Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis.

BACKGROUND: Regulatory T cells (Tregs) are highly prevalent in tumor tissue and can suppress effective anti-tumor immune responses. However, the source of the increased tumor-infiltrating Tregs and their contribution to cancer progression remain poorly understood. METHODOLOGY/PRINCIPAL FINDING: We here investigated the frequency, phenotype and trafficking property of Tregs and their prognostic value in patients with hepatocellular carcinoma (HCC). Our results showed that FoxP3(+) Tregs highly aggregated and were in an activated phenotype (CD69(+)HLA-DR(high)) in the tumor site, where they can suppress the proliferation and INF-γ secretion of CD4(+)CD25(-) T cells. These tumor-infiltrating Tregs could be selectively recruited though CCR6-CCL20 axis as illustrated by (a) high expression of CCR6 on circulating Tregs and their selective migration to CCR6 ligand CCL20, and (b) correlation of distribution and expression between tumor-infiltrating Tregs and intratumoral CCL20. In addition, we found that the number of tumor-infiltrating Tregs was associated with cirrhosis background (P = 0.011) and tumor differentiation (P = 0.003), and was an independent prognostic factor for overall survival (HR = 2.408, P = 0.013) and disease-free survival (HR = 2.204, P = 0.041). The increased tumor-infiltrating Tregs predicted poorer prognosis in HCC patients. CONCLUSIONS: The CCL20-CCR6 axis mediates the migration of circulating Tregs into tumor microenvironment, which in turn results in tumor progression and poor prognosis in HCC patients. Thus, blocking CCL20-CCR6 axis-mediated Treg migration may be a novel therapeutic target for HCC

Phenotypic and functional analysis of CD4⁺CD25⁺ Tregs in HCC patients.

<p>(<b>a</b>) Representative FoxP3, CTLA-4, CD45RO, CD69 and HLA-DR expression profiles in CD4⁺CD25⁺ (thick line) and CD4⁺CD25⁻ (dotted line) T cells from the four studied groups. Specific isotypes were used as negative control. The percentages represent the frequencies of various markers on CD4⁺CD25⁺ T cells. The italic numerical values represent MFI of FoxP3 in CD4⁺CD25⁺ T cells. (b) Statistical analysis shows that the MFI of FoxP3 in CD4⁺CD25⁺ T cells from TIL was significantly higher than those from NIL, cPBMC, and nPBMC. *<i>P</i><0.05, compared with TIL. (c) Purified CD4⁺CD25⁺ T cells (Tregs) from TIL, NIL, and cPBMC could similarly inhibit the proliferation and INF-γ production of autologous CD4⁺CD25⁻ T cells (Tconv) in a dose-dependent manner (n = 3 for each group). *<i>P</i><0.05; **<i>P</i><0.01, compared with autologous controls (Treg∶Tconv = 0∶1). Data in (b) and (c) represent the mean±S.E.M.</p

CD4⁺CD25⁺FoxP3⁺ Tregs are highly enriched in tumors of HCC patients.

<p>Tregs (CD4⁺CD25⁺ T cells) were gated from CD3⁺ T cells by flow cytometry. (a, b) Representative plots (a) and statistical analysis (b) show that the frequency of CD4⁺CD25⁺ T cells was higher in HCC patients, especially among TIL. The percentages in (a) represent the frequency of CD4⁺CD25⁺ T cells among CD4⁺ T cells. The data in (b) are expressed in box plots, in which the horizontal lines illustrate the 25th, 50th and 75th percentiles. (c, d) Representative images (c) and statistical analysis (d) of immunohistochemical staining of FoxP3⁺ lymphocytes in the tumor and non-tumor tissue from HCC patient and normal control liver. Magnification, ×200. The data in (d) show that the number of FoxP3⁺ cells is significantly higher in tumor than in non-tumor or normal control. hpf, high-powered field. (e) Statistical analysis shows FoxP3⁺ cells preferentially aggregate in the parenchyma of tumors.</p

Circulating CD4⁺CD25⁺ Tregs in HCC patients highly express CCR6, and selectively migrate to tumors under recruitment of CCL20.

<p>(a) Representative plots of CCR6, CCR4 and CCR7 on CD4⁺CD25⁺ (solid line) and CD4⁺CD25⁻ (dotted line) T cells from different compartments. Specific isotypes were used as negative control. The percentages represent frequencies of CCR6, CCR4 and CCR7 on CD4⁺CD25⁺ T cells. (b) Statistical analysis shows that cPBMC-derived CD4⁺CD25⁺ Tregs expressed significantly higher CCR6 than autologous CD4⁺CD25⁻ T cells or Tregs from the other groups. **<i>P</i><0.01, ***<i>P</i><0.001. (c) CD4⁺CD25⁺ T cells migrate in response to recombinant human CCL20 or supernatant of SMMC-7721 cells (n = 3). A specific antibody to CCL20 significantly inhibits CD4⁺CD25⁺ T cell migration. Data represent the mean±S.E.M. **<i>P</i><0.01, ***<i>P</i><0.001.</p

Univariate and Multivariate analysis of factors associated with survival and recurrence.

<p>Univariate and multivariate analysis: Cox proportional hazards regression model.</p><p>HR, Hazard Ratio; NA, not adopted.</p><p>*Multivariate variables were adopted by univariate analysis (<i>P</i><0.10).</p

Correlation between tumor FoxP3⁺ cell and clinicopathologic characteristics.

<p>HBsAg, Hepatitis B surface antigen; AFP, α-fetoprotein; ALT, alanine aminotransferase.</p

Accumulation of tumor Treg cells predicts poor survival in patients with hepatocellular carcinoma.

<p>The cumulative overall survival and disease-free survival of HCC patients were estimated using the Kaplan-Meier method and compared by the log-rank test. Patients with high FoxP3⁺ Tregs (dashed lines) had significantly poorer survival compared with individuals with low FoxP3⁺ Treg density (solid lines).</p