Multiple myeloma (MM), a plasma cell (PC) malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply scRNA-seq to study the heterogeneity of 40 individuals along MM progression spectrum including 11 healthy controls, demonstrating high interpatient variability that can be explained by expression of known MM drivers and additional putative factors. We identify extensive sub-clonal structures for 10/29 patients. In asymptomatic patients with early disease and in minimal residual disease post-treatment, we detect rare tumor-PC with similar molecular characteristics of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating-tumor-cells (CTC) allows for accurate liquid biopsy and detection of malignant PC, which reflect the patient BM disease. Our work establishes scRNA-seq for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients.

Background Tobacco smoking is a leading cause of cardiovascular disease (CVD) morbidity and mortality. Evidence on the relation of smoking to different subtypes of CVD, across fatal and non-fatal outcomes, is limited. Methods A prospective study of 188,167 CVD- and cancer-free individuals aged ≥ 45 years from the Australian general population joining the 45 and Up Study from 2006 to 2009, with linked questionnaire, hospitalisation and death data up to the end of 2015. Hazard ratios (HRs) for hospitalisation with or mortality from CVD among current and past versus never smokers were estimated, including according to intensity and recency of smoking, using Cox regression, adjusting for age, sex, urban/rural residence, alcohol consumption, income and education. Population-attributable fractions were estimated. Results During a mean 7.2 years follow-up (1.35 million person-years), 27,511 (crude rate 20.4/1000 person-years) incident fatal and non-fatal major CVD events occurred, including 4548 (3.2) acute myocardial infarction (AMI), 3991 (2.8) cerebrovascular disease, 3874 (2.7) heart failure and 2311 (1.6) peripheral arterial disease (PAD) events. At baseline, 8% of participants were current and 34% were past smokers. Of the 36 most common specific CVD subtypes, event rates for 29 were increased significantly in current smokers. Adjusted HRs in current versus never smokers were as follows: 1.63 (95%CI 1.56–1.71) for any major CVD, 2.45 (2.22–2.70) for AMI, 2.16 (1.93–2.42) for cerebrovascular disease, 2.23 (1.96–2.53) for heart failure, 5.06 (4.47–5.74) for PAD, 1.50 (1.24–1.80) for paroxysmal tachycardia, 1.31 (1.20–1.44) for atrial fibrillation/flutter, 1.41 (1.17–1.70) for pulmonary embolism, 2.79 (2.04–3.80) for AMI mortality, 2.26 (1.65–3.10) for cerebrovascular disease mortality and 2.75 (2.37–3.19) for total CVD mortality. CVD risks were elevated at almost all levels of current smoking intensity examined and increased with smoking intensity, with HRs for total CVD mortality in current versus never smokers of 1.92 (1.11–3.32) and 4.90 (3.79–6.34) for 4–6 and ≥ 25 cigarettes/day, respectively. Risks diminished with quitting, with excess risks largely avoided by quitting before age 45. Over one third of CVD deaths and one quarter of acute coronary syndrome hospitalisations in Australia aged < 65 can be attributed to smoking. Conclusions Current smoking increases the risk of virtually all CVD subtypes, at least doubling the risk of many, including AMI, cerebrovascular disease and heart failure. Paroxysmal tachycardia is a newly identified smoking-related risk. Where comparisons are possible, smoking-associated relative risks for fatal and non-fatal outcomes are similar. Quitting reduces the risk substantially. In an established smoking epidemic, with declining and low current smoking prevalence, smoking accounts for a substantial proportion of premature CVD events. Electronic supplementary mater...

Background Despite generally high smoking prevalences, stemming from colonization, the relationship of smoking to mortality has not been quantified reliably in an Indigenous population. We investigate smoking and mortality among Aboriginal and Torres Strait Islander adults in Australia, where current adult daily smoking prevalence is 40.2%. Methods A prospective study of 1388 cardiovascular disease- and cancer-free Aboriginal adults aged ≥45 years, of the 267 153 45 and Up Study participants randomly sampled from the New South Wales general population over 2006–09. Questionnaire and mortality data were linked (through the Centre for Health Record Linkage) to mid-2019. Adjusted hazard ratios (called relative risks, RRs) for all-cause mortality—among current- and past- versus never-smokers—were estimated overall, by smoking intensity and by age at cessation. Smoking-attributable fractions and associated deaths were estimated. Results Over 14 586 person-years’ follow-up (median 10.6 years), 162 deaths accrued. Mortality RRs [95% confidence interval (CI)] were 3.90 (2.52–6.04) for current- and 1.95 (1.32–2.90) for past- versus never-smokers, with age heterogeneity. RRs increased with smoking intensity, to 4.29 (2.15–8.57) in current-smokers of ≥25 cigarettes/day. Compared with never-smokers, RRs were 1.48 (0.85–2.57) for those quitting at &lt;45 years of age and 2.21 (1.29–3.80) at 45–54 years. Never-smokers lived an average &gt;10 years longer than current-smokers. Around half of deaths among adults aged ≥45 years were attributable to smoking, exceeding 10 000 deaths in the past decade. Conclusions In this population, &gt;80% of never-smokers would survive to 75 years, versus ∼40% of current-smokers. Quitting at all ages examined had substantial benefits versus continuing smoking; those quitting before age 45 years had mortality risks similar to never-smokers. Smoking causes half of deaths in older Aboriginal and Torres Strait Islander adults; Indigenous tobacco control must receive increased priority.

BackgroundDespite growing interest in prevention of lower urinary tract symptoms (LUTS) through better understanding of modifiable risk factors, large-scale population-based evidence is limited.ObjectiveTo describe risk factors associated with severe LUTS in the 45 and Up Study, a large cohort study.Design, Setting, and ParticipantsA cross-sectional analysis of questionnaire data from 106,435 men aged ≥45 years, living in New South Wales, Australia.Outcome Measures and Statistical AnalysisLUTS were measured by a modified version of the International Prostate Symptom Score (m-IPSS). The strength of association between severe LUTS and socio-demographic, lifestyle and health-related factors was estimated, using logistic regression to calculate odds ratios, adjusted for a range of confounding factors.ResultsOverall, 18.3% reported moderate, and 3.6% severe, LUTS. Severe LUTS were more common among men reporting previous prostate cancer (7.6%), total prostatectomy (4.9%) or having part of the prostate removed (8.2%). After excluding men with prostate cancer or prostate surgery, the prevalence of moderate-severe LUTS in the cohort (n = 95,089) ranged from 10.6% to 35.4% for ages 45–49 to ≥80; the age-related increase was steeper for storage than voiding symptoms. The adjusted odds of severe LUTS decreased with increasing education (tertiary qualification versus no school certificate, odds ratio (OR = 0.78 (0.68–0.89))) and increasing physical activity (high versus low, OR = 0.83 (0.76–0.91)). Odds were elevated among current smokers versus never-smokers (OR = 1.64 (1.43–1.88)), obese versus healthy-weight men (OR = 1.27 (1.14–1.41)) and for comorbid conditions (e.g., heart disease versus no heart disease, OR = 1.36 (1.24–1.49)), and particularly for severe versus no physical functional limitation (OR = 5.17 (4.51–5.93)).ConclusionsLUTS was associated with a number of factors, including modifiable risk factors, suggesting potential targets for prevention.

BackgroundCardiovascular disease (CVD) disproportionately affects disadvantaged people, but reliable quantitative evidence on socioeconomic variation in CVD incidence in Australia is lacking. This study aimed to quantify socioeconomic variation in rates of primary and secondary CVD events in mid-age and older Australians.MethodsBaseline data (2006–2009) from the 45 and Up Study, an Australian cohort involving 267,153 men and women aged ≥ 45, were linked to hospital and death data (to December 2013). Outcomes comprised first event – death or hospital admission – for major CVD combined, as well as myocardial infarction and stroke, in those with and without prior CVD (secondary and primary events, respectively). Cox regression estimated hazard ratios (HRs) for each outcome in relation to education (and income and area-level disadvantage), separately by age group (45–64, 65–79, and ≥ 80 years), adjusting for age and sex, and additional sociodemographic factors.ResultsThere were 18,207 primary major CVD events over 1,144,845 years of follow-up (15.9/1000 person-years), and 20,048 secondary events over 260,357 years (77.0/1000 person-years). For both primary and secondary events, incidence increased with decreasing education, with the absolute difference between education groups largest for secondary events. Age-sex adjusted hazard ratios were highest in the 45-64 years group: for major CVDs, HR (no qualifications vs university degree) = 1.62 (95% CI: 1.49–1.77) for primary events, and HR = 1.49 (1.34–1.65) for secondary events; myocardial infarction HR = 2.31 (1.87–2.85) and HR = 2.57 (1.90–3.47) respectively; stroke HR = 1.48 (1.16–1.87) and HR = 1.97 (1.42–2.74) respectively. Similar but attenuated results were seen in older age groups, and with income. For area-level disadvantage, CVD gradients were weak and non-significant in older people (> 64 years).ConclusionsIndividual-level data are important for quantifying socioeconomic variation in CVD incidence, which is shown to be substantial among both those with and without prior CVD. Findings reinforce the opportunity for, and importance of, primary and secondary prevention and treatment in reducing socioeconomic variation in CVD and consequently the overall burden of CVD morbidity and mortality in Australia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12939-016-0471-0) contains supplementary material, which is available to authorized users.