Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial.

BACKGROUND: Tuberculosis remains one of the world's deadliest transmissible diseases despite widespread use of the BCG vaccine. MTBVAC is a new live tuberculosis vaccine based on genetically attenuated Mycobacterium tuberculosis that expresses most antigens present in human isolates of M tuberculosis. We aimed to compare the safety of MTBVAC with BCG in healthy adult volunteers. METHODS: We did this single-centre, randomised, double-blind, controlled phase 1 study at the Centre Hospitalier Universitaire Vaudois (CHUV; Lausanne, Switzerland). Volunteers were eligible for inclusion if they were aged 18-45 years, clinically healthy, HIV-negative and tuberculosis-negative, and had no history of active tuberculosis, chemoprophylaxis for tuberculosis, or BCG vaccination. Volunteers fulfilling the inclusion criteria were randomly assigned to three cohorts in a dose-escalation manner. Randomisation was done centrally by the CHUV Pharmacy and treatments were masked from the study team and volunteers. As participants were recruited within each cohort, they were randomly assigned 3:1 to receive MTBVAC or BCG. Of the participants allocated MTBVAC, those in the first cohort received 5 × 10(3) colony forming units (CFU) MTBVAC, those in the second cohort received 5 × 10(4) CFU MTBVAC, and those in the third cohort received 5 × 10(5) CFU MTBVAC. In all cohorts, participants assigned to receive BCG were given 5 × 10(5) CFU BCG. Each participant received a single intradermal injection of their assigned vaccine in 0·1 mL sterile water in their non-dominant arm. The primary outcome was safety in all vaccinated participants. Secondary outcomes included whole blood cell-mediated immune response to live MTBVAC and BCG, and interferon γ release assays (IGRA) of peripheral blood mononuclear cells. This trial is registered with ClinicalTrials.gov, number NCT02013245. FINDINGS: Between Jan 23, 2013, and Nov 6, 2013, we enrolled 36 volunteers into three cohorts, each of which consisted of nine participants who received MTBVAC and three who received BCG. 34 volunteers completed the trial. The safety of vaccination with MTBVAC at all doses was similar to that of BCG, and vaccination did not induce any serious adverse events. All individuals were IGRA negative at the end of follow-up (day 210). After whole blood stimulation with live MTBVAC or BCG, MTBVAC was at least as immunogenic as BCG. At the same dose as BCG (5×10(5) CFU), although no statistical significance could be achieved, there were more responders in the MTBVAC group than in the BCG group, with a greater frequency of polyfunctional CD4+ central memory T cells. INTERPRETATION: To our knowledge, MTBVAC is the first live-attenuated M tuberculosis vaccine to reach clinical assessment, showing similar safety to BCG. MTBVAC seemed to be at least as immunogenic as BCG, but the study was not powered to investigate this outcome. Further plans to use more immunogenicity endpoints in a larger number of volunteers (adults and adolescents) are underway, with the aim to thoroughly characterise and potentially distinguish immunogenicity between MTBVAC and BCG in tuberculosis-endemic countries. Combined with an excellent safety profile, these data support advanced clinical development in high-burden tuberculosis endemic countries. FUNDING: Biofabri and Bill & Melinda Gates Foundation through the TuBerculosis Vaccine Initiative (TBVI).

Finnish Maritime Personnel's Conceptions on Safety Management and Safety Culture

The purpose of this thesis is to explore Finnish maritime personnel’s conceptions of safety management and its relationship with the concept of safety culture. In addition, the aim is to evaluate the impact of the ISM Code on the prevailing safety culture in the Finnish shipping business. A total of 94 interviewees and seven Finnish shipping companies were involved in this study. Thematic interviews were applied as the main research method for the study. The results were analysed qualitatively. The results indicate that maritime safety culture can simultaneously demonstrate features of integration, differentiation and ambiguity. Basically, maritime personnel have a positive attitude towards safety management systems since they consider safety management beneficial and essential in general. However, the study also found considerable criticism among the interviewees. The interviewed maritime personnel did not criticise the ISM Code as such, yet they criticised the way the ISM Code has been applied in practise. In order to understand the multiple perspectives of safety culture more comprehensively, multiple theoretical perspectives and methodological approaches are needed. This study indicates that safety culture and the impacts of the ISM Code should not be unambiguously studied solely quantitative methods or qualitative methods. By examining safety culture from several methodological and theoretical perspectives, one may gain a more versatile and holistic overview of safety culture.

General regulations and orders, 1804

Bound with: The manual and platoon exercises, &c., &c. (51 p.) and: General orders and observations on the movement and field exercise of infantry (16 p.) Inscribed on front paste-down: L. Colonel Brock. Also inscribed: Maj. Genl T.A. Smith late of the 1st. Rifle Regt. Bookplate of Robert B. Taylor, Norfolk. On front flyleaf: lengthy, two-page transcription in ink, headed /Copy/Circular/ dated "Horse Guards, 25th May '07" and signed: "Harry Calvert Adjt. General.

General regulations and orders, 1804

Bound with: The manual and platoon exercises, &c., &c. (51 p.) and: General orders and observations on the movement and field exercise of infantry (16 p.) Inscribed on front paste-down: L. Colonel Brock. Also inscribed: Maj. Genl T.A. Smith late of the 1st. Rifle Regt. Bookplate of Robert B. Taylor, Norfolk. On front flyleaf: lengthy, two-page transcription in ink, headed /Copy/Circular/ dated "Horse Guards, 25th May '07" and signed: "Harry Calvert Adjt. General.

Liquor Advertising Regulations in Canada, 1938

A document describing provincial regulations for advertising liquor. The document appears to have been written by/for Seagram. At this time, the advertising of liquor is still prohibited in some provinces like Nova Scotia and New Brunswick. In order to still market to these provinces, the document states that "In order to reach this market the Company has used national magazines and other publications published outside these provinces but having substantial circulation within the above two provinces."

Industrial Alcohol: Synopsis of Rules & Regulations of the Dominion & Provincial Governments of Canada

A booklet of rules and regulations for industrial alcohol. A portion of the preparatory note reads: "We endeavoured to bring together in this booklet as much information as possible regarding the Dominion and Provincial rules and regulations at present in force controlling the sale and use of Alcohol for manufacturing, etc."

Dominion Marine Association records, 1972-1986

Established in 1903, the Dominion Marine Association was formed as an association of Canadian shipping companies. The Association had two main objectives. The first was to protect and advance the interests of Canadian shipowners, as well as Canadian consumers and exporters, to the extent that these interests are affected by government legislation and regulations. The second objective was to promote navigational safety through use of the latest technology, and through the continuous progress of vessel design. In 1988, the Association changed its name to the Canadian Shipowners Association.

Rules and Regulations of the St. Catharines Club

The booklet is a printed set of rules and regulations for the St. Catharines Club. It is pocket size and has several blank pages in the back. The blank pages have handwritten names including H.K. Woodruff. Also included in the booklet are lists of past officers. R. Woodruff is listed as president in 1883, and H.K. Woodruff is listed as a committee member in 1885 and 1886.

Crown timber regulations

Crown timber regulations which include: 2 double-sided printed pages issued by the Department of Crown Lands (2 copies). Included with this are 3 printed slips of paper. 2 of these are Order and Regulations by S. Richards, Commissioner of Crown Lands, dated May 28, 1869 and 1 is a notice of sale of timber berths dated Aug.1, 1872 by Richard Wm. Scott, commissioner, 1869, 1872.

Report from the annual meeting of the shareholders held on June 1, 1886 in which amendments and field rules and regulations were made

Report from the annual meeting of the shareholders held on June 1, 1886 in which amendments and field rules and regulations were made (copy of 1 handwritten page). This is signed by Louis N. Hayne, secretary, June 7, 1886.