Depression and Suicide Among American Surgeons-A Grave Threat to the Surgeon Workforce.

This Viewpoint discusses mental health issues and suicide among surgeons in the US and potential solutions to this growing crisis.

Unspoken Truths: Mental Health Among Academic Surgeons.

OBJECTIVE: To characterize the current state of mental health within the surgical workforce in the United States. BACKGROUND: Mental illness and suicide is a growing concern in the medical community; however, the current state is largely unknown. METHODS: Cross-sectional survey of the academic surgery community assessing mental health, medical error, and suicidal ideation. The odds of suicidal ideation adjusting for sex, prior mental health diagnosis, and validated scales screening for depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol use disorder were assessed. RESULTS: Of 622 participating medical students, trainees, and surgeons (estimated response rate=11.4%-14.0%), 26.1% (141/539) reported a previous mental health diagnosis. In all, 15.9% (83/523) of respondents screened positive for current depression, 18.4% (98/533) for anxiety, 11.0% (56/510) for alcohol use disorder, and 17.3% (36/208) for PTSD. Medical error was associated with depression (30.7% vs. 13.3%, P <0.001), anxiety (31.6% vs. 16.2%, P =0.001), PTSD (12.8% vs. 5.6%, P =0.018), and hazardous alcohol consumption (18.7% vs. 9.7%, P =0.022). Overall, 13.2% (73/551) of respondents reported suicidal ideation in the past year and 9.6% (51/533) in the past 2 weeks. On adjusted analysis, a previous history of a mental health disorder (aOR: 1.97, 95% CI: 1.04-3.65, P =0.033) and screening positive for depression (aOR: 4.30, 95% CI: 2.21-8.29, P <0.001) or PTSD (aOR: 3.93, 95% CI: 1.61-9.44, P =0.002) were associated with increased odds of suicidal ideation over the past 12 months. CONCLUSIONS: Nearly 1 in 7 respondents reported suicidal ideation in the past year. Mental illness and suicidal ideation are significant problems among the surgical workforce in the United States.

Predictors of Emergency Room Visits After Ambulatory Breast Cancer Surgery in the Medicare Population.

BACKGROUND: Emergency department (ED) overuse is a large contributor to healthcare spending in the USA. We examined the rate of and risk factors for ED visits following outpatient breast cancer surgery. PATIENTS AND METHODS: Using linked data from the Surveillance, Epidemiology, and End Results (SEER) program and Medicare, we identified women who underwent curative breast cancer surgery between 2003 and 2015. Our outcome of interest was ED visits within 30 days of surgery. Multivariate regression was used to evaluate the odds of ED visit while controlling for clinical and socioeconomic variables. Secondary analyses assessed admission from the ED as well as costs. RESULTS: Of the 78,060 included patients, 5.1% returned to the ED, of which only 29.8% required hospital admission. Rate of ED visits increased with patient age. A higher percentage of Black patients returned to the ED compared with white patients (7.0% versus 5.0%, p < 0.001). Patients with higher income were less likely to visit the ED compared with those with lower income (OR 0.76, p < 0.001). Predictors of ED visits included: being unmarried (OR 1.18, p < 0.001), having stage 2 (OR 1.20, p < 0.001) or stage 3 cancer (OR 1.38, p < 0.001), and those with Charlson comorbidity score of 1 (OR 1.39, p < 0.001) or ≥ 2 (OR 2.29, p < 0.001). CONCLUSION: While a substantial number of patients return to the ED following outpatient breast surgery, most do not require hospital admission, which indicates that a large proportion of these visits could have been avoided. We identified several clinical and socioeconomic predictors of postoperative ED visits, which will aid in the development of patient risk profiling tools.

Evaluation of multiple transcriptomic gene risk signatures in male breast cancer.

Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Several multigene assays are increasingly used to guide clinical treatment decisions in female BCa, however, there are limited data on the utility of these tests in male BCa. Here we present the gene expression results of 381 M0, ER+ve, HER2-ve male BCa patients enrolled in the Part 1 (retrospective analysis) of the International Male Breast Cancer Program. Using a custom NanoString™ panel comprised of the genes from the commercial risk tests Prosigna®, OncotypeDX®, and MammaPrint®, risk scores and intrinsic subtyping data were generated to recapitulate the commercial tests as described by us previously. We also examined the prognostic value of other risk scores such as the Genomic Grade Index (GGI), IHC4-mRNA and our prognostic 95-gene signature. In this sample set of male BCa, we demonstrated prognostic utility on univariate analysis. Across all signatures, patients whose samples were identified as low-risk experienced better outcomes than intermediate-risk, with those classed as high risk experiencing the poorest outcomes. As seen with female BCa, the concordance between tests was poor, with C-index values ranging from 40.3% to 78.2% and Kappa values ranging from 0.17 to 0.58. To our knowledge, this is the largest study of male breast cancers assayed to generate risk scores of the current commercial and academic risk tests demonstrating comparable clinical utility to female BCa.

Innovations for integrated care: The Association of Medicine and Psychiatry recognizes new models.

This editorial looks at the current state of the integration of medicine and psychiatry in clinical practice. We note selected recent triumphs and barriers to implementing integrated care, highlighting some gaps and priorities for future innovations. In contrast to the relatively more orderly culture of health services research, where some notable innovations in integrated care were funded, tested, and published, the health care marketplace can be a difficult place to identify and track the innovations that could shape health care reform. Recognizing the need to find, describe, and disseminate the most innovative models in integrated care, the Association of Medicine and Psychiatry (AMP) launched in 2016 the Innovative Models for Integrated Care Awards. Although many service innovations solve local problems, some can also act as models to be adopted in multiple settings. The projects that win AMP Innovative Models for Integrated Care Awards are selected for their innovativeness, their clinical importance, their generalizability, and their effectiveness. We briefly describe here the four models that earned these awards at the 2017 AMP Annual Meeting. They demonstrate innovations across a range of settings and populations: inpatient general hospital patients under constant observation in New York, severely mentally ill patients in a federally qualified health center in San Francisco, outpatients in a VA women's health center in Chicago, and HIV patients in an academic infectious disease clinic in Charleston, south Carolina. These model descriptions aim to encourage the implementation of innovative models that advance the integration of medicine and psychiatry.

Mind the Gap: Developing an Integrated Behavioral Health Home to Address Health Disparities in Serious Mental Illness.

OBJECTIVE: This study evaluated the impact of an integrated behavioral health home (BHH) pilot on adults with psychotic and bipolar disorders. METHODS: Quasi-experimental methods were used to compare outcomes before (September 2014-August 2015) and after the intervention (September 2015-August 2016) among ambulatory BHH patients and a control group. Electronic health records were compared between 424 BHH patients (N=369, psychotic disorder; N=55, bipolar disorder) and 1,521 individuals from the same urban, safety-net health system who were not enrolled in the BHH. Groups were weighted by propensity score on the basis of sex, age, race-ethnicity, language, 2010 U.S. Census block group characteristics, Medicare and Medicaid enrollment, and diabetes diagnosis. RESULTS: BHH patients had fewer total psychiatric hospitalizations and fewer total emergency visits compared with the control group, a difference that was predominantly driven by patients with at least one psychiatric hospitalization or ED visit. There were no differences in medical hospitalizations. Although BHH patients were more likely to receive HbA1c screening, there were no differences between the groups in lipid monitoring. Regarding secondary outcomes, there were no significant differences in changes in metabolic monitoring parameters among patients with diabetes. CONCLUSIONS: Participation in a pilot ambulatory BHH program among patients with psychotic and bipolar disorders was associated with significant reductions in ED visits and psychiatric hospitalizations and increased HbA1c monitoring. This evaluation builds on prior research by specifying intervention details and the clinical target population, strengthening the evidence base for care integration to support further program dissemination.

Lower education among low-income Brazilian adolescent females is associated with planned pregnancies.

Adolescent pregnancy has social, economic, and educational consequences and is also linked to adverse perinatal outcomes. However, studies show a positive relationship between pregnancy and increased social status among low-income adolescents. This study aims to assess the association between planned pregnancy and years of schooling among low-income Brazilian adolescents. This is a secondary analysis of a cohort study conducted from May 2005 to March 2007 in public primary care clinics in São Paulo, Brazil. Participants (n=168) completed a detailed structured questionnaire. Logistic regression was used to examine the association between years of schooling and planned pregnancy. After adjusting for the covariates income, wealth score, crowding, age, marital status, and race, planned pregnancy was independently associated with lower years of education (odds ratio: 1.82; 95% confidence interval: 1.02-3.23). Although this finding may be related to these adolescents having less access to information and health services, another possible explanation is that they have a greater desire to have children during adolescence.

Comparing Breast Cancer Multiparameter Tests in the OPTIMA Prelim Trial: No Test Is More Equal Than the Others.

BACKGROUND: Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population. METHODS: Three hundred thirteen women with early breast cancer were randomized to standard (chemotherapy and endocrine therapy) or test-directed (chemotherapy if Oncotype DX recurrence score >25) treatment. Risk stratification was also determined with Prosigna (PAM50), MammaPrint, MammaTyper, NexCourse Breast (IHC4-AQUA), and conventional IHC4 (IHC4). Subtype classification was provided by Blueprint, MammaTyper, and Prosigna. RESULTS: Oncotype DX predicted a higher proportion of tumors as low risk (82.1%, 95% confidence interval [CI] = 77.8% to 86.4%) than were predicted low/intermediate risk using Prosigna (65.5%, 95% CI = 60.1% to 70.9%), IHC4 (72.0%, 95% CI = 66.5% to 77.5%), MammaPrint (61.4%, 95% CI = 55.9% to 66.9%), or NexCourse Breast (61.6%, 95% CI = 55.8% to 67.4%). Strikingly, the five tests showed only modest agreement when dichotomizing results between high vs low/intermediate risk. Only 119 (39.4%) tumors were classified uniformly as either low/intermediate risk or high risk, and 183 (60.6%) were assigned to different risk categories by different tests, although 94 (31.1%) showed agreement between four of five tests. All three subtype tests assigned 59.5% to 62.4% of tumors to luminal A subtype, but only 121 (40.1%) were classified as luminal A by all three tests and only 58 (19.2%) were uniformly assigned as nonluminal A. Discordant subtyping was observed in 123 (40.7%) tumors. CONCLUSIONS: Existing evidence on the comparative prognostic information provided by different tests suggests that current multiparameter tests provide broadly equivalent risk information for the population of women with estrogen receptor (ER)-positive breast cancers. However, for the individual patient, tests may provide differing risk categorization and subtype information.

Molecular characterisation of isogenic taxane resistant cell lines identify novel drivers of drug resistance.

BACKGROUND: Taxanes such as paclitaxel and docetaxel are used successfully to treat breast cancer, usually in combination with other agents. They interfere with microtubules causing cell cycle arrest; however, the mechanisms underlying the clinical effects of taxanes are yet to be fully elucidated. METHODS: Isogenic paclitaxel resistant (PACR) MDA‒MB‒231, paclitaxel resistant ZR75‒1 and docetaxel resistant (DOCR) ZR75‒1 cell lines were generated by incrementally increasing taxane dose in native cell lines in vitro. We used aCGH analysis to identify mechanisms driving taxane resistance. RESULTS: Taxane resistant cell lines exhibited an 18-170 fold increased resistance to taxanes, with the ZR75-1 resistant cell lines also demonstrating cross resistance to anthracyclines. Paclitaxel treatment of native cells resulted in a G2/M block and a decrease in the G1 phase of the cell cycle. However, in the resistant cell lines, minimal changes were present. Functional network analysis revealed that the mitotic prometaphase was lost in the resistant cell lines. CONCLUSION: This study established a model system for examining taxane resistance and demonstrated that both MDR and mitosis represent common mechanism of taxane resistance.

Proximity ligation assays for isoform-specific Akt activation in breast cancer identify activated Akt1 as a driver of progression.

The PI3K/Akt signal transduction pathway plays an important role in cancer progression and cell survival. Akt activation is associated with poor outcome in endocrine-treated breast cancer, whereas high levels of cytoplasmic Akt2 are associated with an improved overall survival. Proximity ligation assays (PLAs) were used to determine quantitative expression levels of isoform-specific activation (phosphorylation) of Akt1 and Akt2 in formalin-fixed, paraffin-embedded cell lines and breast cancer tumour tissues in situ. PLAs demonstrated a range of expression in breast cancer samples for total pAkt1 and pAkt2. High levels of pAkt1 were associated with reduced DRFS (HR: 1.45, 95% CI 1.14-1.83, p = 0.002) and OS (HR: 1.42, 95% CI 1.10-1.83, p = 0.007). When PLA results were combined, patients that had high levels of pAkt1 only had a significantly decreased DRFS (HR: 1.92, 95% CI 1.34-2.76, p = 0.005) and OS (HR: 1.94, 95% CI 1.32-2.86, p = 0.008) compared to other patients. Using PLAs to discriminate activation of Akt1 versus Akt2 suggests that Akt1 drives progression in early breast cancers. In cases where both Akt1/Akt2 are activated, Akt2 may act to reverse this effect. Using PLAs, we have measured activation of Akt1 and Akt2 proteins separately in situ in FFPE breast cancer samples.

In situ detection of HER2:HER2 and HER2:HER3 protein-protein interactions demonstrates prognostic significance in early breast cancer.

HER2 overexpression/amplification is linked with poor prognosis in early breast cancer. Co-expression of HER2 and HER3 is associated with endocrine and chemotherapy resistance, driven not simply by expression but by signalling via HER2:HER3 or HER2:HER2 dimers. Proximity ligation assays (PLAs) detect protein-protein complexes at a single-molecule level and allow study of signalling pathways in situ. A cohort of 100 tumours was analyzed by PLA, IHC and FISH. HER complexes were analyzed by PLA in a further 321 tumours from the BR9601 trial comparing cyclophosphamide, methotrexate and fluorouracil (CMF) with epirubicin followed by CMF (epi-CMF). The relationships between HER dimer expression and RFS and OS were investigated, and multivariate regression analysis identified factors influencing patient prognosis. PLA successfully and reproducibly detected HER2:HER2 and HER2:HER3 protein complexes in vivo. A significant association (P < 0.00001) was identified between HER2 homodimerization and HER2 gene amplification. Following a minimum p value approach high levels of HER2:HER2 dimers were significantly associated with reduced relapse-free (RFS; hazard ratio = 1.72, 95% confidence interval 1.15-2.56, P = 0.008) and overall survival (OS HR = 1.69 95% CI = 1.09-2.62, P = 0.019). Similarly, high levels of HER2:HER3 dimers were associated with reduced RFS (HR = 2.18, 95% CI = 1.46-3.26, P = 0.00016) and OS (HR = 2.21, 95% CI = 1.41-3.47, P = 0.001). This study demonstrates that in situ detection of HER2 and HER2:3 protein:protein complexes can be performed robustly and reproducibly in clinical specimens, provides novel prognostic information and opens a significant novel opportunity to probe the clinical impact of cellular signalling processes.

Laser Doppler anemometry measurements of the shear stresses on ultrasonic contrast agent microbubbles attached to agar.

Ultrasonic contrast agents are currently being developed to target and bind to specific areas of interest such as atheromous plaque. A microbubble has been developed in-house which can be targeted to attach to specific cell-lines. To assess the feasibility of using the microbubble in vivo, the shear stresses which the bound microbubbles can withstand need to be known. A flow chamber was developed for use with intravascular ultrasound (IVUS) and laser Doppler anemometry (LDA). Biotin was incorporated into the microbubble shells and streptavidin was used to attach them to agar. IVUS at 40 MHz was then used to image the attached microbubbles under steady flow at a range of flow rates from 75 to 480 mL min(-1) through a flow area of 9 mm(2). LDA was employed to find high resolution velocity profiles of the flow in the chamber at a selection of these flow rates and the shear stresses on the bubbles were calculated. The bubbles were found to remain attached to the agar for shear stresses of up to 3.4 Pa. This compares with mean physiological arterial shear stresses of less than 1.5 Pa for pulsatile flow.