A Compact 3H(p,gamma)4He 19.8-MeV Gamma-Ray Source for Energy Calibration at the Sudbury Neutrino Observatory

The Sudbury Neutrino Observatory (SNO) is a new 1000-tonne D2O Cerenkov solar neutrino detector. A high energy gamma-ray source is needed to calibrate SNO beyond the 8B solar neutrino endpoint of 15 MeV. This paper describes the design and construction of a source that generates 19.8-MeV gamma rays using the 3H(p,gamma)4He reaction (``pt''), and demonstrates that the source meets all the physical, operational and lifetime requirements for calibrating SNO. An ion source was built into this unit to generate and to accelerate protons up to 30 keV, and a high purity scandium tritide target with a scandium-tritium atomic ratio of 1:2.0+/-0.2 was included. This pt source is the first self-contained, compact, and portable high energy gamma-ray source (E>10 MeV).Comment: 33 pages (including 2 table, 12 figures) This is the revised manuscript, accepted for publication in NIM A. This revision relfects minor editorial changes from the previous versio

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Five years experience of Clostridium difficile infection in children at a UK tertiary hospital: proposed criteria for diagnosis and management.

Clostridium difficile infection (CDI) is associated with significant morbidity and mortality in adults. There is increasing evidence of the pathogenic role of C. difficile in the paediatric population. We sought to ascertain the clinical presentation and severity of CDI in children at our institution and develop criteria to aid management.Clinical data was retrospectively collected from all children (0-16 yrs) with a positive C. difficile toxin result over a 5-year period. National adult guidelines were used to assess the severity and management of CDI.Seventy-five patients were included with a mean age of 2.97 years. Forty-nine were hospital onset, 22 community onset and 4 healthcare-associated. The most common co-morbidity among the hospital onset infections was malignancy. Gastrointestinal conditions were most common among community onset infections. Fifty-five cases (73.3%) had received antibiotics in the preceding month, 7 (9.3%) had cow's milk intolerance and 9 (12%) had co-infection with another gut pathogen. According to national adult guidelines 57 cases (76%) were categorised as severe. Thirty cases received oral metronidazole, two patients required intensive care and one patient had a sub-total colectomy for pseudomembranous colitis. No mortality was observed.We confirm the association of paediatric CDI with co-morbidities such as haematological and solid organ malignancies, recent antibiotic use and hospitalisation. We observed an association between cows milk protein intolerance and C. difficile. The use of adult criteria overestimated severity of disease in this cohort, as most cases experienced a mild course of illness with low morbidity and no mortality. This indicates that adult scoring criteria are not useful in guiding management and we propose specific criteria for children

Results comparing hospital onset with community onset cases.

*<p>Note some patients had more than one risk factor.</p>**<p>Of the 18 surgeries 9 were gastrointestinal surgeries (Resection of abdominal mass, appendicectomy).</p>***<p>Severity scoring criteria as recommended by Department of Health and Health Protection Agency.</p

Proposed revised criteria for severity of <i>Clostridium difficile</i> infection in children.

<p>Score</p><p>1–2 =  mild disease.</p><p>3–4 =  moderate disease.</p><p>≥5 =  severe disease.</p

Impact of a new hospital with close to 100% single-occupancy rooms on environmental contamination and incidence of vancomycin-resistant Enterococcus faecium colonisation or infection: a genomic surveillance study.

BACKGROUND: Vancomycin-resistant Enterococcus faecium (VRE) is a leading cause of nosocomial infection, driven by its ability to spread between patients and persist in the hospital environment. Here, we investigated the impact of a long-established cardiothoracic hospital moving to new premises with close to 100% single-occupancy rooms on the rates of environmental contamination and infection or colonisation by VRE. METHOD: Prospective environmental surveillance for VRE was conducted at five time-points between April and November 2019, once in the original building, and four times in the new building. Flocked swabs (n=100/time-point) were used to sample bedspaces, bathrooms, computers and sluices in the critical care unit and the cardiothoracic ward. Environmental VRE was supplemented by clinical VRE isolates from the same time period, and underwent whole genome sequencing. Incidence rate ratios (IRR) of VRE infection/colonisation was determined for the one-year period before and after the hospital move, and compared to a nearby hospital. FINDINGS: In the original location, the first environmental screen found 29% VRE positivity. The following four screens in the new location showed a significant reduction in positivity (1-6%, p<0·0001). The VRE infection/colonisation rates were halved in the new location (IRR 0·56, 95% CI 0·38-0·84), compared to the original location, contrasting to an increase in a nearby hospital (IRR 1·62, 95% CI 1·17-2·27) over the same time period. Genomic analysis of the environmental isolates was consistent with reduced transmission in the new hospital. INTERPRETATION: The use of single-occupancy rooms was associated with reduced environmental contamination with VRE, and lower transmission and isolation of VRE from clinical samples. The cost effectiveness of single-occupancy room hospitals in reducing healthcare-associated infections should be reassessed in the context of operational costs of emerging pandemic and increasing antimicrobial resistance threats. FUNDING: This publication presents independent research supported by the Health Innovation Challenge Fund (WT098600, HICF-T5-342), a parallel funding partnership between the Department of Health and Wellcome Trust. FC reports funding from the Wellcome Trust (LSHTM/Wellcome Institutional Strategic Support Fund Fellowship [204928/Z/16/Z]. KR was supported by an ESCMID Research Grant (ref. 15996)

Secondary Complement Deficiency Impairs Anti-Microbial Immunity to Klebsiella pneumoniae and Staphylococcus aureus During Severe Acute COVID-19.

A high incidence of secondary Klebsiella pneumoniae and Staphylococcus aureus infection were observed in patients with severe COVID-19. The cause of this predisposition to infection is unclear. Our data demonstrate consumption of complement in acute COVID-19 patients reflected by low levels of C3, C4, and loss of haemolytic activity. Given that the elimination of Gram-negative bacteria depends in part on complement-mediated lysis, we hypothesised that secondary hypocomplementaemia is rendering the antibody-dependent classical pathway activation inactive and compromises serum bactericidal activity (SBA). 217 patients with severe COVID-19 were studied. 142 patients suffered secondary bacterial infections. Klebsiella species were the most common Gram-negative organism, found in 58 patients, while S. aureus was the dominant Gram-positive organism found in 22 patients. Hypocomplementaemia was observed in patients with acute severe COVID-19 but not in convalescent survivors three months after discharge. Sera from patients with acute COVID-19 were unable to opsonise either K. pneumoniae or S. aureus and had impaired complement-mediated killing of Klebsiella. We conclude that hyperactivation of complement during acute COVID-19 leads to secondary hypocomplementaemia and predisposes to opportunistic infections

Critical Care Workers Have Lower Seroprevalence of SARS-CoV-2 IgG Compared with Non-patient Facing Staff in First Wave of COVID19

In early 2020, at first surge of the coronavirus disease 2019 (COVID-19) pandemic, many health care workers (HCW) were re-deployed to critical care environments to support intensive care teams looking after patients with severe COVID-19. There was considerable anxiety of increased risk of COVID-19 for these staff. To determine whether critical care HCW were at increased risk of hospital acquired infection, we explored the relationship between workplace, patient facing role and evidence of immune exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within a quaternary hospital providing a regional critical care response. Routine viral surveillance was not available at this time