.2×10−2±0.08) ( P=0.001). In transient transfection experiments, IL-4 increased promoter activity by threefold in BAF and BNF. Sp1 was up-regulated after IL-4 stimulation and AP-1 was down-regulated as shown by electrophoretic mobility shift assay. IL-4 decreased MMP-2 protein and mRNA levels, and did not alter TIMP-2 production. IL-4 positively regulates procollagen I (α1) transcription by direct promoter activation and increases the TIMP-2/MMP-2 ratio, thereby supporting the profibrotic effect of this cytokine. Thus, this study emphasizes that IL-4 may be considered as a link between inflammation and collagen deposition observed in asthmatic airways. [ABSTRACT FROM AUTHOR]

Objective: To investigate matrix metalloproteinases (MMP-2 and MMP-9) in heart failure caused by ischaemic and idiopathic dilated cardiomyopathy, and the impact of angiotensin converting enzyme (ACE) inhibition on MMP.Design and Main Outcome Measures: MMP were extracted from myocardium of patients with heart failure (coronary artery disease, n = 13; idiopathic dilated cardiomyopathy (IDCM), n = 16) and from controls (n = 6). The active form of MMP-2 and MMP-9 was measured by enzyme linked immunosorbent assay; activity of MMPs by zymography; mRNA expression of MMPs by reverse transcriptase polymerase chain reaction.Results: Active MMP-9 was significantly increased in coronary artery disease (mean (SD) 1.6 (0.35) ng/ml) and IDCM (2.11 (0.54) ng/ml) in comparison with controls (0.53 (0.15) ng/ml). Increased MMP-2 was only found in IDCM (3.68 (0.41) ng/ml). There were corresponding increases in MMP activity but no upregulation of mRNA expression was found. The ACE inhibitors captopril and ramiprilate inhibited MMP-2 and MMP-9 activity in vitro (inhibitory capacity (IC50), in mmol/l: MMP-2: captopril 2.0 (0.16), ramiprilate 2.1 (0.3); MMP-9: captopril 1.65 (0.18), ramiprilate 2.0 (0.3)). Lisinopril inhibited MMP-9 significantly but did not inhibit MMP-2 in vitro (IC50 MMP-2: 7.4 (0.88); MMP-9: 7.86 (2.23)). Inhibition of MMP activity by ACE inhibitors was blunted by zinc excess.Conclusions: Upregulation of MMP-9 activity is common in the failing myocardium, independent of the underlying disease. Missing upregulation of transcription suggests that activation of latent forms of MMP is the source of increased MMP activity, rather than increased de novo synthesis. Some ACE inhibitors may influence MMP activity by a direct effect. [ABSTRACT FROM AUTHOR]

The ability of tumors to infiltrate the surrounding tissue is one of the major characteristics of a malignancy. This process is based on the tumors ability to destroy the extracellular matrix (ECM) including the basement membrane (BM). Several previous studies identified matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases to be keyplayers in this process. Since then multiple investigations focused on the expression and activation levels of their extracellular regulators and to a lesser extent of their transcriptional modulators. However, the exact diagnostic and prognostic values of these regulators still remain unclear. Squamous cell carcinomas of the head and neck (HNSCC) are known for their infiltrative growth and there is strong evidence that at least some members of the MMP-family play a crucial role in this process. It turned out that MMP-2, -9, -13 and to a lesser extent MMP-7 are related to the metastatic potential of HNSCC but further studies will be required to establish the exact role of MMPs in HNSCC. This Review will discuss the current literature concerning the role of MMPs in HNSCC. [ABSTRACT FROM AUTHOR]

Background: The host response is a critical component in the pathogenesis of periodontitis. In fact, the clinical benefits associated with regulating the host response have been demonstrated in studies using several different classes of drugs. Bio-phosphates are one host-modulating class of drugs that has demonstrated this ability. These drugs are clinically effective at reducing bone resorption and have shown the ability to inhibit host degradative enzymes, specifically the matrix metalloproteinases (MMPs). Therefore, the purpose of this study was to investigate the regulatory effects of a bisphosphonate, tiludronate, on MMP levels and activity in human periodontal cells. Methods: MMP-1 and MMP-3 were assessed in cultured human periodontal ligament cells treated with a bisphosphonate, tiludronate. Reverse transcription-polym erase chain reaction was used to identify mRNA levels for both enzymes, and also for tissue inhibitors (TIMP-1). Enzyme immunoassay (EIA) and immunocytochemistry were used to assess MMP proteins in these cell cultures. Enzyme activity was assessed using FITC-conjugated substrates and quantitated using spectrophotofluorometry. Results: Tiludronate significantly inhibited both MMP-1 and MMP-3 activity in a concentration-dependent manner. A maximal reduction in activity of 35% was achieved for each of the enzymes at a 10-4 M concentration. Tiludronate did not have a significant effect on the mRNA levels for MMP-1, MMP-3, or MMP-1. Similarly, there were no effects noted for either MMP-1 or MMP-3 on the protein level. Conclusions: This study demonstrates an inhibitory effect of tiludronate on the activity of both MMP-1 and MMP-3. These effects appear to occur without altering either mRNA or protein levels for these enzymes, supporting a possible mechanism of action that involves the ability of bisphosphonates to chelate cations from the MMPs. Furthermore, these results support the continued investigation of these drugs as potential therapeutic agents in periodontal disease. [ABSTRACT FROM AUTHOR]

To estimate the effectiveness of pneumococcal polysaccharide vaccine, we serotyped isolates submitted to the Pneumococcal Sentinel Surveillance System from 1984 to 1996 from 48 vaccinated and 125 unvaccinated children 2 to 5 years of age. Effectiveness against invasive disease caused by serotypes included in the vaccine was 63%. Effectiveness against serotypes in the polysaccharide vaccine but not in a proposed seven-valent protein conjugate vaccine was 94%. [ABSTRACT FROM AUTHOR]

Infiltrative capacity was found to distinguish separate T leukemia cell lines. Of seven T-cell lines four exhibited capacity to infiltrate Matrigel. Analysis of infiltration was performed at the single-cell level throughout the Matrigel using a depth meter. Further, we examined differences in migration capacity and metalloproteinase production between infiltrating and non-infiltrating T-cell lines. The capacity to infiltrate was not directly correlated to the capacity to adhere to the Matrigel or to migrate on/to extracellular matrix components. It is concluded that infiltration capacity does not simply reflect capacity to migrate but represents a distinct functional property. The production of metalloproteinases and their inhibitors by the separate T-cell lines was analyzed using rt PCR, biosynthetic labelling, zymography, immunoprecipitation and ELISA. All T-cell lines with capacity to infiltrate produced matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) while non-infiltrating cell lines did not express MMP-9. Expression of MMP-1, 2, 3, 10, 14 and 17 showed no correlation to capacity to infiltrate. Analysis of infiltration in the presence of a metalloprotease inhibitor showed an increased number of cells within the gel. This enhancement of infiltration suggests that the function of MMPs and/or their inhibitors in lymphocyte infiltration is more complex than previously thought. [ABSTRACT FROM AUTHOR]

Research findings show that pneumococcal capsular polysaccharide vaccines are effective in protecting 94% of the vaccinated preschool-age children with pneumococcal disease., To estimate the effectiveness of pneumococcal polysaccharide vaccine, we serotyped isolates submitted to the Pneumococcal Sentinel Surveillance System from 1984 to 1996 from 48 vaccinated and 125 unvaccinated children 2 [...]