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Background Recurrent miscarriage is defined as three recurrent first trimester pregnancy losses. The Tender Loving Care Clinic is a specialist clinic for women during the first trimester of a pregnancy following recurrent miscarriages. This study's aim was to review cases of those who attended the tender loving care clinic for antenatal care. Methods A retrospective chart review was conducted using anonymous data, collected from the electronic records of women who attended the clinic over a 1-year period. Results A total of 103 women attended the clinic during the study period. The majority (90.3%) were prescribed medication while attending. Pregnancy outcomes for women attending the clinic were good; 69.2% of women went on to have a live birth. Conclusions Pregnancy outcomes following recurrent miscarriages are reassuring with supportive antenatal care. This review highlights the importance of psychological care and reassurance in a pregnancy following recurrent miscarriages.

Scant research has explored the healthcare experiences of people with Down syndrome (DS) in the United States who are Black, African American, of African descent, or of mixed race. The purpose of this study was to identify and describe the barriers and facilitators that such patients and their caregivers face when accessing healthcare. We gathered data in three ways: focus groups with caregivers, a national survey completed by caregivers, and in-depth interviews with primary care providers. Many caregivers and primary care physicians felt that patients with DS who are Black, African American, of African descent, or of mixed race receive a lower quality of medical care than their white counterparts with DS. Caregivers mentioned feeling tired of being reminded by the medical community about their race and wanting acknowledgment that raising a child with DS can be hard at times. Many felt that the medical community's conscious and unconscious racial biases do negatively impact the care of their loved ones with DS. Caregivers desired more race concordant medical providers or, when not possible, medical providers who are willing to learn more about DS and build trusted, longitudinal relationships. Primary care providers discussed the need for funded resources and support services to effectively care for their patients with DS.

Background The obesity paradox is a well-documented phenomenon in cardiovascular disease, however it remains poorly understood. We aimed to investigate the relationship between body mass (as measured by body mass index [BMI]) and 1-year amputation-free survival (AFS) for patients undergoing lower limb revascularisation for chronic limb-threatening ischaemia (CLTI). Methods A retrospective analysis was undertaken of all consecutive patients undergoing lower limb revascularisation for CLTI at the Leicester Vascular Institute between February 2018–19. Baseline demographics and outcomes were collected using electronic records. BMI was stratified using the World Health Organization criteria. One-year AFS (composite of major amputation/death) was the primary outcome. Kaplan-Meier survival analysis and adjusted Cox's proportional hazard models were used to compare groups to patients of normal mass. Results One-hundred and ninety patients were included. Overall, no difference was identified in 1-year AFS across all groups (pooled P = 0.335). Compared to patients with normal BMI (n = 66), obese patients (n = 43) had a significantly lower adjusted combined risk of amputation/death (aHR 0.39, 95% CI 0.16–0.92, P = 0.032), however no significant differences were observed for overweight (aHR 0.89, 95% CI 0.47–1.70, P = 0.741), morbidly obese (aHR 1.15, 95% CI 0.41–3.20, P = 0.797) and underweight individuals (aHR 1.86, 95% CI 0.56–6.20, P = 0.314). Conclusions In the context of CLTI, obesity is potentially associated with favourable amputation-free survival at 1 year, compared to normal body mass. The results of this study support the notion of an obesity paradox existing within CLTI and question whether current guidance on weight management requires a more patient-specific approach.

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

Second-trimester loss is pregnancy loss after the 12th and before the 24th completed weeks of pregnancy. This study aims to review cases of second-trimester miscarriage who attended a large maternity hospital and to examine pregnancy outcomes in this group of women.This study is a review of cases of second-trimester miscarriage using descriptive, exploratory design, involving a retrospective chart review.In this study, 106 cases of second-trimester miscarriage were reviewed. The cause of the miscarriage was found in 42.5% (n = 45) of cases. The majority of women, 84.5% (n = 82) had a normal pelvic ultrasound scan and 18.3% (n = 17) of cases were diagnosed with antiphospholipid syndrome. In women who became pregnant again, 60.9% (n = 39) had a live birth.Establishing the cause of second-trimester miscarriage can be challenging, despite completing all recommended investigations. Outcomes in subsequent pregnancies are reassuring. This review highlights the need to undertake all recommended investigations to elicit the cause of second-trimester miscarriage and underpins the need for further research in this area.

Background Due to the coronavirus infection, visitors to all hospitals were greatly restricted in the UK. In maternity hospitals, only partners of women in labour were permitted to attend the hospital. Aims This study aimed to gain an understanding of women's experiences of visiting restrictions imposed due to COVID-19. Methods Women who attended the hospital for outpatient appointments and who were inpatients on the antenatal or postnatal ward during a two-week period were asked to complete an anonymous survey. Findings A total of 422 surveys were completed. The majority of women (97.6%) agreed that the hospital made adequate preparations for them to feel safe. Most women reported that the restrictions are a good thing and several advantages were identified. Women cited not having their partner with them as the main negative consequence to the restrictions. Conclusions Although women miss having their partner for support during scans and to help after the baby is born, during the COVID-19 pandemic, the safety aspect of the restrictions and the support received from staff is considered by women when making recommendations to a maternity hospital about whether, or how, to ease restrictions on visiting.

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.

BACKGROUND Anemia is potentially associated with increased morbidity and mortality following vascular surgery procedures. This study investigated whether peri-procedural anemia is associated with reduced 1-year amputation-free survival (AFS) in patients undergoing revascularization for chronic limb-threatening ischemia (CLTI). METHODOLOGY A retrospective analysis of patients diagnosed with CLTI between February 2018-February 2019, who subsequently underwent revascularization, was conducted. Hemoglobin concentration measured at index assessment was recorded and stratified by WHO criteria. Subsequent peri-procedural red blood cell transfusions (RBC) were also recorded. The primary outcome was 1-year AFS. Kaplan Meier survival analysis and Cox's proportional hazard modelling were conducted to assess the effect of anemia and peri-procedure transfusion on outcomes. RESULTS 283 patients were analyzed, of which 148 (52.3%) were anemic. 53 patients (18.7%) underwent RBC transfusion. Patients with anemia had a significantly lower 1-year AFS (64.2% vs. 78.5%, P = 0.009). A significant difference in 1-year AFS was also observed based upon anemia severity (P = 0.008) and for patients who received RBC transfusion (45.3% vs 77.0%, P < 0.001). On multivariable analysis, moderately severe anemia was independently associated with increased risk of major amputation/death (aHR 1.90, 95% CI 1.06-3.38, P = 0.030). After adjusting for severity of baseline anemia, peri-procedural RBC transfusion was associated with a significant increase in the combined risk of major amputation/death (aHR 3.15, 95% CI 1.91-5.20, P < 0.001). CONCLUSION Moderately severe peri-procedural anemia and subsequent RBC transfusion are independently associated with reduced 1-year AFS in patients undergoing revascularization for CLTI. Future work should focus on investigating alternative measures to managing anemia in this cohort.

An amendment to the 1962 Coroner’s Act in the Republic of Ireland mandated that all stillbirths and neonatal deaths were to be reported to the local coroner’s office. In response to this, the bereavement team and department of anatomic pathology modified the pathway for placental examination following stillbirth and reporting deaths to the coroner. This paper is a review of the effect of this practice. This study is a review of all cases of stillbirths for 9 months following the amendment of the Coroner’s Act. A descriptive, exploratory design was used involving a retrospective chart review. Twenty-nine cases of stillbirth occurred during the study period. In cases where a placental examination was performed (n = 22), a cause of death was identified in the placenta or cord for seventeen (68%) of these cases. Seven cases had a consented autopsy with six cases confirming the initial diagnosis made at the time of gross placental examination. In one case, the cause of the stillbirth remained unexplained following placental examination and a full autopsy. No new information was gained from the autopsy in these seven cases. A further two cases had an autopsy directed by the coroner; the cause of death in these cases will be decided by the coroner. The introduction of the pathway has improved the care provided to bereaved parents by providing parents with timely information about the potential cause of stillbirth and thereby reduces the need for an autopsy examination.

Background Working in maternity hospital is usually a rewarding experience for staff. However, it can also be stressful and emotionally difficult work. Schwartz Rounds are a multidisciplinary forum which provides staff with an opportunity to reflect on the emotional impact of their work and support each other. Aims This paper will discuss the implementation of Schwartz Rounds in a maternity hospital and gives details of a pilot study to evaluate the initiative. Methods Schwartz Rounds were commenced in the hospital in September 2019, and an evaluation is in progress. A pilot study which evaluated 2 rounds has been completed. Staff who attended Schwartz Rounds were asked to complete an anonymous feedback form immediately following the Round. The data from feedback forms were analysed using descriptive statistics. Results Seventy-eight members of staff from almost all departments attended the rounds. Feedback forms were completed by 55 members of staff. Overall, the rounds were very positively evaluated by those who participated in the study. Conclusions Schwartz Rounds are an effective way to support staff working in a maternity hospital.

Background Clinical training should be efficient, intellectually rigorous, and integrated into practice. This interactive workshop was developed to support student midwives in bereavement care. Aims To improve student midwives' confidence in providing bereavement care to parents after pregnancy loss and perinatal death. Methods Two focus groups were held, where students' (n=12) discussed their experiences of attending the workshop, barriers and facilitators to gaining confidence, and any further education needs. Findings All students agreed that the workshop increased their confidence, and said that role-plays were the most beneficial aspect of the day. Lack of exposure and support from mentors and senior staff was seen as the largest barrier to gaining further confidence. Conclusions The results suggest that all students could benefit from a workshop to increase confidence in bereavement care. The content of this workshop can be used in other maternity settings in Ireland and is recommended for all staff members caring for parents after perinatal bereavement or pregnancy loss.

Background Second trimester miscarriage is defined as pregnancy loss after 12 weeks and before 24 weeks gestation. The care that parents receive has been shown to greatly influence the woman's recovery after pregnancy. Aims To explore parents' experiences of hospital care during a second trimester miscarriage, from the time of diagnosis through to follow-up care. Methods A focused ethnographic design to conduct semi-structured interviews with 14 bereaved parents before thematic data analysis. Findings Parents highlighted the need for effective medical care in relation to medical treatment, pain relief and length of hospital stay, going home to prepare for the delivery and follow-up care. Parents emphasised the importance of appropriate facilities and being separate from other parents and babies. Clear communication and finding a cause for their miscarriage was also important for parents. Conclusion Second trimester miscarriage is a significant life event for parents. Effective, individualised clinical care is needed to meet the medical needs of bereaved parents.

Background Second-trimester miscarriage is defined as pregnancy loss after 12 and before 24 weeks' gestation. Little is known about parents' experiences of hospital care during a second trimester miscarriage in Ireland. Aims This study aimed to explore parents' experiences of hospital care during a second-trimester miscarriage. Methods A focused ethnographic design was used. A series of semi-structured interviews were completed with 14 bereaved parents. The data were analysed using thematic network data analysis. Findings This paper discusses the global theme of relational and social experiences of miscarriage. Parents highlighted the need for compassionate care and expressed the importance of empathy and sensitivity from hospital staff to avoid further distress. Conclusions Compassionate care received by bereaved parents positively influenced their hospital experience, whereas a perceived lack of compassion or insensitivity had a lasting negative impact on bereaved parents.

Perinatal autopsy is one the most valuable investigations to ascertain the cause of death (Nijkamp et al., Seminars in Fetal & Neonatal Medicine. 22:167-175, 2017; Korteweg et al., AJOG 53, e1-12, 2012; Late Interuterine Death and Stillbirth’ RCOG Green-top Guideline No.55, 2015). Discussions about perinatal autopsy can be difficult for parents and healthcare professionals. Perinatal staff need a good level of knowledge and understanding regarding perinatal autopsy in order to discuss the procedure with parents. This study aims to investigate healthcare professionals’ knowledge regarding perinatal autopsy. An audit conducted in a large teaching hospital using a questionnaire was developed and distributed to healthcare professionals in the hospital. Seventy healthcare professionals participated in the audit. Of those surveyed, 64% (n = 45) have discussed perinatal autopsy with a mother and the majority of healthcare professionals (67%) found this difficult. Self-reported levels of understanding were found to be low with just 10% reporting ‘excellent understanding’. The results of this audit highlight the need for further education among all healthcare professionals working with bereaved families.

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

To improve the confidence in student Midwives to provide bereavement careto parents following pregnancy loss and perinatal death.The one-day interactive Educational Training Workshop in Bereavement Care (ETWBC) was developed for student midwives in their final year of their B.Sc. Midwifery Degree Programme and those completing a Higher Diploma in Midwifery to help improve their confidence to provide bereavement care in clinical practice.A longitudinal sequential mixed-methods design was used to evaluate the outcome and processes of participation in the Workshop. This paper reports on the outcome evaluation.Participants completed the study questionnaires at all 3 time points: pre/post workshop and 3 month follow-up. Thirty nine of the 41 student midwives (Higher Diploma and 4th year B.Sc.) participated in the workshop. 97.44% (n = 38) of the participants completed all the questionnaires.Participation in the ETWBC increased student's midwives confidence (measured using knowledge and skills scales); Bereavement support skills [F(2,72) = 21.150, p .000, partial eta squared = 0.370] and Bereavement support knowledge [F(1.6,60) = 48.460, p .000, partial eta squared = 0.567]to provide bereavement care. Improvement in Student Midwives' level of self-awareness of the needs of bereaved parents [F(2,72 )= 20.311, p .000, partial eta squared = 0.361] and of their own personal needs [F (1.7, 61) = 30.387, p .000, partial eta squared = 0.458] in relation to providing bereavement support were also found.Participation in the Education Training Workshop on Bereavement Care helped increase student midwives confidence to provide bereavement care to grieving parents and to increase their self-awareness around their clinical practice in this area. The ETWBC is recommended as a brief effective educational intervention for inclusion in Midwifery curricula which could be modified for use with other relevant professional groups.

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.

Examining surveillance and “sousveillance” (or under-veillance) strategies employed throughout Frederick Douglass’s slavery narratives, this chapter illustrates how Douglass brings about an ironic reversal of control on the part of the slave. Arguing that white surveillance depends upon the threat and realisation of violence, it illustrates how Douglass’ narratives use counter-strategies known as dark sousveillance to undermine the slaveholder’s control. It also considers how the opportunistic nature of white surveillance used the policing of the black population as an excuse to extend its scope and powers, which may have sowed the seeds for contemporary acts of domestic and international surveillance in America. The chapter concludes by examining modern white surveillance and dark sousveillance, highlighting how recent events in Charlottesville, Virginia, demonstrate a continuing conflict between the two.

Background Short bouts of exercise can reduce cravings, attentional bias (AB) and substance use among abstaining smokers and snackers. Only one study has shown reduced alcohol cravings following exercise but none have investigated the effects on attentional bias. The aim of the present study was to examine whether a single session of exercise reduces AB towards alcohol-related images and alcohol urges among high alcohol consumers. Methods The study involved 20 abstaining (for ≥3 days) alcohol drinkers, consuming more than weekly recommendations, with a mean age (SD) = 20.8 (0.8) years. Participants were initially randomised in a counterbalanced cross-over design to undertake either (1) 15 min of brisk walking or (2) 15 min of passive seating on different days. Participants completed an adapted dot probe task, with matched neutral and alcohol images randomly presented for either 200 ms or 1000 ms to respectively measure initial (IAB) or maintained attentional bias (MAB) pre- and post-treatment. The Alcohol Urge Questionnaire (AUQ) was administered before, immediately after, and 5 and 10 min post treatment. Results A two-way fully repeated measures ANOVA revealed a significant condition × time interaction for MAB F (1, 17) = 6.96, p = 0.017, and AUQ scores F (1.47, 27.96) = 60.19, p Conclusions A short bout of exercise, compared with a passive control condition, may acutely reduce MAB to alcohol cues and alcohol urges, and thus may help with self-regulation of alcohol consumption.

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

Background The neural correlates of anxiety associated with obsessive-compulsive symptomlike provocation in normal volunteers are unknown. Methods Ten healthy volunteers participated in four functional magnetic resonance experiments. Subjects were scanned while viewing alternating blocks of emotional (normally aversive, washing-relevant, checking-relevant, or hoarding-relevant pictures) and neutral pictures, and imagining scenarios related to the content of each picture type. Nonparametric brain mapping analyses were used. Results In response to the provocative pictures in all experiments, increases in subjective anxiety and activation in bilateral ventral prefrontal, limbic, dorsal prefrontal, and visual regions were demonstrated. Anxiety related to different symptom dimensions was associated with different patterns of activation: provocation of washing-relevant anxiety predominantly activated dorsal and ventral prefrontal regions; checking-relevant anxiety predominantly activated dorsal prefrontal regions; and hoarding-relevant anxiety predominantly activated ventral prefrontal regions and the left amygdala. Conclusions Our findings support a dimensional model of obsessive-compulsive disorder (OCD) whereby 1) the brain systems implicated in the mediation of anxiety in response to symptom-related material in normal subjects are similar to those identified in OCD patients during symptom provocation, and 2) anxiety associated with different symptom dimensions is associated with differential patterns of activation of these neural systems. Further investigation of the neural basis of OCD symptom dimensions is required.

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.

Chronic fatigue syndrome (CFS) is a disorder of uncertain aetiology which attracts increasing research interest. This paper describes the development of a multidimensional measure incorporating the diverse symptoms associated with the illness. The Profile of Fatigue-Related Symptoms (PFRS) has four scales: emotional distress, cognitive difficulty, fatigue and somatic symptoms. These showed good convergence with comparison measures, high reliability and high internal consistency. CFS patients had markedly elevated scores compared with a student comparison group, and these scores correlated with indices of illness severity. The PFRS is a short and easily administered measure which, it is suggested, may be used to assess patients in terms of the severity and pattern of their disorder, to relate subjective symptoms to immunological and other findings, to evaluate the effects of treatments, and to compare the symptomatology of CFS with that in other fatiguing illnesses.

Background Thrombospondin-1 (TSP-1) induces vascular smooth muscle cell (VSMC) migration after arterial injury. TSP-1 up-regulates hyaluronic acid (HyA)-inducing genes in VSMCs. HyA also induces VSMC migration. Our hypothesis was that TSP-1–induced VSMC migration is dependent on the CD44 receptor, and that HyA and TSP-1 share migratory signaling pathways. Methods VSMC migration was assessed using TSP-1, HyA, or serum-free medium as chemoattractants. VSMCs were treated with inhibitors to CD44, Ras, phosphatidylinositol-3 kinase, Raf-1 kinase, or c-SRC. TSP-1– and HyA-induced epidermal growth factor receptor (EGFR) activity was determined by enzyme-linked immunosorbent assay. Comparisons were made by the Student t test and a P value less than .05 was considered significant. Results Inhibiting CD44 reduced TSP-1– and HyA-induced migration. Phosphatidylinositol-3 kinase and c-SRC inhibitors prevented TSP-1– and HyA-induced migration, whereas Ras and Raf-1 kinase inhibitors only affected TSP-1. TSP-1 and HyA activate the EGFR. Conclusions TSP-1– and HYA-induced migration share some of the same signaling pathways and the EGFR/CD44 receptors may be a common link.

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

Mid-trimester loss (MTL) is an area that is poorly defined in the literature and often under reported in clinical practice. The prevalence of MTL in Ireland is uncertain and has a huge impact on the woman, her family and maternity care services. To explore the prevalence and patterns of care for women with MTL in a large Maternity hospital in Ireland. A descriptive, exploratory study was used involving a retrospective chart audit. 220 women presented with MTL over the 3 year data collection period (January 2011–December 2013), giving a rate of 0.8 % of all deliveries. The majority of women had no previous pregnancy losses and were multiparous (i.e., had a previous pregnancy >500 g). The mean gestational age was 17.69 weeks (SD = 2.73). The mean length of hospital stay was 1.89 days. Intra muscular (IM) analgesia was the most commonly (58.5 %) used medication. Follow up hospital care was received in over 78 % of cases. The majority of women were referred the CMS Bereavement and Chaplain services, with a small number (approx. 5 %) referred to the social worker. Over 46.4 % of families availed of the hospital burial service. Results suggest the incidence of mid-trimester loss may be slightly lower than the 1 or 2 % of pregnancies reported in the literature. The incidence of mid-trimester loss in multiparous women is approximately twice that of nulliparous women. The referral services offered in the study were utilised by most of the women, as were follow-up clinic appointments.