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Infections with Sudan virus (SUDV), a member of the genus Ebolavirus , result in a severe hemorrhagic fever with a fatal outcome in over 50% of human cases. The paucity of prophylactics and therapeutics against SUDV is attributed to the lack of a small-animal model to screen promising compounds. By repeatedly passaging SUDV within the livers and spleens of guinea pigs in vivo , a guinea pig-adapted SUDV variant (SUDV-GA) uniformly lethal to these animals, with a 50% lethal dose (LD 50 ) of 5.3 × 10 −2 50% tissue culture infective doses (TCID 50 ), was developed. Animals infected with SUDV-GA developed high viremia and died between 9 and 14 days postinfection. Several hallmarks of SUDV infection, including lymphadenopathy, increased liver enzyme activities, and coagulation abnormalities, were observed. Virological analyses and gross pathology, histopathology, and immunohistochemistry findings indicate that SUDV-GA replicates in the livers and spleens of infected animals similarly to SUDV infections in nonhuman primates. These developments will accelerate the development of specific medical countermeasures in preparation for a future disease outbreak due to SUDV. IMPORTANCE A disease outbreak due to Ebola virus (EBOV), suspected to have emerged during December 2013 in Guinea, with over 11,000 dead and 28,000 infected, is finally winding down. Experimental EBOV vaccines and treatments were administered to patients under compassionate circumstances with promising results, and availability of an approved countermeasure appears to be close. However, the same range of experimental candidates against a potential disease outbreak caused by other members of the genus Ebolavirus , such as Sudan virus (SUDV), is not readily available. One bottleneck contributing to this situation is the lack of a small-animal model to screen promising drugs in an efficient and economical manner. To address this, we have generated a SUDV variant (SUDV-GA) that is uniformly lethal to guinea pigs. Animals infected with SUDV-GA develop disease similar to that of SUDV-infected humans and monkeys. We believe that this model will significantly accelerate the development of life-saving measures against SUDV infections.

TPS274 Background: Although 5-FU-based regimens such as FOLFOX and FOLFIRI remain the cornerstone of treatment for patients (pts) with colorectal cancer (CRC), their clinical utility is limited by resistance mechanisms and toxicity. Anti-cancer activity of 5-FU is dependent on conversion to an active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), which binds to and inhibits thymidylate synthase (TS), a critical enzyme in de novo nucleotide synthesis and cell survival. However, due to multiple limitations including: reliance on enzymatic activation; catabolism by dihydropyrimidine dehydrogenase (DPD) and a short plasma half-life, 5-FU is not efficiently converted to FUDR-MP. NUC-3373, a phosphoramidate transformation of FUDR-MP, was designed to bypass the key resistance mechanisms that limit the clinical utility of 5-FU. NUC-3373 demonstrated a favorable PK/PD profile and promising efficacy signals in the first-in-human study (NuTide:301) in pts with advanced solid tumors. NUC-3373 has a longer plasma t1/2 (9.7 hours) than 5-FU (8-14 minutes) and generates high intracellular levels of FUDR-MP (Ghazaly et al ESMO, 2017). TS is efficiently inhibited and sequestered into TS-ternary complexes, depleting the pool of deoxythymidine monophosphate (dTMP) within 2-4 hours. Methods: NuTide:302 is a three-part, Phase Ib study in pts with advanced CRC who have relapsed after ≥2 prior lines of 5-FU-containing therapies. Primary objective is to identify a RP2D of NUC-3373 when administered weekly and q2w in combination with standard agents used in CRC treatment. Secondary objectives include safety, PK/PD and anti‐tumor activity. In Part 1, patients are receiving NUC-3373 with leucovorin (LV) to determine if LV augments TS inhibition. In Part 2, NUC-3373 (±LV) will be administered in dose escalating cohorts, in a modified 3+3 design, with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). In Part 3, the NUFOX and NUFIRI regimens selected in Part 2 will be combined with biologics targeting VEGF or EGFR pathways. To date, 22 pts have received study treatment. Recruitment is ongoing in the US and Europe. Clinical trial information: NCT03428958.

709 Background: Olaparib is a potent inhibitor of PARP-1, which has a critical role in signalling DNA single strand breaks (SSB) as part of the base excision repair pathway, and may have radio-sensitizing effects due to impaired resolution of radiation induced SSB. We hypothesize that O may potentiate the effects of X-CRT in pts with LAPC. Methods: Eligible pts with LAPC, ECOG < 1, tumor diameter < 6cm, with stable disease (SD) or response after 12 weeks’ induction chemotherapy, were treated with 1 of 4 escalating doses of O given bid po starting on day -3, and then in combination with X (830 mg/m2 bid) and radiation (50·4 Gy in 28 fractions) all administered Mon-Fri. Dose limiting toxicities (DLT) were determined on clinical and lab toxicity assessments (NCI-CTC AE v4.03) performed weekly from the start of O until completion of O plus X-CRT (i.e. 6 weeks). Dose escalation continued with a rolling-six design until the Maximum Tolerated Dose (MTD) was reached. Blood samples for PK analyses of O and PD measurement (inhibition of PARP activity) were collected on day -3 (O monotherapy) and during week 1 of O + X-CRT. Results: 18 pts, (9 m, 9 f, ECOG 0/1 [n=6/12]), age range 49-81 (median=70) years, with histologic (14) or cytologic (4) proven LAPC, had received induction chemotherapy with gemcitabine [GEM] (n=2), GEM + X (12), or FOLFIRINOX (3) with partial response (n=4) or stable disease (14). Pts received 50 (3), 100 (4), 150 (6), or 200 (5) mgs bid of O with X+CRT. DLTs were observed in 2 pts (both at 200mgs bid): 1 pt with grade 3 nausea (on optimal anti-emetics) and grade 3 fatigue, 1 pt with grade 3 anorexia. 6 pts were subsequently recruited at 150mgs bid with no DLTs. No pts had complete response, 2 pts had partial response (1 pt each at 100 and 150 mgs bid) and 1 pt (at 100 mgs bid) had progressive disease; the remaining 14 pts had SD. Conclusions: The recommended dose (RP2) of O is 150mgs bid when given in combination with X + CRT in LAPC. Recruitment of up to 12 pts with borderline operable LAPC at the RP2 is ongoing. PK analyses of O, PD studies (PARP inhibition – PBMCs; cytokeratin 18 – serum; γH2AX foci – hair follicles), and exploratory predictive marker studies (tumor – NGS; RNA exome sequencing) are ongoing. Clinical trial information: ISRCTN10361292.

The C. elegans germline and somatic gonad are actively developing until the animal reaches adulthood, and then continue to undergo striking changes as the animal ages. Reported changes include a depletion of available sperm, a decrease in oocyte quality up till mid-life, a reduction in germline nuclei, a decrease in fertility, and an accumulation of DNA in the midbody of aging C. elegans. Here, we have focused on the aging gonad in old animals, and show in detail that the aging gonad undergoes a massive uterine growth composed of endoreduplicating oocytes, yolk, and expanses of chromatin. We use a novel series of imaging techniques in combination with histological methodology for reconstructing aged worms in 3-dimensions, and show in old animals growing masses swelling inside the uterus to occupy most of the diameter of the worm. We link this accelerated growth to the cep-1/p53 tumor suppressor. Because cep-1 is required for DNA damage induced apoptosis, and daf-2 limits longevity, these results suggest a role for age-related DNA damage in dysplastic uterine growths, which in some respects resemble premalignant changes that can occur in aging mammals.

Dietary restriction can extend lifespan in model organisms such as the nematode Caenorhabditis elegans. Although a number of key players in lifespan extension have been identified, little is known about the signals that coordinate the metabolic response of the organism. The endocannabinoid system is one candidate for the role, as it is known to regulate nutrient intake and energy balance in mammals. These pathways, and cannabinoid receptors, are absent in C. elegans, but a possible alternative has now been identified in this important model for ageing studies. Abundance of a class of lipid-derived signalling molecules, the N-acylethanolamines (NAEs), is reduced in C. elegans by dietary restriction, and NAE deficiency alone is sufficient to extend lifespan. In mammals, an arachidonic acid containing NAE elicits many — though not all — of its effects through cannabinoid receptors. Dietary restriction is a robust means of extending adult lifespan and postponing age-related disease in many species, including yeast, nematode worms, flies and rodents1,2. Studies of the genetic requirements for lifespan extension by dietary restriction in the nematode Caenorhabditis elegans have implicated a number of key molecules in this process3,4,5, including the nutrient-sensing target of rapamycin (TOR) pathway6 and the Foxa transcription factor PHA-4 (ref. 7). However, little is known about the metabolic signals that coordinate the organismal response to dietary restriction and maintain homeostasis when nutrients are limited. The endocannabinoid system is an excellent candidate for such a role given its involvement in regulating nutrient intake and energy balance8. Despite this, a direct role for endocannabinoid signalling in dietary restriction or lifespan determination has yet to be demonstrated, in part due to the apparent absence of endocannabinoid signalling pathways in model organisms that are amenable to lifespan analysis9. N-acylethanolamines (NAEs) are lipid-derived signalling molecules, which include the mammalian endocannabinoid arachidonoyl ethanolamide. Here we identify NAEs in C. elegans, show that NAE abundance is reduced under dietary restriction and that NAE deficiency is sufficient to extend lifespan through a dietary restriction mechanism requiring PHA-4. Conversely, dietary supplementation with the nematode NAE eicosapentaenoyl ethanolamide not only inhibits dietary-restriction-induced lifespan extension in wild-type worms, but also suppresses lifespan extension in a TOR pathway mutant. This demonstrates a role for NAE signalling in ageing and indicates that NAEs represent a signal that coordinates nutrient status with metabolic changes that ultimately determine lifespan.

Influenza virus infections continue to cause production losses in the agricultural industry in addition to being a human public health concern. The primary method to control influenza is through vaccination. However, currently used killed influenza virus vaccines must be closely matched to the challenge virus. The ability of an elastase-dependent live attenuated influenza A virus was evaluated to protect pigs against the pandemic H1N1 2009 influenza virus. Pigs vaccinated intranasally or intratracheally with the elastase-dependent swine influenza virus (SIV) vaccine had significantly reduced macroscopic and microscopic lung lesions and lower viral loads in the lung and in nasal swabs. Thus, elastase-dependent SIV mutants can be used as live-virus vaccines against swine influenza in pigs. In addition, low levels of cross-neutralizing antibodies to H1N1 2009 were elicited prior to challenge by the swine adapted H1N1 avian strain vaccine.

A panel of monoclonal antibodies (MAbs) was generated from mice immunized with binary ethylenimine (BEI)-inactivated H7N1 (A/TK/ON/18-2/00) virus. Using a dot blot assay, six of seven MAbs reacted with viruses of the H7 subtype, but not with any of the other 15 hemagglutinin (HA) subtypes tested. Four of the seven MAbs reacted with 14 different H7 isolates, indicating that the MAbs binding epitopes are conserved among viruses of the H7 subtype. The binding epitopes of all seven MAbs were conformational and reacted with the HA1 fraction of the HA protein in Western blots under nonreducing conditions. Applications of these MAbs in the development of rapid tests for H7 subtype viruses were evaluated. The MAbs demonstrated reactivity with AI virus H7 antigen in immunofluorescence and immunohistochemistry assays. Monoclonal antibody 3 showed a very strong immunostaining in the formalin-fixed and paraffin-embedded tissue from the H7N3 virus-infected chicken. A double-antibody sandwich (DAS) enzyme-linked immunosorbent assay (ELISA) was developed using two of the MAbs. The DAS ELISA specifically detected all H7 strains tested in this study. A competitive ELISA (cELISA) for the detection of H7-specific antibodies was evaluated using one MAb and BEI-inactivated H7N1 virus as the antigen. All infected birds showed positive antibody responses at 7 days postinfection. The sensitivity of this cELISA was comparable with that of an influenza A nucleoprotein-based cELISA. This panel of MAbs is valuable in the development of various immunoassays.

Aim: To report details concerning symptoms (especially pain) preceding the development of malignant cord compression (MCC); delays between onset/reporting of symptoms and confirmed diagnosis of MCC; accuracy of investigations carried out. Methods: A prospective observational study examined the diagnosis, management and outcome of 319 patients diagnosed with MCC at three Scottish cancer centres between January 1998–April 1999. The process was considered from the perspectives of the patient, the GP and the hospital doctor. Results: At diagnosis, most patients (82%) were either unable to walk or only able to do so with help. Pain was reported by nearly all patients interviewed (94%) and had been present for approximately 3 months (median=90 days). It was severe in 84% of cases, with the distribution and characteristics of nerve root pain in 79%. The site of pain did not correspond to the site of compression. Where reported, weakness and/or sensory problems had been noticed by the patient for some time before diagnosis (median intervals 20 and 12 days, respectively). Most patients reported early symptoms to their General Practitioner (GP) and diagnosis was established, following referral and investigation, approximately 2 months (median=66 days) later. Conclusion: Patients who develop spinal metastases are at risk of irreversible spinal cord damage. Weakness and sensory abnormalities are reported late and identified even later, despite patients having reported pain for a considerable time. Patients with cancer who describe severe back or spinal nerve root pain need urgent assessment on the basis of their symptoms, as signs may occur too late. Plain films and bone scans requested for patients in this audit predicted accurately the level of compression in only 21% and 19% of cases, respectively. The only accurate investigation to establish the presence and site of a compressive lesion is magnetic resonance imaging (MRI). A referral guideline based on suspicious symptoms in addition to suspicious signs is suggested. Levack

A national questionnaire-based survey has found that palliative physicians report lower levels of burnout and similar levels of psychiatric morbidity than those reported by consultants in other specialties. To try to explain these findings, this study compared the sources of job stress and satisfaction reported by consultant palliative physicians with those reported by consultants working in four other specialties: surgery, gastroenterology, radiology and oncology. Stressful and satisfying aspects of work were assessed using questionnaires designed specifically for the study. The response rate for the palliative physicians was 126/154 (82%) and for the consultants in the other specialties 882/1133 (78%). Palliative physicians reported that feeling overloaded and its effect on home life made the greatest contribution to their job stress, and having good relationships with patients, relatives and staff made the greatest contribution to their job satisfaction. However, compared with the other specialist groups, palliative physicians reported less stress from overload ( p < 0.001) and more satisfaction from having good relationships ( p < 0.001). They also reported less stress and more satisfaction with the way they are managed and resourced (both p < 0.001). Hospital-based palliative physicians reported more stress and less satisfaction from their management and resources than their colleagues working in hospices (both p = 0.05). Thirty-five percent of palliative physicians felt insufficiently trained in communication skills and 81% felt insufficiently trained in management skills. Burnout was more prevalent among consultants who felt insufficiently trained in communication and management skills than among those who felt sufficiently trained. It is important therefore that effective training in communication and management skills are provided and that, at the very least, existing levels of resourcing and management practices within palliative medicine are maintained in order that physicians working in the specialty are able to provide care to dying patients without prejudicing their own mental health.

Summary Background Burnout and psychiatric morbidity among gastroenterologists, surgeons, radiologists, and oncologists in the UK have been estimated by means of a questionnaire-based survey. The relationship between consultants' mental health and their job stress and satisfaction, as well as their job and demographic characteristics, were also examined. Methods Psychiatric morbidity was estimated using the 12-item General Health Questionnaire. The three components of burnout—emotional exhaustion, depersonalisation, and low personal accomplishment—were assessed using the Maslach Burnout Inventory. Job stress and satisfaction were measured using study-specific questions. Findings Of 1133 consultants, 882 (78%) returned questionnaires. The estimated prevalence of psychiatric morbidity was 27%, with no significant differences between the four specialist groups. Radiologists reported the highest level of burnout in terms of low personal accomplishment. Job satisfaction significantly protected consultants' mental health against job stress. Three sources of stress were associated with both burnout and psychiatric morbidity: feeling overloaded, and its effect on home life; feeling poorly managed and resourced; and dealing with patients' suffering. Burnout was also associated with low satisfaction in three domains: relationships with patients, relatives, and staff; professional status/esteem; intellectual stimulation. In addition, being aged 55 years or less and being single were independent risk factors for burnout. Burnout was also more prevalent among consultants who felt insufficiently trained in communication and management skills. Interpretation Consultants' mental health is likely to be protected against the high demands of medical practice by maintaining or enhancing job satisfaction, and by providing training in communication and management skills.

The prevalence and causes of 'burnout' and psychiatric disorder among senior oncologists and palliative care specialists have been measured in a national questionnaire-based survey. All consultant non-surgical oncologists in the UK were asked to participate. Sources of work-related stress and satisfaction were measured using study-specific questions which were aggregated into factors. Psychiatric disorder was estimated using the 12-item General Health Questionnaire. The three components of 'burnout'--emotional exhaustion, depersonalisation and low personal accomplishment--were assessed using the Maslach Burnout Inventory. Three hundred and ninety-three out of 476 (83%) consultants returned their questionnaires. The estimated prevalence of psychiatric disorder in cancer clinicians was 28%, and this is similar to the rate among British junior house officers. The study group had equivalent levels of emotional exhaustion and low personal accomplishment to those found in American doctors and nurses, but lower levels of depersonalisation. Among cancer clinicians, 'burnout' was more prevalent among clinical oncologists than among medical oncologists and palliative care specialists. Psychiatric disorder was independently associated with the stress of feeling overloaded (P < 0.0001), dealing with treatment toxicity/errors (P < 0.004) and deriving little satisfaction from professional status/esteem (P = 0.002). 'Burnout' was also related to these factors, and in addition was associated with high stress and low satisfaction from dealing with patients, and with low satisfaction from having adequate resources (each at a level of P < or = 0.002). Clinicians who felt insufficiently trained in communication and management skills had significantly higher levels of distress than those who felt sufficiently trained. If 'burnout' and psychiatric disorder among cancer clinicians are to be reduced, increased resources will be required to lessen overload and to improve training in communication and management skills.

To present further findings from the Scottish Cord Compression Study, in which the diagnosis, management and outcome of 319 patients with a definitive diagnosis of malignant cord compression (MCC) were examined.In total, 256 (80%) patients in the study consented to be interviewed shortly after diagnosis and at follow-up interviews. One hundred and twenty-eight patients were interviewed 1 month after diagnosis (40% of the total; 57% [128/224] of patients alive 1 month after diagnosis; 68% [128/188] of patients who also consented to follow-up). Survival data of the whole MCC population and data from interviewing 128 patients 1 month after diagnosis are presented.The median survival of all patients was 59 days (95% confidence interval [CI] 43-75 days). The median Karnofsky performance status was 50 (interquartile range 40-60), indicating a need for considerable nursing and medical care, and was poorest for patients with lung cancer (median 40; interquartile range 30-60). The place of care was dependent on mobility at diagnosis; patients walking at diagnosis were more likely to be at home, whereas patient requiring assistance or who were unable to walk were more likely to be in institutional care (P = 0.019). Mobility and bladder function were determined by mobility and bladder function at diagnosis (P0.001). Of those unable to walk at diagnosis, 7% regained full mobility. Of those catheterised at presentation, 28% regained full bladder function. Forty-seven per cent (56/120, 95% CI 40-54) of patients interviewed were in pain despite oncological treatment and 18% (22/ 120; 95% CI 8-19) reported the pain as severe (visual analogue scale7). The median quality-of-life (Schedule for Evaluation of Individualised Quality of Life) score was 72/100, and was higher in patients with a better performance status (P = 0.026). A minority of patients (8%) screened positive for anxiety and depression using the Hospital Anxiety and Depression scale.Notwithstanding the difficulties in following up this group of patients, this paper reports valuable findings detailing the experience of patients with MCC 1 month after diagnosis and treatment.

Few GPs adhere to primary care guidelines and protocols on the management of eating disorders, and many feel dissatisfied with the treatment they are providing, according to a British study presented at the seventh international eating disorders conference, held in London last week. Researchers at the Institute of Psychiatry sent questionnaires to all GPs and university counsellors in south London, Surrey, Sussex, and Kent, who together serve a population of 6.4 million. Half of the GPs who responded had had at least one new case of an eating disorder during the previous year. Overall, around a quarter of these patients were managed exclusively in primary care. However, individual GPs tended to refer either all or none of the affected patients, a practice that …

Objective To examine the prevalence of, and risk factors for, depression and anxiety in women with early breast cancer in the five years after diagnosis. Design Observational cohort study. Setting NHS breast clinic, London. Participants 222 women with early breast cancer: 170 (77%) provided complete interview data up to either five years after diagnosis or recurrence. Main outcome measures Prevalence of clinically important depression and anxiety (structured psychiatric interview with standardised diagnostic criteria) and clinical and patient risk factors, including stressful life experiences (Bedford College life events and difficulties schedule). Results Nearly 50% of the women with early breast cancer had depression, anxiety, or both in the year after diagnosis, 25% in the second, third, and fourth years, and 15% in the fifth year. Point prevalence was 33% at diagnosis, falling to 15% after one year. 45% of those with recurrence experienced depression, anxiety, or both within three months of the diagnosis. Previous psychological treatment predicted depression, anxiety, or both in the period around diagnosis (one month before diagnosis to four months after diagnosis). Longer term depression and anxiety, were associated with previous psychological treatment, lack of an intimate confiding relationship, younger age, and severely stressful non-cancer life experiences. Clinical factors were not associated with depression and anxiety, at any time. Lack of intimate confiding support also predicted more protracted episodes of depression and anxiety. Conclusion Increased levels of depression, anxiety, or both in the first year after a diagnosis of early breast cancer highlight the need for dedicated service provision during this time. Psychological interventions for women with breast cancer who remain disease free should take account of the broader social context in which the cancer occurs, with a focus on improving social support.

Results from ab initio STO-3G calculations on C 60 and C 60 H are presented and compared with recent MNDO-PM3 calculations. These results, and those from recent MNDO-PM3 calculations on C 60 H 2 , are interpreted using resonance theory

SummaryIn a survey of 1794 UK NHS hospital consultants 1308 (73%) responded. Psychiatric morbidity (General Health Questionnaire—12 score ⩾4) was present in 32% of responders, who were twice as likely to report drinking hazardous levels of alcohol, being irritable with patients and colleagues, reducing their standards of care and intending to retire early (all P

To many of us, “half doing” something is quite unthinkable. We are programmed by our upbringing and medical training to believe that if a job's worth doing it must be done properly. In the real world, however, life's not quite like that. In general practice we often have to cut corners because we simply don't have time to do a full examination on every patient. To diverge slightly, I was once told that many people with messy desks are actually very tidy. This apparent paradox arises from the fact that they prefer to live with the mess if they haven't time to do a thorough job tidying up. They …

Objective: To confirm, using an observational cohort design, the relation between severely stressful life experiences and relapse of breast cancer found in a previous case-control study. Design: Prospective follow up for five years of a cohort of women newly diagnosed as having breast cancer, collecting data on stressful life experiences, depression, and biological prognostic factors. Setting: NHS breast clinic, London; 1991-9. Participants: A consecutive series of women aged under 60 newly diagnosed as having a primary operable breast tumour. 202/222 (91%) eligible women participated in the first life experiences interview. 170 (77%) provided complete interview data either up to 5 years after diagnosis or to recurrence. Main outcome measure: Recurrence of disease. Results: We controlled for biological prognostic factors (lymph node infiltration and tumour histology), and found no increased risk of recurrence in women who had had one or more severely stressful life experiences in the year before diagnosis compared with women who did not (hazard ratio 1.01, 95% confidence interval 0.58 to 1.74, P=0.99). Women who had had one or more severely stressful life experiences in the 5 years after diagnosis had a lower risk of recurrence (0.52, 0.29 to 0.95, P=0.03) than those who did not. Conclusion: These data do not confirm an earlier finding from a case-control study that severely stressful life experiences increase the risk of recurrence of breast cancer. Differences in case control and prospective methods may explain the contradictory results. We took the prospective study as the more robust, and the results suggest that women with breast cancer need not fear that stressful experiences will precipitate the return of their disease.