A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours

BACKGROUND: Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment. PATIENTS AND METHODS: Patients with advanced cancer received olaparib (20-200 mg PO) on days 1-7 with dacarbazine (600-800 mg m(-2) IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells. RESULTS: The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m(-2) dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma. CONCLUSION: This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses

Recreational and occupational field exposure to freshwater cyanobacteria – a review of anecdotal and case reports, epidemiological studies and the challenges for epidemiologic assessment

Cyanobacteria are common inhabitants of freshwater lakes and reservoirs throughout the world. Under favourable conditions, certain cyanobacteria can dominate the phytoplankton within a waterbody and form nuisance blooms. Case reports and anecdotal references dating from 1949 describe a range of illnesses associated with recreational exposure to cyanobacteria: hay fever-like symptoms, pruritic skin rashes and gastro-intestinal symptoms are most frequently reported. Some papers give convincing descriptions of allergic reactions while others describe more serious acute illnesses, with symptoms such as severe headache, pneumonia, fever, myalgia, vertigo and blistering in the mouth. A coroner in the United States found that a teenage boy died as a result of accidentally ingesting a neurotoxic cyanotoxin from a golf course pond. This death is the first recorded human fatality attributed to recreational exposure to cyanobacteria, although uncertainties surround the forensic identification of the suspected cyanotoxin in this case. We systematically reviewed the literature on recreational exposure to freshwater cyanobacteria. Epidemiological data are limited, with six studies conducted since 1990. Statistically significant increases in symptoms were reported in individuals exposed to cyanobacteria compared to unexposed counterparts in two Australian cohort studies, though minor morbidity appeared to be the main finding. The four other small studies (three from the UK, one Australian) did not report any significant association. However, the potential for serious injury or death remains, as freshwater cyanobacteria under bloom conditions are capable of producing potent toxins that cause specific and severe dysfunction to hepatic or central nervous systems. The exposure route for these toxins is oral, from ingestion of recreational water, and possibly by inhalation. A range of freshwater microbial agents may cause acute conditions that present with features that resemble illnesses attributed to contact with cyanobacteria and, conversely, acute illness resulting from exposure to cyanobacteria or cyanotoxins in recreational waters could be misdiagnosed. Accurately assessing exposure to cyanobacteria in recreational waters is difficult and unreliable at present, as specific biomarkers are unavailable. However, diagnosis of cyanobacteria-related illness should be considered for individuals presenting with acute illness following freshwater contact if a description is given of a waterbody visibly affected by planktonic mass development

Inequalities in public water supply fluoridation in Brazil: An ecological study

Background. The literature is scarce on the social and geographic inequalities in the access to and implementation of the fluoridation of public water supplies. This study adds knowledge to the Brazilian experience of the chronic privation of water and wastewater policies, access to potable water and fluoridation in the country. Thus, the aim of this study was to verify possible inequalities in the population's access to fluoridated drinking water in 246 Brazilian municipalities. Methods. The information on the process of water fluoridation in the municipalities and in the macro region in which each municipality is located was obtained from the national epidemiological survey which was concluded in 2003. The data relating to the human development index at municipal level (HDI-M) and access to mains water came from the Brazilian Human Development Atlas, whilst the size of the population was obtained from a governmental source. The Fisher exact test (P < 0.05) was employed to identify significant associations between the explanatory variables and their ability to predict the principal outcomes of interest to this study, namely the presence or absence of the water fluoridation process in the municipalities as well as the length of time during which this measure has been implemented. Linear regression was used to observe the associations between the relevant variables in a multivariate environment. Results. The results clearly showed that there is a relationship between municipalities with larger populations, located in more socio-economically advantaged regions and with better HDI-M, and where fluoridation is both present and has been implemented for a longer period of time (started before 1990). Conclusion. The findings suggest that the aim of treating water with fluoride may not be being adequately achieved, requiring more effective strategies so that access to this measure can be expanded equitably.81Hart, J.T., The inverse care law (1971) Lancet, 1 (7696), pp. 405-12. , 4100731Victora, C.G., Vaughan, J.P., Barros, F.C., Silva, A.C., Tomasi, E., Explaining trends in inequities: Evidence from Brazilian child health studies (2000) Lancet, 356 (9235), pp. 1093-98. , 10.1016/S0140-6736(00)02741-0 11009159Basting, R.T., Pereira, A.C., Meneghim, M.C., Evaluation of dental caries prevalence in students from Piracicaba, SP, Brazil, after 25 years of fluoridation of the public water supply (1997) Rev Odontol Univ São Paulo, 11 (4), pp. 287-92. , 10.1590/S0103-06631997000400010Lawrence, H.P., Sheiham, A., Caries progression in 12 to 16-year-old schoolchildren in fluoridated and fluoride-deficient areas in Brazil (1997) Community Dent Oral Epidemiol, 25 (6), pp. 402-11. , 10.1111/j.1600-0528.1997.tb01730.x 9429812Pereira, A.C., Mialhe, F.L., Bianchini, F.L.C., Prevalence of caries and dental floozies in scholars from cities with different fluoride concentrations in drinking water (2001) Rev Bras Odontol Sade Coletiva, 2 (1), pp. 34-9For Disease Control, C., Prevention, Achievementsin Public Health, 1900-1999: Fluoridation of drinking water to prevent dental caries (1999) Morbidity and Mortality Weekly Report, 48 (41), pp. 933-40For Disease Control, C., Prevention, Ten great public health achievements -United Sates, 1900-1999 (1999) Morbidity and Mortality Weekly Report, 48 (12), pp. 241-3. , 10220250American Health Organization, P., XV Directing Council of the Pan American Health Organization - Resolutions, 1964, , http://www.paho.org/English/GOV/CD/ftcd_15.htm(2003) The World Oral Health Report 2003, , http://www.who.int/oral_health, Geneva: WHOMcDonagh, M.S., Whiting, P.F., Wilson, P.M., Sutton, A.J., Chestnutt, I., Cooper, J., Misso, K., Kleijnen, J., Systematic review of water fluoridation (2000) BMJ, 321 (7265), pp. 855-9. , 11021861 10.1136/bmj.321.7265.855Bratthall, D., Hänsel-Petersson, G., Sundberg, H., Reasons for the caries decline: What do the experts believe? (1996) Eur J Oral Sci, 104 (4 PART 2), pp. 416-22. , 10.1111/j.1600-0722.1996.tb00104.x 8930592Narvai, P.C., Dental caries and fluorine: A twentieth century relation (2000) Cinc Sade Coletiva, 5 (2), pp. 381-92. , 10.1590/S1413-81232000000200011Peres, M.A., Fernandes, L.S., Peres, K.G., Inequality of water fluoridation in Southern Brazil - The inverse equity hypothesis revisited (2004) Soc Sci Med, 58 (6), pp. 1181-9. , 10.1016/S0277-9536(03)00289-2 14723912Peres, M.A., Antunes, J.L.F., Peres, K.G., Is water fluoridation effective in reducing inequalities in dental caries distribution in developing countries? (2006) Sozial und Präventiv Medizin, 51 (5), pp. 1-9Peres, K.G., Bastos, J.R., Mrdo, L., Relationship between severity of dental caries and social and behavioral factors in children (2000) Rev Saude Publica, 34 (4), pp. 402-8. , 10973161Maltz, M., Barbachan Silva, E.B., Relationship between caries, gingivitis and fluorosis and the socioeconomic status among school children (2001) Rev Saude Publica, 35 (2), pp. 170-6. , 11359204Moysés, S.J., Desigualdades em Sade Bucal e Desenvolvimento Humano: Um ensaio em preto, branco e alguns tons de cinza (2001) Rev Bras Odontol Sade Coletiva, 1 (1), pp. 7-17Patussi, M.P., Marcenes, W., Croucher, R., Sheiham, A., Social deprivation, income inequality, social cohesion and dental caries in Brazilian school children (2001) Soc Sci Med, 53 (7), pp. 915-25. , 10.1016/S0277-9536(00)00391-9 11522137Antunes, J.L.F., Frazão, P., Narvai, P.C., Bispo, C.M., Pegoretti, T., Spatial analysis to identify differentials in dental needs by area-based measures (2002) Community Dent Oral Epidemiol, 30 (2), pp. 133-42. , 10.1034/j.1600-0528.2002.300207.x 12000354Peres, M.A., Peres, K.G., Antunes, J.L.F., Junqueira, S.R., Frazão, P., Narvai, P.C., The association between socioeconomic development at the town level and the distribution of dental caries in Brazilian children (2003) Rev Panam Salud Publica, 14 (3), pp. 149-57. , 10.1590/S1020-49892003000800001 14653902Antunes, J.L.F., Narvai, P.C., Nugent, Z.J., Measuring inequalities in the distribution of dental caries (2004) Community Dent Oral Epidemiol, 32 (1), pp. 41-8. , 10.1111/j.1600-0528.2004.00125.x 14961839Antunes, J.L.F., Peres, M.A., De Campos Mello, T.R., Waldman, E.A., Multilevel assessment of determinants of dental caries experience in Brazil (2006) Community Dent Oral Epidemiol, 34 (2), pp. 146-152. , 10.1111/j.1600-0528.2006.00274.x 16515679Narvai, P.C., Frazão, P., Roncalli, A.G., Antunes, J.L.F., Dental caries in Brazil: Decline, polarization, inequality and social exclusion (2006) Rev Panam Salud Publica, 19 (6), pp. 385-93. , 10.1590/S1020-49892006000600004 16968593Projeto, S.B., Brasil, Condiçes de sade bucal da população brasileira 2002-2003. Resultados principais (2004) Brasília-DF: Ministério da Sade, Secretaria de Atenção Sade, Departamento de Atenção Básica, Coordenação Nacional de Sade BucalCarmichael, C.L., Rugg-Gunn, A.J., French, A.D., Cranage, J.D., The effect of fluoridation upon the relationship between caries experience and social class in 5-year-old children in Newcastle and Northumberland in 1987 (1980) Br Dent J, 149 (6), pp. 163-7. , 10.1038/sj.bdj.4804479 6931610Bradnock, G., Marchment, M.D., Anderson, R.J., Social background, fluoridation and caries experience in 5-year-old population in the West Midlands (1984) Br Denl J, 156 (4), pp. 127-31. , 10.1038/sj.bdj.4805287 6584119Jones, C.M., Taylor, G.O., Whittle, J.G., Evans, D., Trotter, D.P., Water fluoridation, tooth decay in 5 years olds, and social deprivation measured by the Jarman score: Analysis of data from British dental surveys (1997) BMJ, 315 (7107), pp. 514-17. , 9329305Riley, J.C., Lennon, M.A., Ellwood, R.P., The effect of water fluoridation and social inequalities on dental caries in 5-year-old children (1999) Int Dent J, 28 (2), pp. 300-5. , 10342695Congresso Nacional, Brasil., Lei Federal no. de 19/09/1990 (1990) Diário Oficial da União 20 Set, p. 18055Morgenstern, H., Ecological studies (1998) Modern Epidemiology, pp. 459-80. , Baltimore: Lippincot Williamns & Wilkins Rothman K, Greenland S(2000) Informaçes de Sade: População Residente, , http://w3.datasus.gov.br/datasus/datasus.php?area= 359A1B379C6D0E0F359G23HIJd6L26M0N&VInclude=./site/infsaude.php, Departamento de Informática do Sistema nico de Sade (DATASUS)(2003) Atlas Do Desenvolvimento Humano No Brasil, Versão 1.0.0, , Programa das Naçes Unidas para o Desenvolvimento Brasília: PNUDLallo, R., Myburgh, N.G., Hobdell, M.H., Dental caries, socio-economic development and national oral health profiles (1999) Int Dent J, 49, pp. 196-202. , 10858754Baldani, M.H., Narvai, P.C., Antunes, J.L.F., Cárie dentária e condiçes scio-econômicas no Estado do Paraná, Brasil, 1996 (2002) Cad Sade Pblica, 18 (3), pp. 755-63. , 10.1590/S0102-311X2002000300024Qizilbash, M., On the Measurement of Human Development (2002) UNDP, , http://hdr.undp.org/docs/training/oxford/presentations/ Qizilbash_HDIcritique.pdfBurt, B.A., Fluoridation and social equity (2002) J Public Health Dent, 62 (4), pp. 195-200. , 10.1111/j.1752-7325.2002.tb03445.x 12474623For Disease Control, C., Prevention, Recommendation focusing fluoride to prevent and control dental caries in the United States (2001) Morbidity and Mortality Weekly Report, 50 (14), pp. 1-42Griffin, S.O., Jones, K., Tomar, S.L., An economic evaluation of community water fluoridation (2001) J Public Health Dent, 61 (2), pp. 78-86. , 10.1111/j.1752-7325.2001.tb03370.x 11474918Bleicher, L., Frota, F.H.S., Fluoretação da água: Uma questão de política pblica - O caso do Estado do Ceará (2006) Cin Sade Coletiva, 11 (1), pp. 71-8Frias, A.C., Narvai, P.C., Arajo, M.E., Zilbovicius, C., Antunes, J.L.F., Custo da fluoretação das águas de abastecimento pblico, estudo de caso -Município de São Paulo, Brasil, período de 1985-2003 (2006) Cad Sade Pblica, 22 (6), pp. 1237-46. , 10.1590/S0102-311X2006000600013Congresso Nacional, Brasil., (1974) Lei Federal No. 6.050, 3, p. 107. , Brasília: Departamento de Imprensa Nacional Atos do Poder Legislativo. Leis de Abril a JunhoDuarte, C.M.R., Eqüidade na legislação: Um princípio do sistema de sade brasileiro? (2000) Cin Sade Coletiva, 5 (2), pp. 443-63Whitehead, M., The concepts and principles of equity and health (1992) Int J Health Serv, 22 (3), pp. 429-45. , 10.2190/986L-LHQ6-2VTE-YRRN 164450

Genetic epidemiology of SARS-CoV-2 transmission in renal dialysis units - a high risk community-hospital interface

OBJECTIVES: Patients requiring haemodialysis are at increased risk of serious illness with SARS-CoV-2 infection. To improve the understanding of transmission risks in six Scottish renal dialysis units, we utilised the rapid whole-genome sequencing data generated by the COG-UK consortium. METHODS: We combined geographical, temporal and genomic sequence data from the community and hospital to estimate the probability of infection originating from within the dialysis unit, the hospital or the community using Bayesian statistical modelling and compared these results to the details of epidemiological investigations. RESULTS: Of 671 patients, 60 (8.9%) became infected with SARS-CoV-2, of whom 16 (27%) died. Within-unit and community transmission were both evident and an instance of transmission from the wider hospital setting was also demonstrated. CONCLUSIONS: Near-real-time SARS-CoV-2 sequencing data can facilitate tailored infection prevention and control measures, which can be targeted at reducing risk in these settings

Testing a global standard for quantifying species recovery and assessing conservation impact

Recognizing the imperative to evaluate species recovery and conservation impact, in 2012 the International Union for Conservation of Nature (IUCN) called for development of a “Green List of Species” (now the IUCN Green Status of Species). A draft Green Status framework for assessing species’ progress toward recovery, published in 2018, proposed 2 separate but interlinked components: a standardized method (i.e., measurement against benchmarks of species’ viability, functionality, and preimpact distribution) to determine current species recovery status (herein species recovery score) and application of that method to estimate past and potential future impacts of conservation based on 4 metrics (conservation legacy, conservation dependence, conservation gain, and recovery potential). We tested the framework with 181 species representing diverse taxa, life histories, biomes, and IUCN Red List categories (extinction risk). Based on the observed distribution of species’ recovery scores, we propose the following species recovery categories: fully recovered, slightly depleted, moderately depleted, largely depleted, critically depleted, extinct in the wild, and indeterminate. Fifty-nine percent of tested species were considered largely or critically depleted. Although there was a negative relationship between extinction risk and species recovery score, variation was considerable. Some species in lower risk categories were assessed as farther from recovery than those at higher risk. This emphasizes that species recovery is conceptually different from extinction risk and reinforces the utility of the IUCN Green Status of Species to more fully understand species conservation status. Although extinction risk did not predict conservation legacy, conservation dependence, or conservation gain, it was positively correlated with recovery potential. Only 1.7% of tested species were categorized as zero across all 4 of these conservation impact metrics, indicating that conservation has, or will, play a role in improving or maintaining species status for the vast majority of these species. Based on our results, we devised an updated assessment framework that introduces the option of using a dynamic baseline to assess future impacts of conservation over the short term to avoid misleading results which were generated in a small number of cases, and redefines short term as 10 years to better align with conservation planning. These changes are reflected in the IUCN Green Status of Species Standard