Thermally Robust ALD and Silver Nanocube based Plasmonic Probe for High Temperature and Microfluidic SERS Measurement

Raman spectroscopy is normally a non-destructive, highly selective technique that has become an ubiquitous tool for analytical chemists. One of the primary limitations of Raman spectroscopy, however, is the relatively low cross-section of the technique. With signal enhancements relative to normal Raman scattering as high as 1011, the ultra-trace detection of adsorbates down to the single molecule level has been achieved with SERS. Despite the dramatic improvement in the sensitivity and the high selectivity afforded by the SERS method, the acceptance of SERS as a general analytical tool has been hindered by a lack of stability and reproducibility in the substrates. This lack of stability has been particularly troublesome because unstable substrates exhibit reduced shelf lives as well as a reduced ability to monitor processes that occur under non-ideal conditions such as high temperature or harsh chemical environments. In this thesis, two different works are reported that address the two major hurdles facing the SERS field in the development of a stable and reproducible SERS substrate. First, the development of a SERS-active substrate that exhibits improved temporal and thermal stability and is capable of in-situ high temperature measurement of analytes adsorbed on the surface is presented. The substrates are prepared by depositing an ultra-thin layer of alumina by Atomic Layer Deposition (ALD) onto silver island films grown by thermal evaporation. We demonstrate the application of alumina-coated substrates to the measurement of the dehydration of trace amounts of calcium nitrate tetrahydrate as a function of temperature. As a development of the above mentioned work, the combination of a silver/gold layered architecture obtained by thermal evaporation with an ultra-thin alumina overlayer to generate a re-usable SERS substrate that is simple, relatively inexpensive and stable is reported. The relative thicknesses of the silver and gold and the alumina overlayer was optimized to deliver the maximum SERS enhancement and optimal stability when the substrate was subjected to high temperature. Utilizing the method of thermal desorption of the analyte, the substrate surface is regenerated and able to be reused multiple times with little reduction in SERS activity. Second, in the development of a reproducible SERS substrate, the application of monodisperse silver nanocube colloidal substrate in microfluidic SERS is demonstrated. In static SERS experiments, one often has to search for “hot spots”, which are positions of a drastically increased SERS signal compared to the rest of the probe volume, in an inhomogeneous solution. To overcome this problem and prevent the decomposition and or fragmentation of SERS substrate and analyte, respectively, the implementation of flow cell is a promising way. At the beginning analyte, colloidal solution and aggregation agent were brought into a mixing chamber, where they were thoroughly mixed before being directed to a sample cell for detection. With this method, a relatively high amount of sample volume is necessary. In addition to the advantages listed above, efforts have been made to reduce the required amount of the sample solution by the design of low-cost poly (dimethylsiloxane) chips via soft lithography technique. The sample solution is passively pumped through the microfluidic channel, where an optical detection window is implemented for acquisition of a SERS spectrum

Erectile Dysfunction Severity as a Risk Marker for Cardiovascular Disease Hospitalisation and All-Cause Mortality: A Prospective Cohort Study

BACKGROUND Erectile dysfunction is an emerging risk marker for future cardiovascular disease (CVD) events; however, evidence on dose response and specific CVD outcomes is limited. This study investigates the relationship between severity of erectile dysfunction and specific CVD outcomes. METHODS AND FINDINGS We conducted a prospective population-based Australian study (the 45 and Up Study) linking questionnaire data from 2006-2009 with hospitalisation and death data to 30 June and 31 Dec 2010 respectively for 95,038 men aged ≥45 y. Cox proportional hazards models were used to examine the relationship of reported severity of erectile dysfunction to all-cause mortality and first CVD-related hospitalisation since baseline in men with and without previous CVD, adjusting for age, smoking, alcohol consumption, marital status, income, education, physical activity, body mass index, diabetes, and hypertension and/or hypercholesterolaemia treatment. There were 7,855 incident admissions for CVD and 2,304 deaths during follow-up (mean time from recruitment, 2.2 y for CVD admission and 2.8 y for mortality). Risks of CVD and death increased steadily with severity of erectile dysfunction. Among men without previous CVD, those with severe versus no erectile dysfunction had significantly increased risks of ischaemic heart disease (adjusted relative risk [RR] = 1.60, 95% CI 1.31-1.95), heart failure (8.00, 2.64-24.2), peripheral vascular disease (1.92, 1.12-3.29), "other" CVD (1.26, 1.05-1.51), all CVD combined (1.35, 1.19-1.53), and all-cause mortality (1.93, 1.52-2.44). For men with previous CVD, corresponding RRs (95% CI) were 1.70 (1.46-1.98), 4.40 (2.64-7.33), 2.46 (1.63-3.70), 1.40 (1.21-1.63), 1.64 (1.48-1.81), and 2.37 (1.87-3.01), respectively. Among men without previous CVD, RRs of more specific CVDs increased significantly with severe versus no erectile dysfunction, including acute myocardial infarction (1.66, 1.22-2.26), atrioventricular and left bundle branch block (6.62, 1.86-23.56), and (peripheral) atherosclerosis (2.47, 1.18-5.15), with no significant difference in risk for conditions such as primary hypertension (0.61, 0.16-2.35) and intracerebral haemorrhage (0.78, 0.20-2.97). CONCLUSIONS These findings give support for CVD risk assessment in men with erectile dysfunction who have not already undergone assessment. The utility of erectile dysfunction as a clinical risk prediction tool requires specific testing.JC has received research grants from Servier, administered through the University of Sydney and The George Institute, as principal investigator for the ADVANCE trial and ADVANCE-ON post trial follow-up study, and have received honoraria from Servier for speaking about ADVANCE at Scientific meetings. PM has received payment from Pfizer for giving a lecture on the treatment of pulmonary hypertension. All other authors have declared that no competing interests exis

Who pays for standardised testing? A cost-benefit study of mandated testing in three Queensland secondary schools

This paper reports on an Australian study that explored the costs and benefits of the National Assessment Programme, Literacy and Numeracy (NAPLAN) testing, both tangible and intangible, of Year 9 students in three Queensland schools. The study commenced with a review of pertinent studies and other related material about standardised testing in Australia, the USA and UK. Information about NAPLAN testing and reporting, and the pedagogical impacts of standardised testing were identified, however little about administrative costs to schools was found. A social constructivist perspective and a multiple case study approach were used to explore the actions of school managers and teachers in three Brisbane secondary schools. The study found that the costs of NAPLAN testing to schools fell into two categories: preparation of students for the testing; and administration of the tests. Whilst many of the costs could not be quantified, they were substantial and varied according to the education sector in which the school operated. The benefits to schools of NAPLAN testing were found to be limited. The findings have implications for governments, curriculum authorities and schools, leading to the conclusion that, from a school perspective, the benefits of NAPLAN testing do not justify the costs

Disability, psychological distress and quality of life in relation to cancer diagnosis and cancer type: population-based Australian study of 22,505 cancer survivors and 244,000 people without cancer

Background Improved survival means that cancer is increasingly becoming a chronic disease. Understanding and improving functional outcomes are critical to optimising survivorship. We quantified physical and mental health-related outcomes in people with versus without cancer, according to cancer type. Methods Questionnaire data from an Australian population-based cohort study (45 and Up Study (n = 267,153)) were linked to cancer registration data to ascertain cancer diagnoses up to enrolment. Modified Poisson regression estimated age- and sex-adjusted prevalence ratios (PRs) for adverse person-centred outcomes—severe physical functional limitations (disability), moderate/high psychological distress and fair/poor quality of life (QoL)—in participants with versus without cancer, for 13 cancer types. Results Compared to participants without cancer (n = 244,000), cancer survivors (n = 22,505) had greater disability (20.6% versus 12.6%, respectively, PR = 1.28, 95%CI = (1.25–1.32)), psychological (22.2% versus 23.5%, 1.05 (1.02–1.08)) and poor/fair QoL (15.2% versus 10.2%; 1.28 (1.24–1.32)). The outcomes varied by cancer type, being worse for multiple myeloma (PRs versus participants without cancer for disability 3.10, 2.56–3.77; distress 1.53, 1.20–1.96; poor/fair QoL 2.40, 1.87–3.07), lung cancer (disability 2.81, 2.50–3.15; distress 1.67, 1.46–1.92; poor/fair QoL 2.53, 2.21–2.91) and non-Hodgkin’s lymphoma (disability 1.56, 1.37–1.78; distress 1.20, 1.05–1.36; poor/fair QoL 1.66, 1.44–1.92) and closer to those in people without cancer for breast cancer (disability 1.23, 1.16–1.32; distress 0.95, 0.90–1.01; poor/fair QoL 1.15, 1.05–1.25), prostate cancer (disability 1.11, 1.04–1.19; distress 1.09, 1.02–1.15; poor/fair QoL 1.15, 1.08–1.23) and melanoma (disability 1.02, 0.94–1.10; distress 0.96, 0.89–1.03; poor/fair QoL 0.92, 0.83–1.01). Outcomes were worse with recent diagnosis and treatment and advanced stage. Physical disability in cancer survivors was greater in all population subgroups examined and was a major contributor to adverse distress and QoL outcomes. Conclusions Physical disability, distress and reduced QoL are common after cancer and vary according to cancer type suggesting priority areas for research, and care and support.This research was supported by the National Health and Medical Research Council (NHMRC) of Australia

Workforce participation in relation to cancer diagnosis, type and stage: Australian population-based study of 163,556 middle-aged people

Purpose To quantify the relationship of cancer diagnosis to workforce participation in Australia, according to cancer type, clinical features and personal characteristics. Methods Questionnaire data (2006–2009) from participants aged 45–64 years (n=163,556) from the population-based 45 and Up Study (n=267,153) in New South Wales, Australia, were linked to cancer registrations to ascertain cancer diagnoses up to enrolment. Modified Poisson regression estimated age- and sex-adjusted prevalence ratios (PRs) for non-participation in the paid workforce—in participants with cancer (n=8,333) versus without (n=155,223), for 13 cancer types. Results Overall, 42% of cancer survivors and 29% of people without cancer were out of the workforce (PR=1.18; 95%CI=1.15– 1.21). Workforce non-participation varied substantively by cancer type, being greatest for multiple myeloma (1.83; 1.53–2.18), oesophageal (1.70; 1.13–2.58) and lung cancer (1.68; 1.45–1.93) and moderate for colorectal (1.23; 1.15–1.33), breast (1.11; 1.06–1.16) and prostate cancer (1.06; 0.99–1.13). Long-term survivors, 5 or more years post-diagnosis, had 12% (7–16%) greater non-participation than people without cancer, and non-participation was greater with recent diagnosis, treatment or advanced stage. Physical disability contributed substantively to reduced workforce participation, regardless of cancer diagnosis. Conclusions Cancer survivors aged 45–64 continue to participate in the workforce. However, participation is lower than in people without cancer, varying by cancer type, and is reduced particularly around the time of diagnosis and treatment and with advanced disease. Implications for Cancer Survivors While many cancer survivors continue with paid work, participation is reduced. Workforce retention support should be tailored to survivor preferences, cancer type and cancer journey stage

Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents.

BACKGROUND: Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up. METHODS: Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4-14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5-<25·0 kg/m(2). FINDINGS: All-cause mortality was minimal at 20·0-25·0 kg/m(2) (HR 1·00, 95% CI 0·98-1·02 for BMI 20·0-<22·5 kg/m(2); 1·00, 0·99-1·01 for BMI 22·5-<25·0 kg/m(2)), and increased significantly both just below this range (1·13, 1·09-1·17 for BMI 18·5-<20·0 kg/m(2); 1·51, 1·43-1·59 for BMI 15·0-<18·5) and throughout the overweight range (1·07, 1·07-1·08 for BMI 25·0-<27·5 kg/m(2); 1·20, 1·18-1·22 for BMI 27·5-<30·0 kg/m(2)). The HR for obesity grade 1 (BMI 30·0-<35·0 kg/m(2)) was 1·45, 95% CI 1·41-1·48; the HR for obesity grade 2 (35·0-<40·0 kg/m(2)) was 1·94, 1·87-2·01; and the HR for obesity grade 3 (40·0-<60·0 kg/m(2)) was 2·76, 2·60-2·92. For BMI over 25·0 kg/m(2), mortality increased approximately log-linearly with BMI; the HR per 5 kg/m(2) units higher BMI was 1·39 (1·34-1·43) in Europe, 1·29 (1·26-1·32) in North America, 1·39 (1·34-1·44) in east Asia, and 1·31 (1·27-1·35) in Australia and New Zealand. This HR per 5 kg/m(2) units higher BMI (for BMI over 25 kg/m(2)) was greater in younger than older people (1·52, 95% CI 1·47-1·56, for BMI measured at 35-49 years vs 1·21, 1·17-1·25, for BMI measured at 70-89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46-1·56, vs 1·30, 1·26-1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI. INTERPRETATION: The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.UK MRC, BHF, NIHR; US NIHThis is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/S0140-6736(16)30175-

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation