Detailed breast cancer pathology data for large-scale studies - access and completeness in NSW, Australia.

OBJECTIVES: We sought to determine the ease with which breast cancer pathology data could be ascertained for a large cohort of Australian women, to support epidemiological research. METHOD: We assessed a range of options for accessing breast cancer pathology data. Manual review of the pathology report provided to the New South Wales Cancer Registry (NSWCR) was considered most feasible, complete and reliable. Incident breast cancers (ICD-10 C50) in female 45 and Up Study participants, resident in NSW, were identified from linked NSWCR data for the period 2006-2012. Data not routinely available in the NSWCR, including hormone receptor status, were extracted from the pathology report provided to the registry. RESULTS: Among 143 079 eligible women, 2051 had a first registration of breast cancer following cohort recruitment. The mean age at cancer diagnosis was 64.5 years. Based on cancer registry data, the cancers were predominantly ductal (74.1%), 54.4% were localised to the breast at diagnosis and 24.2% were >50 mm in size. Based on manually extracted data from pathology records, 23.9% of cancers were histological grade 1, 79.6% were oestrogen receptor positive and 71.2% were progestogen receptor positive. These data were mostly complete (<10% missing). HER2 receptor status was less well reported, with 31.9% of cancers having indeterminate or missing data, while 11.3% were reported as positive. Data on lymph node status was missing in 16.1% of breast cancer reports, 33.7% were node positive. 8.0% of breast cancers had involved surgical margins, and this data was missing for 14.1% of cases. CONCLUSION: Pathology information, in addition to that available from routine registry data, is required both for breast cancer research and for monitoring trends in the types of breast cancer occurring over time in Australia. All the important additional data items required are recorded on the pathology report, which is provided to the NSWCR as part of cancer notification but is not routinely coded, and are generally fairly complete. However, access to these data for large-scale studies requires substantial effort. Coding the pathology data and making it routinely available would substantially improve cancer research and enable proper monitoring of breast cancer trends in Australia.

The integration and interpretation of pharmacogenomics - a comparative study between the United States of America and Europe: towards better health care.

The study of pharmacogenomics has, by harnessing sequence information from human genomes, the potential to lead to novel approaches in drug discovery, an individualized application of drug therapy, and new insights into disease prevention. For this potential to be realized results need to be interpreted to the prescriber into a format which dictates an action. This mini review briefly describes the history, the regulatory environment, opinions towards, and implementation, integration and interpretation of pharmacogenomics in the United States of America and Europe. The article discusses also how interpretation of pharmacogenomics could move forward to better implementation in health care.

ProPhenol-catalyzed asymmetric additions by spontaneously assembled dinuclear main group metal complexes.

The development of catalytic enantioselective transformations has been the focus of many research groups over the past half century and is of paramount importance to the pharmaceutical and agrochemical industries. Since the award of the Nobel Prize in 2001, the field of enantioselective transition metal catalysis has soared to new heights, with the development of more efficient catalysts and new catalytic transformations at increasing frequency. Furthermore, catalytic reactions that allow higher levels of redox- and step-economy are being developed. Thus, alternatives to asymmetric alkene dihydroxylation and the enantioselective reduction of α,ß-unsaturated ketones can invoke more strategic C-C bond forming reactions, such as asymmetric aldol reactions of an aldehyde with α-hydroxyketone donors or enantioselective alkynylation of an aldehyde, respectively. To facilitate catalytic enantioselective addition reactions, including the aforementioned aldol and alkynylation reactions, our lab has developed the ProPhenol ligand. In this Account, we describe the development and application of the ProPhenol ligand for asymmetric additions of both carbon- and heteroatom-based nucleophiles to various electrophiles. The ProPhenol ligand spontaneously forms chiral dinuclear metal complexes when treated with an alkyl metal reagent, such as Et2Zn or Bu2Mg. The resulting complex contains both a Lewis acidic site to activate an electrophile and a Brønsted basic site to deprotonate a pronucleophile. Initially, our research focused on the use of Zn-ProPhenol complexes to facilitate the direct aldol reaction. Fine tuning of the reaction through ligand modification and the use of additives enabled the direct aldol reaction to proceed in high yields and stereoselectivities with a broad range of donor substrates, including acetophenones, methyl ynones, methyl vinyl ketone, acetone, α-hydroxy carbonyl compounds, and glycine Schiff bases. Additionally, an analogous magnesium ProPhenol complex was used to facilitate enantioselective diazoacetate aldol reactions with aryl, α,ß-unsaturated, and aliphatic aldehydes. The utility of bimetallic ProPhenol catalysts was extended to asymmetric additions with a wide range of substrate combinations. Effective pronucleophiles include oxazolones, 2-furanone, nitroalkanes, pyrroles, 3-hydroxyoxindoles, alkynes, meso-1,3-diols, and dialkyl phosphine oxides. These substrates were found to be effective with a number of electrophiles, including aldehydes, imines, nitroalkenes, acyl silanes, vinyl benzoates, and α,ß-unsaturated carbonyls. A truly diverse range of enantioenriched compounds have been prepared using the ProPhenol ligand, and the commercial availability of both ligand enantiomers makes it ideally suited for the synthesis of complex molecules. To date, enantioselective ProPhenol-catalyzed reactions have been used in the synthesis of more than 20 natural products.

13C NMR analysis of 3,6-dihydro-2H-pyrans: assignment of remote stereochemistry using axial shielding effects.

The rational analysis of (13)C NMR axial shielding effects has enabled the assignment of remote relative stereochemistry in 3,6-oxygen-substituted 3,6-dihydro-2H-pyrans. Comparison of the (13)C NMR shifts of equivalent centers in cis- and trans-substituted 3,6-dihydro-2H-pyrans allows the relative configuration at the C3 and C6 positions to be defined in diastereoisomeric mixtures. Density functional calculations were used to validate this method and assess the conformational bias present in the ring system. Ultimately, the coupling of computational chemistry with this (13)C NMR-based method provided a reliable and convenient method for stereochemical assignment of a single diastereomer. This approach provides a facile and complementary alternative to the practices previously employed for determining the relative configuration in 3,6-dihydro-2H-pyrans.

Cooperative tandem catalysis by an organometallic complex and a metalloenzyme.

Although chemical and enzymatic catalysts have been combined, reactions in which an organometallic catalyst and a metalloenzyme work cooperatively to create products, which cannot be generated with either catalyst alone or in comparable yields by sequential reactions of the two catalysts, have not been reported. Such reactions are challenging to achieve, in part because the milieu in which these catalysts operate are typically different. Herein, two classes of catalysts are demonstrated to react cooperatively in the same system. Combination of a metathesis catalyst and a P450 enzyme lead to a dynamic equilibration of alkenes and a selective epoxidation of the cross-metathesis products. These results show the potential of combining the two classes of catalysts for synthetic transformations.

Improving cardiovascular disease management in Australia: NPS MedicineWise.

OBJECTIVES: To determine the impact of four NPS MedicineWise programs targeting quality use of medicines in cardiovascular management in primary care. DESIGN: Interrupted time-series analysis using the Department of Veterans' Affairs (DVA) claims dataset from 1 January 2002 to 31 August 2010. We examined the use of antithrombotics in people with atrial fibrillation and in those who had had a stroke, and the use of echocardiography and spironolactone in the population with heart failure. PARTICIPANTS: All veterans and their dependants in Australia who had received cardiovascular medicines or health services related to the targeted intervention. INTERVENTION: NPS MedicineWise national programs to improve cardiovascular management in primary care, which included prescriber feedback, academic detailing, case studies and audits as well as printed educational materials. MAIN OUTCOME MEASURES: Changes in medication and health service use before and after the interventions. RESULTS: All national programs were positively associated with significant improvements in related prescribing or test request practice. The interventions to improve the use of antithrombotics resulted in a 1.27% (95% CI, 1.26%-1.28%) and 0.63% (95% CI, 0.62%-0.64%) relative increase in the use of aspirin or warfarin in the population with atrial fibrillation 6 and 12 months after the program, respectively, and in a 1.51% (95% CI, 1.49%-1.53%) relative increase in the use of aspirin as monotherapy for secondary stroke prevention 12 months after the intervention. The heart failure programs resulted in a 3.69% (95% CI, 3.67%-3.71%) relative increase in the use of low-dose spironolactone and a 4.31% (95% CI, 4.27%-4.35%) relative increase in the use of echocardiogram tests 12 months after the intervention. CONCLUSIONS: NPS MedicineWise programs were effective in achieving positive changes in medicine and health service use for patients with cardiovascular diseases.

Pd-catalyzed allylic alkylation cascade with dihydropyrans: regioselective synthesis of furo[3,2-c]pyrans.

A regioselective palladium-catalyzed allylic alkylation cascade forms furo[3,2-c]pyrans from various cyclic ß-dicarbonyl bis-nucleophiles and 3,6-dihydro-2H-pyran bis-electrophiles. The combination of allylic carbonate and anomeric siloxy leaving groups in the dihydropyran substrate allows control of the many regiochemical possibilities in this reaction. Annulation proceeds stereoconvergently to give cis-fused furopyrans from either cis- or trans-substituted starting material.

Development of Zn-ProPhenol-catalyzed asymmetric alkyne addition: synthesis of chiral propargylic alcohols.

The development of a general and practical zinc-catalyzed enantioselective alkyne addition methodology is reported. The commercially available ProPhenol ligand (1) has facilitated the addition of a wide range of zinc alkynylides to aryl, aliphatic, and α,ß-unsaturated aldehydes in high yield and enantioselectivity. New insights into the mechanism of this reaction have resulted in a significant reduction in reagent stoichiometry, enabling the use of precious alkynes and avoiding the use of excess dimethylzinc. The enantioenriched propargylic alcohols from this reaction serve as versatile synthetic intermediates and have enabled efficient syntheses of several complex natural products.

Transition-metal-catalyzed synthesis of aspergillide B: an alkyne addition strategy.

A catalytic enantioselective formal total synthesis of aspergillide B is reported. This linchpin synthesis was enabled by the development of new conditions for Zn-ProPhenol catalyzed asymmetric alkyne addition. This reaction was used in conjunction with ruthenium-catalyzed trans-hydrosilylation to affect the rapid construction of a late-stage synthetic intermediate of aspergillide B to complete a formal synthesis of aspergillide B in a highly efficient manner.

Thionium ion initiated medium-sized ring formation: the total synthesis of asteriscunolide D.

The first synthesis of the biologically active humulene natural product asteriscunolide D has been accomplished in nine steps without the use of protecting groups. The challenging 11-membered ring was forged via a diastereoselective thionium ion initiated cyclization, which constitutes a formal aldol disconnection to form a strained macrocycle. A stereospecific thioether activation-elimination protocol was developed for selective E-olefin formation, thus providing access to the most biologically active asteriscunolide. The absolute stereochemical configuration was established by the Zn-ProPhenol catalyzed enantioselective addition of methyl propiolate to an aliphatic aldehyde to afford a γ-hydroxy propiolate as a handle for butenolide formation via Ru-catalyzed alkene-alkyne coupling.

Characteristics of HIV diagnoses in Australia, 1993-2006.

OBJECTIVE: To describe recent trends in the diagnosis of HIV infection in Australia. METHODS: National HIV surveillance data from 1993 to 2006 were analysed with a focus on geographic differences by HIV exposure route and late presentation (HIV within 3 months of a first AIDS-defining illness or a CD4 count of less than 200 cells muL(-1)). RESULTS: In 1993-99, the number of HIV diagnoses declined by 32%, and then increased by 39% from 1999 to 2006. From 2000 onwards, rates increased significantly in Victoria, Queensland, South Australia and Western Australia. The most frequently reported routes of HIV exposure were male to male sex (71%) and heterosexual contact (18%), and the population rate of diagnoses have increased in both categories. Among the cases reported as heterosexually acquired (n = 2199), 33% were in people born in a high-prevalence country and 19% in those with partners from a high-prevalence country. Late presentation was most frequent in heterosexually acquired infections in persons who had a partner from a high-prevalence country: 32% compared with 20% overall. CONCLUSIONS: Recent increases in annual numbers of HIV diagnoses in Australia underline the continuing need for HIV-prevention programs, particularly among men having male to male sex. Early diagnosis and access to care and treatment should also be emphasised, as a substantial proportion of people with HIV infection are unaware of their status until late in the course of disease.

HIV diagnoses in Australia: diverging epidemics within a low-prevalence country.

OBJECTIVE: To describe recent trends in the diagnosis of HIV infection in Australia. DESIGN AND SETTING: Analysis of national surveillance system data for 1993-2006. MAIN OUTCOME MEASURES: Number and population rate of new HIV diagnoses by year, exposure route and demographic characteristics. RESULTS: Between 1993 and 2006, 12 313 new diagnoses of HIV infection were reported in Australia. From 1993 to 1999, the annual number of diagnoses declined by 32% from 1056 to 718, and then increased by 31% from 763 in 2000 to 998 in 2006. Between 2000 and 2006, diagnosis rates significantly increased in Victoria, Queensland, South Australia and Western Australia. The most frequent route of HIV exposure was male-to-male sex, accounting for 70% of diagnoses. Heterosexual contact accounted for 18% of cases, with just over half of these people born in or having a sexual partner from a high-prevalence country. Exposure by injecting drug use remained infrequent. CONCLUSIONS: The number of HIV diagnoses has risen in the past 7 years, but not in New South Wales, which has long had the highest rates. The differences in rates between states/territories are likely to be due to divergent trends in sexual risk behaviour in men having male-to-male sex, which remains the predominant route of HIV transmission in Australia. There is a need for effective, innovative and evidence-based programs for HIV prevention, particularly among men having male-to-male sex.

Planning for pandemic influenza surveillance in NSW.

Early detection of a novel strain (genotype) of influenza virus in the NSW population is the key to controlling a pandemic. If this occurs, ongoing surveillance will help determine the epidemiology and risk factors of the virus as well as its impact on essential services. Important components of surveillance preparedness in NSW include: border surveillance; hospital-based screening for suspected cases; protocols for efficient transport and testing of viral specimens; flexible, robust electronic tools for rapid surveillance data collection; management and reporting; and creation of surveillance surge capacity.

Do we practice what we preach? Health care worker screening and vaccination.

OBJECTIVE: To describe the current screening and immunization practices in New South Wales (NSW) hospitals and the experience of NSW nurses in relation to screening and immunization and to identify areas that can be targeted for improvement. DESIGN: This was a cross-sectional survey. SETTING: The study was performed in NSW, Australia. METHODS: We used a written questionnaire to survey the infection control/occupational health coordinators of all of the 85 private hospitals and 204 eligible public hospitals in NSW and 800 randomly sampled registered nurses. RESULTS: Response rates were high (hospitals [90%], nurses [70%]). Hospitals almost universally offered hepatitis B vaccination to nurses (251/261, 96%), but more than one quarter (132/473, 28%) of nurses reported incomplete vaccination. Provision to physicians was relatively poor (142/261, 54%). The majority of nurses (> 80%) had been vaccinated with bacille Calmette-Guérin vaccine, but hospitals reported variable tuberculosis screening practices. Both hospitals and nurses reported low rates (< 30%) of screening and vaccination provision for varicella and measles-mumps-rubella. Two thirds of NSW hospitals (174/261, 67%) provided annual influenza vaccination. CONCLUSIONS: Even though hepatitis B immunization programs were widespread, their effectiveness could be improved by ensuring that vaccination schedules are completed and by targeting physicians. Varicella and measles-mumps-rubella screening and immunization programs are currently lacking. Better strategies are needed to improve the implementation of health care worker protection guidelines in hospitals.