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Background: Many staff supports, such as the internationally accredited Schwartz Center Rounds were suspended worldwide during the Covid-19 restrictions, at a time when they were most needed. Schwartz Rounds are multi-disciplinary forums where staff can discuss the emotional, social and ethical challenges of care in a confidential and safe environment, intending to improve staff well-being and patient care. In a bid to improve staff support after the suspension of full Schwartz Rounds, virtual, then blended (limited spaces for socially distanced in-person attendance and virtual access) Rounds were initiated.Purpose: This study aimed to evaluate Schwartz Rounds in a maternity setting in Ireland and compare full-in person Rounds with virtual and blended Rounds.Methods: Standard Schwartz Rounds evaluation forms were completed by Rounds attendees. Data were analysed using SPSS (Version 24). Respondents were invited to include a comment at the end of the form, and these free-text comments were analysed thematically.Results: Six Rounds were evaluated (2 full in-person Rounds attended before the pandemic, 1 virtual, 3 blended) and a total of 115 evaluation forms were completed. The Rounds were rated extremely high. Some, but not all aspects of the Rounds were rated more positively from the full in-person Rounds. Some technical difficulties were a barrier to fully experiencing the Round when attending remotely.Conclusion: Schwartz Rounds are attended by staff in over 560 healthcare organisations, internationally and have been reported to improve staff well-being and teamwork. The pandemic saw Schwartz Rounds being suspended in most organisations due to social distancing guidelines. Virtual and blended Rounds are recommended as an effective replacement for full Schwartz Rounds while social distancing and infection control measures are in place. However, in order to improve post-panellist discussion and gain the full Schwartz Round experience, recommencement of full, in-person Rounds are recommended as soon as public health measures allow

We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We also sought to determine if primary care providers (PCPs) and caregivers are satisfied with this personalized online health tool. In a national, randomized controlled trial of 230 caregivers who had children or dependents with DS without access to a DS specialist, 117 were randomized to receive DSC2U and 113 to receive usual care. The primary outcome was adherence to five health evaluations indicated by national guidelines for DS. DSC2U is completed electronically, in all mobile settings, by caregivers at home. The outputs—personalized checklists—are used during annual wellness visits with the patient’s PCP. A total of 213 participants completed a 7-month follow-up evaluation. In the intention-to-treat analysis, the intervention group had a 1.6-fold increase in the number of indicated evaluations that were recommended by the primary care provider or completed compared with controls. Both caregivers and PCPs reported high levels of satisfaction with DSC2U. DSC2U improved adherence to the national DS health-care guidelines with a novel modality that was highly valued by both caregivers and PCPs.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background and Issues: Eliminating treatment delays for acute ischemic stroke patients to meet the national door to needle (DTN) Target Stroke Phase II goals continues to present a challenge for many facilities. Although the Stroke Alert process is usually guided by strict protocols it can still suffer delays from a lack of communication and facilitation to ensure rapid patient assessment and treatment. Purpose: The purpose of this project was to eliminate Stroke Alert delays related to communication and lack of facilitation by implementing a Stroke Nurse Facilitator (SNF) and allow intravenous tissue plasminogen activator (tPA) to be successfully started in the CT room. Methods: An interdisciplinary team conducted a Pareto analysis on DTN delays and found communication to be the most common. Communication was also felt to be the biggest barrier to starting tPA in the CT room. The role of a SNF was created and mapped into the Stroke Alert process to overcome these barriers. The role launched in November 2016. Six months later, after the role became an integral part in the Stroke Alert process, the team moved forward with administering tPA in the CT room as part of the process. Results: DTN was measured in 61 emergency department stroke patients, 34 in the pre-intervention, 12 in the SNF only, and 15 in the SNF and tPA in CT groups. Data were analyzed using the non-parametric Mann Whitney U test. Although not statistically significant due to the small sample size, there was a large improvement in DTN from pre (n=34) to the first intervention group [Z= 11.19, p=.06, d =.84]. The improvement from DTN from pre to the second intervention group was very large and statistically significant [Z= 24.00, p Conclusions: Successful communication and facilitation is crucial to achieve positive outcomes or process improvements. Implementing a SNF to overcome these barriers could prove to be a successful strategy to improving DTN times for acute stroke patients.

Treatment of EGFR-mutant lung cancer with erlotinib results in dramatic tumor regression but it is invariably followed by drug resistance. In characterizing early transcriptional changes following drug treatment of mutant EGFR-addicted cells, we identified the stem cell transcriptional regulator SOX2 as being rapidly and specifically induced, both in vitro and in vivo. Suppression of SOX2 sensitizes cells to erlotinib-mediated apoptosis, ultimately decreasing the emergence of acquired resistance, whereas its ectopic expression reduces drug-induced cell death. We show that erlotinib relieves EGFR-dependent suppression of FOXO6, leading to its induction of SOX2, which in turn represses the pro-apoptotic BH3-only genes BIM and BMF. Together, these observations point to a physiological feedback mechanism that attenuates oncogene addiction-mediated cell death associated with the withdrawal of growth factor signaling and may therefore contribute to the development of resistance. DOI: http://dx.doi.org/10.7554/eLife.06132.001, eLife digest Tumors can form when cells gain mutations in genes that enable them to grow and divide rapidly. In some human lung cancers, genetic mutations are found in a gene that makes a protein called EGFR. This protein encourages cells to divide and the mutations can lead to the cancer cells producing more EGFR, or producing a form of the protein that is more active. Treating these cancers with a drug called erlotinib inhibits EGFR and makes the tumors shrink dramatically, but the tumors will usually re-grow because any tumor cells that survive often become resistant to the drug. There are several ways that the tumor cells can become resistant, which makes the task of developing a solution to this problem more difficult. It has been suggested that the tumor cells may enter a temporary ‘drug-tolerant’ state that helps them to survive and makes it more likely that they will develop resistance to the drug. However, it is not clear how this drug-tolerant state might work. To address this question, Rothenberg et al. examined which genes are switched on (or ‘expressed’) in tumor cells with a mutant version of EGFR after they were treated with the erlotinib drug. The experiments show that a gene called SOX2 is expressed in these cells. Cells that had lower levels of SOX2 expression were more sensitive to the effects of the drug and fewer cells developed resistance. On the other hand, cells that had higher levels of SOX2 expression were less sensitive to the drug and resistance was more likely to develop. A protein called FOXO6—which is usually suppressed by EGFR—activates the SOX2 gene in these cells. Therefore, using erlotinib to inhibit EGFR to kill the cancer cells increases the activity of FOXO6, which in turn promotes the survival of some of the cells by activating the SOX2 gene. A better understanding of the ways in which cancer cells adapt to erlotinib and other drugs may help us to design more effective treatments with better outcomes for patients. DOI: http://dx.doi.org/10.7554/eLife.06132.002

Sensory experience is influenced by emotional context. Although perception of emotion and unpleasant visceral sensation are associated with activation within the insula and dorsal and ventral anterior cingulate gyri (ACG), regions important for attention to and perception of sensory and emotional information, the neural mechanisms underlying the effect of emotional context upon visceral sensation remain unexplored. Using functional MRI, we examined neural responses to phasic, non-painful oesophageal sensation (OS) in eight healthy subjects (seven male; age range 27-36 years) either during neutral or negative emotional contexts produced, respectively, by presentation of neutral or fearful facial expressions. Activation within right insular and bilateral dorsal ACG was significantly greater (P < 0.01) during OS with fearful than with neutral faces. In a second experiment, we measured anxiety, discomfort and neural responses in eight healthy male subjects (age range 22-41 years) to phasic, non-painful OS during presentation of faces depicting either low, moderate or high intensities of fear. Significantly greater (P < 0.01) discomfort, anxiety and activation predominantly within the left dorsal ACG and bilateral anterior insulae occurred with high-intensity compared with low-intensity expressions. Clusters of voxels were also detected in this region, which exhibited a positive correlation between subjective behaviour and blood oxygenation level-dependent effect (P < 0.05). We report the first evidence for a modulation of neural responses, and perceived discomfort during, non-painful visceral stimulation by the intensity of the negative emotional context in which the stimulation occurs, and suggest a mechanism for the effect of negative context on symptoms in functional pain disorders.

Tumor progression depends on the support of cells in the microenvironment, and is driven in part by the generation of reactive oxygen species (ROS). ROS can damage DNA, and the repair of damaged DNA is a well-known process involved in tumor initiation and promotion, but the role of DNA repair in tumor progression is not fully understood. In this regard the X-ray cross complementing 1 (XRCC1) protein is known to orchestrate the assembly of repair complexes at sites of DNA single strand breaks either directly or indirectly through repair of damaged bases, largely as the result of ROS-induced damage. XRCC1 polymorphisms have been shown to be associated with increased cancer. It was therefore of interest to investigate the effect of XRCC1 gene mutations on cancer progression. In an attempt to make XRCC1 point mutant mice, we generated a truncated protein (XRCC1tp) by the insertion of a neomycin cassette in intron12 of the XRCC1 gene. This unique finding allowed us to investigate cellular and tumor progression phenotypes in mice associated with expression and function of an altered XRCC1 protein on one allele. XRCC1tp cells showed increased toxicity to MMS, enhanced MMS-induced depletion of NADH suggesting increased PARP activity, and normal functional repair of MMS-induced DNA damage. Six months following treatment with the alkylating carcinogen azoxymethane (AOM) at 10 mg/kg once a week for 6 weeks, XRCC1tp mice had a decrease in average colon tumor volume of 14±3 mm(3) compared to 34±4 mm(3) in WT littermates (p ≤ 0.03, N= 20/genotype). XRCC1tp mice had a 72 per cent decrease in B16 melanoma tumor burden compared to wt littermates. Average tumor volume in transgenic PyMT metastatic breast cancer mice expressing XRCC1tp was 359 cubic mm in PyMT mice expressing XRCC1tp compared to 730 cubic mm in PyMT mice expressing XRCC1wt (p ≤ 0.001, N= 20/genotype). These data suggest that the presence of an XRCC1 truncated protein alters XRCC1 function independent of DNA repair, and is associated with anti-tumor activity.

Treatment of EGFR-mutant lung cancer with erlotinib results in dramatic tumor regression but it is invariably followed by drug resistance. In characterizing early transcriptional changes following drug treatment of mutant EGFR-addicted cells, we identified the stem cell transcriptional regulator SOX2 as being rapidly and specifically induced, both in vitro and in vivo. Suppression of SOX2 sensitizes cells to erlotinib-mediated apoptosis, whereas its ectopic expression reduces drug-induced cell death. We show that erlotinib relieves EGFR-dependent suppression of FOXO6, leading to SOX2 induction and repression of the pro-apoptotic BH3-only genes BIM and BMF. Together, these observations point to a physiological feedback mechanism that attenuates oncogene addiction-mediated cell death and may contribute to the acquisition of drug resistance. Citation Format: Stephen Michael Rothenberg, Kyle Concannon, Sarah Cullen, Alexa B. Turke, Anthony C. Faber, Jeffrey A. Engelman, Shyamala Maheswaran, Daniel A. Haber. Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6 dependent survival pathways. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4773. doi:10.1158/1538-7445.AM2014-4773