Now is the time to redefine safety in healthcare.

Throughout the COVID-19 pandemic, frontline healthcare workers around the globe provided exceptional patient care despite fears of infection, shortages of staff and supplies, and the frustrations of trying to treat a novel pathogen. At the same time, COVID-19 exposed deep and systemic risks to healthcare team members' physical, psychological, and emotional safety driving burnout to crisis levels. Burnout is arising not only from the emotional toll of caring for sick and dying patients, but COVID-19 also exposed flaws in our health system and infrastructure. Systemic inequities were amplified as COVID-19 disproportionately impacted people of colour and Indigenous community members. A renewed and expanded definition of safety is needed to restore trust, recruit, and retain individuals to the healing professions, enable care to be provided with the greatest skill and humanity, and ensure the well-being of every person working in healthcare. In collaboration with CEOs of a diverse group of health systems in the United States, the author drafted a Declaration of Principles that expands the definition of safety to include safeguarding psychological and emotional well-being of team members, promoting health justice by declaring equity and anti-racism as core components of safety, and ensuring physical safety, which includes a zero-harm program to eliminate workplace violence, both physical and verbal. We invite Canadian leaders to embrace these concepts and commit to supporting team member safety and well-being as an essential foundation for public health. We must humanize healthcare and the time to act is now.

Results from the National Taskforce for Humanity in Healthcare's Integrated, Organizational Pilot Program to Improve Well-Being.

BACKGROUND: In health care, burnout remains a persistent and significant problem. Evidence now exists that organizational initiatives are vital to address health care worker (HCW) well-being in a sustainable way, though system-level interventions are pursued infrequently. METHODS: Between November 2018 and May 2020, researchers engaged five health system and physician practice sites to participate in an organizational pilot intervention that integrated evidence-based approaches to well-being, including a comprehensive culture assessment, leadership and team development, and redesign of daily workflow with an emphasis on cultivating positive emotions. RESULTS: All primary and secondary outcome measures demonstrated directionally concordant improvement, with the primary outcome of emotional exhaustion (0-100 scale, lower better; 43.12 to 36.42, p = 0.037) and secondary outcome of likelihood to recommend the participating department's workplace as a good place to work (1-10 scale, higher better; 7.66 to 8.20, p = 0.037) being statistically significant. Secondary outcomes of emotional recovery (0-100 scale, higher better; 76.60 to 79.53, p = 0.20) and emotional thriving (0-100 scale, higher better; 76.70 to 79.23, p = 0.27) improved but were not statistically significant. CONCLUSION: An integrated, skills-based approach, focusing on team culture and interactions, leadership, and workflow redesign that cultivates positive emotions was associated with improvements in HCW well-being. This study suggests that simultaneously addressing multiple drivers of well-being can have significant impacts on burnout and workplace environment.

A zinc phthalocyanine-benzoperylenetriimide conjugate for solvent dependent ultrafast energy vs. electron transfer.

A novel zinc phthalocyanine-benzoperylenetriimide conjugate has been synthesized and its ability to undergo ultrafast energy and electron transfer as a function of solvent polarity has been demonstrated using the femtosecond transient absorption (fs-TA) technique operating at a femto- to nanosecond time scale.

Trends in vitamin D supplement use in a general female and breast cancer population in Ireland: A repeated cross-sectional study.

BACKGROUND: Vitamin D has been linked with improved survival after breast cancer diagnosis but little is known about prescribing rates. This study investigates trends in vitamin D supplement use in both a general female and breast cancer population. METHODS: Women with a breast cancer diagnosis were identified from the National Cancer Registry of Ireland (n = 19870). Women who had any vitamin D claim between 2005 and 2011 were identified from pharmacy claims data (n = 8556). Prevalence rates were calculated as a proportion of all eligible women and by age (< 55 years, ≥ 55 years). Poisson regression was used to compare rates of vitamin D prescribing across years (risk ratio (RR), 95% CI). RESULTS: There was a statistically significant increase in women with a claim for vitamin D between 2005-2011, with the largest increase among breast cancer patients aged ≥ 55 years (RR = 2.26; 95% CI, 2.11-2.42). CONCLUSION: This may have significant public health implications if associations between vitamin D and improved breast cancer survival prove to be causal.

Bereaved mothers' and fathers' perceptions of a legacy intervention for parents of infants in the NICU.

BACKGROUND: Legacy-making, actions or behaviors aimed at being remembered, may be one strategy to enhance coping and improve grief outcomes for bereaved parents and siblings. While legacy interventions have been developed and tested in pediatric and adult populations, legacy activities specific to bereaved parents in the neonatal intensive care unit remain unexplored. This study explored bereaved parents' perceptions of a digital storytelling legacy-making intervention for parents after the death of an infant. METHODS: Six bereaved mothers and fathers participated in a focus group interview three to 12 months after the death of an infant in the NICU. A semi-structured interview guide with open-ended questions was used to obtain parent self-reports. Qualitative content analysis identified emerging themes. RESULTS: Four major themes emerged regarding participants' perceptions of a legacy intervention: (a) parents' willingness to participate in a legacy intervention, (b) parents' suggestions for a feasible intervention, (c) parents' suggestions for an acceptable intervention, and (d) parents' perceived benefits of legacy-making. CONCLUSIONS: Participants reported that a legacy-making intervention via digital storytelling would be feasible, acceptable, and beneficial for NICU parents. Study results support the need and desire for legacy-making services to be developed and offered in the NICU.

Electro-mechanical response of a 3D nerve bundle model to mechanical loads leading to axonal injury.

Traumatic brain injuries and damage are major causes of death and disability. We propose a 3D fully coupled electro-mechanical model of a nerve bundle to investigate the electrophysiological impairments due to trauma at the cellular level. The coupling is based on a thermal analogy of the neural electrical activity by using the finite element software Abaqus CAE 6.13-3. The model includes a real-time coupling, modulated threshold for spiking activation, and independent alteration of the electrical properties for each 3-layer fibre within a nerve bundle as a function of strain. Results of the coupled electro-mechanical model are validated with previously published experimental results of damaged axons. Here, the cases of compression and tension are simulated to induce (mild, moderate, and severe) damage at the nerve membrane of a nerve bundle, made of 4 fibres. Changes in strain, stress distribution, and neural activity are investigated for myelinated and unmyelinated nerve fibres, by considering the cases of an intact and of a traumatised nerve membrane. A fully coupled electro-mechanical modelling approach is established to provide insights into crucial aspects of neural activity at the cellular level due to traumatic brain injury. One of the key findings is the 3D distribution of residual stresses and strains at the membrane of each fibre due to mechanically induced electrophysiological impairments, and its impact on signal transmission.

Electro-mechanical response of a 3D nerve bundle model to mechanical loads leading to axonal injury.

Axonal damage is one of the most common pathological features of traumatic brain injury, leading to abnormalities in signal propagation for nervous systems. We present a 3D fully coupled electro-mechanical model of a nerve bundle, made with the finite element software Abaqus 6.13-3. The model includes a real-time coupling, modulated threshold for spiking activation and independent alteration of the electrical properties for each 3-layer fibre within the bundle. Compression and tension are simulated to induce damage at the nerve membrane. Changes in strain, stress distribution and neural activity are investigated for myelinated and unmyelinated nerve fibres, by considering the cases of an intact and of a traumatized nerve membrane. Results show greater changes in transmitting action potential in the myelinated fibre.

Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM).

Biomarkers play an essential role in the management of patients with invasive breast cancer. For selecting patients likely to respond to endocrine therapy, both oestrogen receptors (ERs) and progesterone receptors (PRs) should be measured on all newly diagnosed invasive breast cancers. On the other hand, for selecting likely response to all forms of anti-HER2 therapy (trastuzumab, pertuzumab, lapatinib or ado-trastuzumab emtansine), determination of HER2 expression or gene copy number is mandatory. Where feasible, measurement of ER, PR and HER2 should be performed on recurrent lesions and the primary invasive tumour. Although methodological problems exist in the determination of Ki67, because of its clearly established clinical value, wide availability and low costs relative to the available multianalyte signatures, Ki67 may be used for determining prognosis, especially if values are low or high. In oestrogen receptor (ER)-positive, HER2-negative, lymph node-negative patients, multianalyte tests such as urokinase plasminogen activator (uPA)-PAI-1, Oncotype DX, MammaPrint, EndoPredict, Breast Cancer Index (BCI) and Prosigna (PAM50) may be used to predict outcome and aid adjunct therapy decision-making. Oncotype DX, MammaPrint, EndoPredict and Prosigna may be similarly used in patients with 1-3 metastatic lymph nodes. All laboratories measuring biomarkers for patient management should use analytically and clinically validated assays, participate in external quality assurance programs, have established assay acceptance and rejection criteria, perform regular audits and be accredited by an appropriate organisation.

Mutant p53: a novel target for the treatment of patients with triple-negative breast cancer?

The identification and validation of a targeted therapy for patients with triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. One of the key reasons for the failure to develop a new therapy for this subgroup of breast cancer patients has been the difficulty in identifying a highly prevalent, targetable molecular alteration in these tumors. Recently however, the p53 gene was found to be mutated in approximately 80% of basal/TNBC, raising the possibility that targeting the mutant p53 protein product might be a new approach for the treatment of this form of breast cancer. In this study, we investigated the anti-cancer activity of PRIMA-1 and PRIMA-1MET (APR-246), two compounds which were previously reported to reactivate mutant p53 and convert it to a form with wild-type (WT) properties. Using a panel of 18 breast cancer cell lines and 2 immortalized breast cell lines, inhibition of proliferation by PRIMA-1 and PRIMA-1MET was found to be cell-line dependent, but independent of cell line molecular subtype. Although response was independent of molecular subtype, p53 mutated cell lines were significantly more sensitive to PRIMA-1MET than p53 WT cells (p = 0.029). Furthermore, response (measured as IC50 value) correlated significantly with p53 protein level as measured by ELISA (p = 0.0089, r=-0.57, n = 19). In addition to inhibiting cell proliferation, PRIMA-1MET induced apoptosis and inhibited migration in a p53 mutant-dependent manner. Based on our data, we conclude that targeting mutant p53 with PRIMA-1MET is a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease.

π-Conjugated phospholes and their incorporation into devices: components with a great deal of potential.

This review serves as a brief introduction to phospholes and discusses their unique favorable properties for application in organic electronic materials. Over the past several years, π-conjugated phospholes have been slowly making their way into devices. We report here the mode of synthesis of these π-conjugated phospholes as well as discuss the performances of the devices.

The relevance of coagulation factor X protection of adenoviruses in human sera.

Intravenous delivery of adenoviruses is the optimal route for many gene therapy applications. Once in the blood, coagulation factor X (FX) binds to the adenovirus capsid and protects the virion from natural antibody and classical complement-mediated neutralisation in mice. However, to date, no studies have examined the relevance of this FX/viral immune protective mechanism in human samples. In this study, we assessed the effects of blocking FX on adenovirus type 5 (Ad5) activity in the presence of human serum. FX prevented human IgM binding directly to the virus. In individual human sera samples (n=25), approximately half of those screened inhibited adenovirus transduction only when the Ad5-FX interaction was blocked, demonstrating that FX protected the virus from neutralising components in a large proportion of human sera. In contrast, the remainder of sera tested had no inhibitory effects on Ad5 transduction and FX armament was not required for effective gene transfer. In human sera in which FX had a protective role, Ad5 induced lower levels of complement activation in the presence of FX. We therefore demonstrate for the first time the importance of Ad-FX protection in human samples and highlight subject variability and species-specific differences as key considerations for adenoviral gene therapy.

Comparison between Urine Protein: Creatinine Ratios of Samples Obtained from Dogs in Home and Hospital Settings.

BACKGROUND: The urine protein:creatinine ratio (UPC) is used to quantify urine protein excretion and guide recommendations for monitoring and treatment of proteinuria. HYPOTHESIS/OBJECTIVES: Home urine samples will have lower UPCs than hospital samples. The objectives were to compare UPCs of samples collected in each setting and to determine whether environment of sample collection might affect staging, monitoring or treatment recommendations. ANIMALS: Twenty-four client-owned dogs. METHODS: Prospective, nonmasked study. Clients collected a urine sample from their dog at home and a second sample was collected at the hospital. Dogs receiving corticosteroids or angiotensin-converting enzyme inhibitors were excluded, as were those with urine samples of inadequate volume, no protein on dipstick analysis, or active urine sediment. Samples were refrigerated after collection, dipstick and sediment evaluations were completed and each sample was frozen at -80°C within 12 hours. UPCs were performed on frozen samples within 2 months. RESULTS: From 81 paired samples, 57 were excluded. Of the remaining 24, 12/24 (50%) had higher hospital sample UPCs, 9/24 (38%) had identical UPCs, and 3/24 (12%) had lower hospital UPCs. The UPCs of hospital samples were higher than home samples for the total population (P = .005) and the subset with UPC > 0.5 (P = .001). CONCLUSIONS: Setting and related circumstances of urine collection in dogs is associated with UPC differences; results are usually higher in hospital than in home samples. This difference has the potential to affect clinical interpretation.

Targeting ADAM-17 with an inhibitory monoclonal antibody has antitumour effects in triple-negative breast cancer cells.

BACKGROUND: Identification and validation of a targeted therapy for triple-negative breast cancer (TNBC), that is, breast cancers negative for oestrogen receptors, progesterone receptors and HER2 amplification, is currently one of the most urgent problems in breast cancer treatment. EGFR is one of the best-validated driver genes for TNBC. EGFR is normally activated following the release of ligands such as TGFα, mediated by the two MMP-like proteases ADAM (a disintegrin and metalloproteinase)-10 and ADAM-17. The aim of this study was to investigate the antitumour effects of a monoclonal antibody against ADAM-17 on an in vitro model of TNBC. METHODS: We investigated an inhibitory cross-domain humanised monoclonal antibody targeting both the catalytic domain and the cysteine-rich domain of ADAM17-D1(A12) in the HCC1937 and HCC1143 cell lines. RESULTS: D1(A12) was found to significantly inhibit the release of TGFα, and to decrease downstream EGFR-dependent cell signalling. D1(A12) treatment reduced proliferation in two-dimensional clonogenic assays, as well as growth in three-dimensional culture. Furthermore, D1(A12) reduced invasion of HCC1937 cells and decreased migration of HCC1143 cells. Finally, D1(A12) enhanced cell death in HCC1143 cells. CONCLUSION: Our in vitro findings suggest that targeting ADAM-17 with D1(A12) may have anticancer activity in TNBC cells.

Plasticity, not genetic variation, drives infection success of a fungal parasite.

Hosts strongly influence parasite fitness. However, it is challenging to disentangle host effects on genetic vs plasticity-driven traits of parasites, since parasites can evolve quickly. It remains especially difficult to determine the causes and magnitude of parasite plasticity. In successive generations, parasites may respond plastically to better infect their current type of host, or hosts may produce generally 'good' or 'bad' quality parasites. Here, we characterized parasite plasticity by taking advantage of a system in which the parasite (the yeast Metschnikowia bicuspidata, which infects Daphnia) has no detectable heritable variation, preventing rapid evolution. In experimental infection assays, we found an effect of rearing host genotype on parasite infectivity, where host genotypes produced overall high or low quality parasite spores. Additionally, these plastically induced differences were gained or lost in just a single host generation. Together, these results demonstrate phenotypic plasticity in infectivity driven by the within-host rearing environment. Such plasticity is rarely investigated in parasites, but could shape epidemiologically important traits.

Thermo-electrical equivalents for simulating the electro-mechanical behavior of biological tissue.

Equivalence is one of most popular techniques to simulate the behavior of systems governed by the same type of differential equation. In this case, a thermo-electrical equivalence is considered as a method for modelling the inter-dependence of electrical and mechanical phenomena in biological tissue. We seek to assess this approach for multi-scale models (from micro-structure to tissue scale) of biological media, such as nerve cells and cardiac tissue, in which the electrical charge distribution is modelled as a heat distribution in an equivalent thermal system. This procedure allows for the reduction in problem complexity and it facilitates the coupling of electrical and mechanical phenomena in an efficient and practical way. Although the findings of this analysis are mainly addressed towards the electro-mechanics of tissue within the biomedical domain, the same approach could be used in other studies in which a coupled finite element analysis is required.

Dosimetric factors associated with weight loss during (chemo)radiotherapy treatment for lung cancer.

BACKGROUND/OBJECTIVES: Thoracic radiotherapy (RT) is associated with acute toxicities, including oesophagitis, which can have an impact on nutritional intake and subsequently lead to malnutrition. This study aimed to identify RT dosimetric factors associated with ⩾5% weight loss in patients receiving treatment for non-small-cell lung cancer (NSCLC). METHODS: Radiation dose data to the oesophagus (including mean, maximum dose and oesophageal length) were retrospectively analysed for a cohort of 54 NSCLC patients treated with concurrent chemoradiotherapy between 2004 and 2006. Weight change was calculated using the lowest weight during the 90 days from RT commencement compared with the start of RT. RESULTS: Four patients for whom weight was not available at the start or end of treatment were excluded, leaving 50 patients for analysis. The prevalence of significant weight loss during the 90 days from RT commencement was 22% (median weight loss=9.1%, range=5.9-22.1). Dosimetric factors significantly associated with ⩾5% weight loss were maximum dose to the oesophagus (P=0.046), absolute oesophageal length receiving 40 Gy (odds ratio (OR)=1.18, P=0.04), 50 Gy (OR=1.20, P=0.02) and 60 Gy (OR=1.32, P=0.005) to the partial circumference, relative oesophageal length receiving 50 Gy (OR=1.03, P=0.03) and 60 Gy (OR=1.07, P=0.005) to the partial circumference. CONCLUSIONS: Multiple dosimetric factors were associated with significant weight loss. Of these factors, absolute and relative length of the oesophagus receiving 60 Gy to the partial circumference were more strongly related. Understanding the dosimetric factors associated with weight loss may aid early identification and intervention in patients at nutritional risk.

Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.

Biomarkers currently play an important role in the detection and management of patients with several different types of gastrointestinal cancer, especially colorectal, gastric, gastro-oesophageal junction (GOJ) adenocarcinomas and gastrointestinal stromal tumors (GISTs). The aim of this article is to provide updated and evidence-based guidelines for the use of biomarkers in the different gastrointestinal malignancies. Recommended biomarkers for colorectal cancer include an immunochemical-based fecal occult blood test in screening asymptomatic subjects ≥50 years of age for neoplasia, serial CEA levels in postoperative surveillance of stage II and III patients who may be candidates for surgical resection or systemic therapy in the event of distant metastasis occurring, K-RAS mutation status for identifying patients with advanced disease likely to benefit from anti-EGFR therapeutic antibodies and microsatellite instability testing as a first-line screen for subjects with Lynch syndrome. In advanced gastric or GOJ cancers, measurement of HER2 is recommended in selecting patients for treatment with trastuzumab. For patients with suspected GIST, determination of KIT protein should be used as a diagnostic aid, while KIT mutational analysis may be used for treatment planning in patients with diagnosed GISTs.