A case-cohort study of the association between adiponectin and mortality in EPIC-Heidelberg: NT-proBNP may explain the adiponectin paradox.

BACKGROUND AND AIMS: NT-proBNP has been hypothesized as a possible explanation for the paradoxical association between adiponectin and cardiovascular and all-cause mortality. We examined the heterogeneities by NT-proBNP, sex, BMI, smoking status, hypertension and diabetes status in the association between adiponectin and cardiovascular disease risk and mortality. METHODS AND RESULTS: We used a case-cohort design nested within the EPIC-Heidelberg cohort, including 1387 incident cases of myocardial infarction or stroke, 582 deaths from cardiovascular causes and 2352 total deaths. We estimated hazard ratios for the association between 1SD increase in log-transformed total adiponectin levels and cardiovascular disease risk, cardiovascular mortality and mortality using Prentice-weighted Cox-proportional hazard models and assessed heterogeneity of the associations across strata of covariates. Overall, adiponectin was significantly associated with all-cause mortality [HR = 1.09, 95% CI: 1.03-1.16, p = 0.004]. The association with cardiovascular mortality did not reach statistical significance [1.10 (0.99-1.37), p = 0.073]. There was significant heterogeneity by NT-proBNP in the association between total adiponectin and all-cause mortality (phet = 0.019) such that significant increase in hazards of mortality were restricted to participants in the highest tertile of NT-proBNP. Among these participants, adiponectin showed a dose-response relationship with total mortality such that; compared to participants in the lowest quintile, those in the third, fourth and fifth were at 1.22 (0.87-1.70), 1.50 (1.07-2.11), and 1.59 (1.15-2.21) higher hazards of mortality respectively. CONCLUSIONS: Significant association between adiponectin and mortality was only observed in the context of high NT-proBNP. Our findings provide further support for hypothesis that NT-proBNP may explain the adiponectin paradox.

Prospective evaluation of 92 serum protein biomarkers for early detection of ovarian cancer.

BACKGROUND: CA125 is the best available yet insufficiently sensitive biomarker for early detection of ovarian cancer. There is a need to identify novel biomarkers, which individually or in combination with CA125 can achieve adequate sensitivity and specificity for the detection of earlier-stage ovarian cancer. METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we measured serum levels of 92 preselected proteins for 91 women who had blood sampled ≤18 months prior to ovarian cancer diagnosis, and 182 matched controls. We evaluated the discriminatory performance of the proteins as potential early diagnostic biomarkers of ovarian cancer. RESULTS: Nine of the 92 markers; CA125, HE4, FOLR1, KLK11, WISP1, MDK, CXCL13, MSLN and ADAM8 showed an area under the ROC curve (AUC) of ≥0.70 for discriminating between women diagnosed with ovarian cancer and women who remained cancer-free. All, except ADAM8, had shown at least equal discrimination in previous case-control comparisons. The discrimination of the biomarkers, however, was low for the lag-time of >9-18 months and paired combinations of CA125 with any of the 8 markers did not improve discrimination compared to CA125 alone. CONCLUSION: Using pre-diagnostic serum samples, this study identified markers with good discrimination for the lag-time of 0-9 months. However, the discrimination was low in blood samples collected more than 9 months prior to diagnosis, and none of the markers showed major improvement in discrimination when added to CA125.

Sex differences in the mortality rate for coronavirus disease 2019 compared to other causes of death: an analysis of population-wide data from 63 countries.

Men are more likely than women to die due to coronavirus disease 2019 (COVID-19). An open question is whether these sex differences reflect men's generally poorer health and lower life expectancy compared to women of similar ages or if men face a unique COVID-19 disadvantage. Using age-specific data on COVID-19 mortality as well as cause-specific and all-cause mortality for 63 countries, we compared the sex difference in COVID-19 mortality to sex differences in all-cause mortality and mortality from other common causes of death to determine the magnitude of the excess male mortality disadvantage for COVID-19. We found that sex differences in the age-standardized COVID-19 mortality rate were substantially larger than for the age-standardized all-cause mortality rate and mortality rate for most other common causes of death. The excess male mortality disadvantage for COVID-19 was especially large in the oldest age groups. Our findings suggest that the causal pathways that link male sex to a higher mortality from a SARS-CoV-2 infection may be specific to SARS-CoV-2, rather than shared with the pathways responsible for the shorter life expectancy among men or sex differences for other common causes of death. Understanding these causal chains could assist in the development of therapeutics and preventive measures for COVID-19 and, possibly, other coronavirus diseases.

Risk of prostate cancer in relatives of prostate cancer patients in Sweden: A nationwide cohort study.

BACKGROUND: Evidence-based guidance for starting ages of screening for first-degree relatives (FDRs) of patients with prostate cancer (PCa) to prevent stage III/IV or fatal PCa is lacking in current PCa screening guidelines. We aimed to provide evidence for risk-adapted starting age of screening for relatives of patients with PCa. METHODS AND FINDINGS: In this register-based nationwide cohort study, all men (aged 0 to 96 years at baseline) residing in Sweden who were born after 1931 along with their fathers were included. During the follow-up (1958 to 2015) of 6,343,727 men, 88,999 were diagnosed with stage III/IV PCa or died of PCa. The outcomes were defined as the diagnosis of stage III/IV PCa or death due to PCa, stratified by age at diagnosis. Using 10-year cumulative risk curves, we calculated risk-adapted starting ages of screening for men with different constellations of family history of PCa. The 10-year cumulative risk of stage III/IV or fatal PCa in men at age 50 in the general population (a common recommended starting age of screening) was 0.2%. Men with ≥2 FDRs diagnosed with PCa reached this screening level at age 41 (95% confidence interval (CI): 39 to 44), i.e., 9 years earlier, when the youngest one was diagnosed before age 60; at age 43 (41 to 47), i.e., 7 years earlier, when ≥2 FDRs were diagnosed after age 59, which was similar to that of men with 1 FDR diagnosed before age 60 (41 to 45); and at age 45 (44 to 46), when 1 FDR was diagnosed at age 60 to 69 and 47 (46 to 47), when 1 FDR was diagnosed after age 69. We also calculated risk-adapted starting ages for other benchmark screening ages, such as 45, 55, and 60 years, and compared our findings with those in the guidelines. Study limitations include the lack of genetic data, information on lifestyle, and external validation. CONCLUSIONS: Our study provides practical information for risk-tailored starting ages of PCa screening based on nationwide cancer data with valid genealogical information. Our clinically relevant findings could be used for evidence-based personalized PCa screening guidance and supplement current PCa screening guidelines for relatives of patients with PCa.

Risk-adapted starting age of breast cancer screening in women with a family history of ovarian or other cancers: A nationwide cohort study.

BACKGROUND: There is a lack of evidence-based recommendations for the age at which women with a family history of cancers other than breast cancer should start breast cancer screening. METHODS: Using Swedish family cancer data sets, the authors conducted a nationwide cohort study including 5,099,172 Swedish women born after 1931 (follow-up, 1958-2015). Accounting for calendar time, they calculated the relative risk of breast cancer for women with a family history of a discordant cancer in 1 first-degree relative. Furthermore, the authors used 10-year cumulative risk to determine the ages at which women with a family history of discordant cancer reached risk thresholds at which women in the general population were recommended to start breast cancer screening. RESULTS: A family history of cancer at 15 sites was associated with an increased risk of breast cancer. Among women younger than 50 years, the highest risk of breast cancer was observed for those with a family history of ovarian cancer (standardized incidence ratio, 1.44; 95% confidence interval, 1.26-1.64). In these women, the risk of breast cancer associated with a family history at other cancer sites ranged from 1.08-fold for prostate cancer to 1.18-fold for liver cancer. When breast cancer screening was recommended to be started at the age of 50 years for the general population, women with 1 first-degree relative with ovarian cancer attained the threshold risk for screening at the age of 46 years. Women with a family history of other discordant cancers did not reach the risk thresholds for screening at younger ages. CONCLUSIONS: Many cancers showed familial associations with breast cancer, but women with a family history of these cancers (except for ovarian cancer) did not reach risk thresholds for screening at younger ages.

Familial risk of breast cancer by dynamic, accumulative, and static definitions of family history.

BACKGROUND: Familial breast cancer risk studies usually overlook the dynamic nature of family history. METHODS: The authors assessed the effect of incorporating the timing of cancer diagnosis events into the assessment of familial risks of breast cancer in first-degree and second-degree relatives in a nationwide cohort study of 5,099,172 women (follow-up was between 1958-2015). Family history was assessed using 3 approaches: 1) as a static variable (ever having a relative with breast cancer); 2) as accumulative history; and 3) as a dynamic variable (time-dependent variable). RESULTS: For women aged <50 years, familial risk was mostly higher when family history was assessed as a dynamic variable compared with using a static or accumulative family history. For example, the cumulative risk of receiving a breast cancer diagnosis until age 50 years for women with a history of breast cancer in 1 first-degree relative was 2.6% (95% CI, 2.5%-2.7%) using the static method, 2.4% (95% CI, 2.3%-2.4%) using the accumulative method, and 3.1% (95% CI, 3.0%-3.2%) using the dynamic method. Relative risk in women aged <50 years with a breast cancer diagnosis in a sister was 1.40-fold (95% CI, 1.31-fold to 1.48-fold) using the static method, 1.66-fold (95% CI, 1.57-fold to 1.76-fold) using the accumulative method, and 2.28-fold (95% CI, 2.07-fold to 2.51-fold) using the dynamic method. CONCLUSIONS: The results of the current study demonstrated that assessing family history as static, accumulative, or dynamic results in different familial risk estimates. The answer as to which method to use for family history assessment depends on the implications of the study, with the dynamic method appearing to be better suited for risk stratification studies, the accumulative method being the most convenient in practice and the least favored for risk prediction, and the static method being suitable for etiological impact and risk attribution studies.

Risk of invasive prostate cancer and prostate cancer death in relatives of patients with prostatic borderline or in situ neoplasia: A nationwide cohort study.

BACKGROUND: The question of whether having a family history of prostatic borderline or in situ neoplasia (PBISN) is associated with an increased risk of invasive prostate cancer (PCa) or death from PCa remains unanswered. The objective of the current study was to provide an evidence-based risk estimation for the relatives of patients with PBISN. METHODS: Nationwide Swedish family cancer data sets were used for the current study, including data regarding all residents of Sweden who were born after 1931 and their parents. Standardized incidence ratios (SIRs), standardized mortality ratios (SMRs), and lifetime cumulative risks of PCa were calculated for men with different constellations of family history. Family history was defined as a dynamic (time-dependent) variable considering changes during follow-up (1958-2015). RESULTS: Of the 6,343,727 men in the current study, a total of 238,961 developed invasive PCa and 5756 were diagnosed with PBISN during the follow-up. Men with 1 first-degree relative who was diagnosed with PBISN had a 70% increased risk of invasive PCa (SIR, 1.7; 95% confidence interval, 1.5-1.9) and PCa death (SMR, 1.7; 95% confidence interval, 1.3-2.2) compared with men with no family history of PBISN or invasive PCa. These were rather close to estimates in men with 1 first-degree relative diagnosed with invasive PCa (SIR, 2.1 and SMR, 1.8). A higher risk of PCa in family members was found among patients with a family history of PBISN and/or PCa diagnosed before age 60 years. The results in terms of cumulative risk resembled this trend. CONCLUSIONS: A family history of PBISN appears to be as important as a family history of invasive PCa with regard to an increased risk of invasive PCa or PCa mortality. Such a history should not be overlooked in PCa screening recommendations or in future research regarding familial PCa.

Risk of invasive breast cancer in relatives of patients with breast carcinoma in situ: a prospective cohort study.

BACKGROUND: Wide implementation of mammography screening has resulted in increased numbers of women diagnosed with breast carcinoma in situ. We aimed to determine the risk of invasive breast cancer in relatives of patients with breast carcinoma in situ in comparison to the risk in relatives of patients with invasive breast cancer. METHODS: We analyzed the occurrence of cancer in a nationwide cohort including all 5,099,172 Swedish women born after 1931 with at least one known first-degree relative. This was a record linkage study of Swedish family cancer datasets, including cancer registry data collected from January 1, 1958, to December 31, 2015. We calculated standardized incidence ratios (SIRs) and 10-year cumulative risk of breast cancer diagnosis for women with a family history of in situ and invasive breast cancer. RESULTS: Having one first-degree relative with breast carcinoma in situ was associated with 50% increased risk of invasive breast cancer (SIR = 1.5, 95% CI 1.4-1.7) when compared to those who had no family history of invasive breast cancer or breast carcinoma in situ in either first- or second-degree relatives. Similarly, having one first-degree relative with invasive breast cancer was associated with 70% (1.7, 1.7-1.8) increased risk. The 10-year cumulative risk for women at age 50 with a relative with breast carcinoma in situ was 3.5% (2.9-3.9%) and was not significantly different from 3.7% (3.6-3.8%) risk for 50-year-old women with a relative with invasive breast cancer (95% confidence intervals overlapped). CONCLUSIONS: The risk of invasive breast cancer for women with a family history of breast carcinoma in situ was comparable to that for women with a family history of invasive breast cancer. Therefore, family history of breast carcinoma in situ should not be overlooked in recommendations for breast cancer prevention for women with a family history of breast cancer.

Women's knowledge and attitudes towards cervical cancer prevention: a cross sectional study in Eastern Uganda.

BACKGROUND: Cervical cancer is a leading cause of morbidity and mortality among women in Uganda, often due to late disease diagnosis. Early screening for the cancer has been shown to be the most effective measure against the disease. Studies conducted elsewhere have reported the lack of awareness and negative attitudes towards cervical cancer as barriers to early screening. This study assessed the knowledge and attitudes of Ugandan women about cervical cancer prevention with the aim of informing prevention and control interventions. METHODS: This study was conducted in Bugiri and Mayuge districts in eastern Uganda. It was a cross-sectional community based survey and collected data by means of a questionnaire. A total of 900 women aged 25-49 years participated in the study. Women's knowledge and attitudes towards cervical cancer prevention were assessed and scored. Data were analysed using STATA 12.0 software. Bivariate and multivariate analyses were carried out to establish the relationship between knowledge levels and demographic characteristics. RESULTS: Most (794; 88.2%) of the respondents had heard about cervical cancer, the majority (557; 70.2%) having received information from radio and 120 (15.1%) from health facilities. Most women (562; 62.4%) knew at least one preventive measure and (743; 82.6%) at least one symptom or sign of the disease. The majority (684; 76.0%) of respondents perceived themselves to be at risk of cervical cancer, a disease most (852; 94.6%) thought to be very severe. Living in peri-urban areas (AOR = 1.62, 95% CI: 1.15 - 2.28), urban areas (AOR = 3.64, 95% CI: 2.14 - 6.19), having a higher monthly income (AOR = 0.50, 95% CI: 0.37 - 0.68) and having had an HIV test (AOR = 1.99, 95% CI: 1.34-2.96) were associated with level of knowledge about cervical cancer prevention. CONCLUSION: Although general knowledge about cervical cancer prevention was relatively high among women, and attitudes mostly encouraging, specific knowledge about screening was low. There were also undesirable perceptions and beliefs regarding cervical cancer among respondents. There is therefore need for more education campaigns to bridge identified knowledge gaps, and scale up of cervical cancer screening services to all women to increase service uptake.

Women's intention to screen and willingness to vaccinate their daughters against cervical cancer - a cross sectional study in eastern Uganda.

BACKGROUND: The World Health Organization recommends cervical cancer screening and vaccination programmes as measures to combat cervical cancer. The uptake of these measures remains low in Uganda, most especially in rural areas. An understanding of the factors that influence women's decision to attend screening, and willingness to have their daughters vaccinated against cervical cancer is essential for any attempts to increase uptake of these services. This study assessed the factors associated with intention to screen for cervical cancer among women in eastern Uganda, and willingness to have their daughters vaccinated against the disease. METHODS: This cross sectional study involved 900 females aged 25 to 49 years in Bugiri and Mayuge districts in eastern Uganda. Data were collected using a pretested semi-structured questionnaire, entered in Epidata version 3.02 and analysed in STATA version 12.0. Unadjusted and adjusted prevalence ratios (PR) were computed using a generalized linear model with Poisson family, and a log link with robust standard errors. RESULTS: Majority 819 (91.0%) of respondents stated that they intended to go for cervical cancer screening in the subsequent six months. Among them, 603 (73.6%) wanted to know their status, 256 (31.3%) thought it was important, 202 (24.7%) wanted to reduce their chances of getting the disease, and 20 (2.4%) had been told to do so by a health worker. Majority 813 (90.4%) of respondents were willing to vaccinate their daughters against cervical cancer. Higher income (adjusted PR = 1.11, 95% CI: 1.03-1.20), cervical cancer screening status (adjusted PR = 0.81, 95% CI: 0.67-0.99) and knowledge of at least one test for cervical cancer (adjusted PR = 0.92, 95% CI: 0.85-0.98) were significantly associated with intention to screen for cervical cancer. No socio-demographic characteristic was associated with willingness to vaccinate daughters among women. CONCLUSION: There is a very high intention to screen and willingness to vaccinate daughters against cervical cancer among women in eastern Uganda. To take advantage of this, there is need to avail opportunities for women to access cervical cancer screening and vaccinations particularly among rural communities.

Nottingham Trent University and Makerere University School of Public Health partnership: experiences of co-learning and supporting the healthcare system in Uganda.

Partnerships between developed and developing country institutions are increasingly becoming important in addressing contemporary global health challenges faced by health systems. Inter-university health collaboration such as the Nottingham Trent University (UK) and Makerere University School of Public Health (Uganda) partnership provide opportunities for working together in training, research and service delivery while strengthening health systems. This paper shares the experiences, achievements and opportunities of this partnership in co-learning and supporting the health system in Uganda. This includes a project being implemented to strengthen the training, supervision and motivation of community health workers in rural Uganda. Training and research are a key focus of the partnership and have involved both staff and students of both institutions including guest lectures, seminars and conference presentations. The partnership's collaboration with stakeholders such as the Ministry of Health (Uganda) and local health authorities has ensured participation necessary in supporting implementation of sustainable interventions. The partnership uses several channels such as email, telephone, Skype, Dropbox and WhatsApp which have been useful in maintaining constant and effective communication. The challenges faced by the partnership include lack of funding to support student mobility, and varying academic schedules of the two institutions. The experiences and prospects of this growing partnership can inform other collaborations in similar settings.

Longer Interval Between First Colonoscopy With Negative Findings for Colorectal Cancer and Repeat Colonoscopy.

Importance: For individuals without a family history of colorectal cancer (CRC), colonoscopy screening every 10 years is recommended to reduce CRC incidence and mortality. However, debate exists about whether and for how long this 10-year interval could be safely expanded. Objective: To assess how many years after a first colonoscopy with findings negative for CRC a second colonoscopy can be performed. Design, Setting, and Participants: This cohort study leveraged Swedish nationwide register-based data to examine CRC diagnoses and CRC-specific mortality among individuals without a family history of CRC. The exposed group included individuals who had a first colonoscopy with findings negative for CRC at age 45 to 69 years between 1990 and 2016. The control group included individuals matched by sex, birth year, and baseline age (ie, the age of their matched exposed individual when the exposed individual's first colonoscopy with findings negative for CRC was performed). Individuals in the control group either did not have a colonoscopy during the follow-up or underwent colonoscopy that resulted in a CRC diagnosis. Up to 18 controls were matched with each exposed individual. Individuals were followed up from 1990 to 2018, and data were analyzed from November 2022 to November 2023. Exposure: A first colonoscopy with findings negative for CRC, defined as a first colonoscopy without a diagnosis of colorectal polyp, adenoma, carcinoma in situ, or CRC before or within 6 months after screening. Main Outcomes and Measures: The primary outcomes were CRC diagnosis and CRC-specific death. The 10-year standardized incidence ratio and standardized mortality ratio were calculated to compare risks of CRC and CRC-specific death in the exposed and control groups based on different follow-up screening intervals. Results: The sample included 110 074 individuals (65 147 females [59.2%]) in the exposed group and 1 981 332 (1 172 646 females [59.2%]) in the control group. The median (IQR) age for individuals in both groups was 59 (52-64) years. During up to 29 years of follow-up of individuals with a first colonoscopy with findings negative for CRC, 484 incident CRCs and 112 CRC-specific deaths occurred. After a first colonoscopy with findings negative for CRC, the risks of CRC and CRC-specific death in the exposed group were significantly lower than those in their matched controls for 15 years. At 15 years after a first colonoscopy with findings negative for CRC, the 10-year standardized incidence ratio was 0.72 (95% CI, 0.54-0.94) and the 10-year standardized mortality ratio was 0.55 (95% CI, 0.29-0.94). In other words, the 10-year cumulative risk of CRC in year 15 in the exposed group was 72% that of the 10-year cumulative risk of CRC in the control group. Extending the colonoscopy screening interval from 10 to 15 years in individuals with a first colonoscopy with findings negative for CRC could miss the early detection of only 2 CRC cases and the prevention of 1 CRC-specific death per 1000 individuals, while potentially avoiding 1000 colonoscopies. Conclusions and Relevance: This cohort study found that for the population without a family history of CRC, the 10-year interval between colonoscopy screenings for individuals with a first colonoscopy with findings negative for CRC could potentially be extended to 15 years. A longer interval between colonoscopy screenings could be beneficial in avoiding unnecessary invasive examinations.

Strategies for integrating artificial intelligence into mammography screening programmes: a retrospective simulation analysis.

BACKGROUND: Integrating artificial intelligence (AI) into mammography screening can support radiologists and improve programme metrics, yet the potential of different strategies for integrating the technology remains understudied. We compared programme-level performance metrics of seven AI integration strategies. METHODS: We performed a retrospective comparative evaluation of seven strategies for integrating AI into mammography screening using datasets generated from screening programmes in Germany (n=1 657 068), the UK (n=223 603) and Sweden (n=22 779). The commercially available AI model used was Vara version 2.10, trained from scratch on German data. We simulated the performance of each strategy in terms of cancer detection rate (CDR), recall rate, and workload reduction, and compared the metrics with those of the screening programmes. We also assessed the distribution of the stages and grades of the cancers detected by each strategy and the AI model's ability to correctly localise those cancers. FINDINGS: Compared with the German screening programme (CDR 6·32 per 1000 examinations, recall rate 4·11 per 100 examinations), replacement of both readers (standalone AI strategy) achieved a non-inferior CDR of 6·37 (95% CI 6·10-6·64) at a recall rate of 3·80 (95% CI 3·67-3·93), whereas single reader replacement achieved a CDR of 6·49 (6·31-6·67), a recall rate of 4·01 (3·92-4·10), and a 49% workload reduction. Programme-level decision referral achieved a CDR of 6·85 (6·61-7·11), a recall rate of 3·55 (3·43-3·68), and an 84% workload reduction. Compared with the UK programme CDR of 8·19, the reader-level, programme-level, and deferral to single reader strategies achieved CDRs of 8·24 (7·82-8·71), 8·59 (8·12-9·06), and 8·28 (7·86-8·71), without increasing recall and while reducing workload by 37%, 81%, and 95%, respectively. On the Swedish dataset, programme-level decision referral increased the CDR by 17·7% without increasing recall and while reducing reading workload by 92%. INTERPRETATION: The decision referral strategies offered the largest improvements in cancer detection rates and reduction in recall rates, and all strategies except normal triaging showed potential to improve screening metrics. FUNDING: Vara.

Dehydroepiandrosterone Sulfate and Mortality in Middle-Aged and Older Men and Women-A J-shaped Relationship.

CONTEXT: The relationship between dehydroepiandrosterone sulfate (DHEAS) and mortality is of scientific and public health interest, yet it remains poorly understood. OBJECTIVE: We examined the association between DHEAS and mortality from cancer, cardiovascular disease, and all causes in middle-aged and older men and women. METHODS: DHEAS was measured in stored serum samples collected from 1994 to 1998 from a case-cohort nested within EPIC-Heidelberg, that included 7370 men (mean age = 55.0) and women (mean age = 52.4 years). Median follow-up for incident mortality events was 17.7 years. All deaths due to cancer (n = 1040), cardiovascular diseases (n = 598), and all causes (n = 2407) that occurred in EPIC-Heidelberg until end of 2014 were included. RESULTS: The association between DHEAS and mortality was nonlinear such that both participants in the lowest (Q1) and highest (Q5) sex- and 5-year age-group specific quintiles of DHEAS were at increased hazard ratios (HR) of mortality from cardiovascular [Q1: HR = 1.83 (95% CI: 1.33-2.51), Q5: 1.39 (1.00-1.94)], cancer [Q1: 1.27 (1.01-1.60), Q5: 1.27 (1.02-1.60)] and all causes [Q1: 1.51 (1.25-1.82), Q5: 1.31 (1.08-1.58)], compared with participants in Q3. In men and women with below-median DHEAS levels, doubling of DHEAS was associated with lower hazards of cardiovascular [0.87, (0.78-0.96)], cancer [0.90, (0.83-0.97)], and total mortality [0.89, (0.83-0.95)]. In contrast, a doubling in DHEAS among participants with above-median levels was associated with 1.20, (1.01-1.42), 1.28, (1.01-1.62), and 1.19 (1.03-1.37) higher hazards of mortality from cancer, cardiovascular, and all causes, respectively. CONCLUSION: In this large population-based study, DHEAS showed a J-shaped association with mortality. Both participants with lowest and highest levels experienced higher hazards of mortality from cancer, cardiovascular disease, and all causes.

Effect of Iso-Caloric Substitution of Animal Protein for Other Macro Nutrients on Risk of Overall, Cardiovascular and Cancer Mortality: Prospective Evaluation in EPIC-Heidelberg Cohort and Systematic Review.

Ecological studies showed correlations between a shift toward animal-protein-rich diets and longer life-expectancy; however, only a few studies examined individual-level association of protein source and mortality risks using appropriate iso-caloric substitution models adjusted for total energy intake. We used EPIC-Heidelberg (European Prospective Investigation into Cancer and nutrition) to create iso-caloric substitution models and determined relative all-cause, cardiovascular and cancer mortality hazards associated with dietary intake of animal protein and other macronutrients, employing Cox proportional hazard models. For comparison with other studies, we also synthesized evidence from a systematic review relating animal protein intake to mortality risk from seven prospective cohort studies in the USA, Europe and Japan. Substitution of 3% of total energy from animal protein for fat (saturated, mono-unsaturated) and carbohydrate (simple, complex) was associated with all-cause mortality (Hazard Ratios [HR] from 1.05 to 1.11), mostly driven by cardiovascular mortality (HR from 1.13 to 1.15). Independently of animal protein, substituting poly-unsaturated fat for saturated fat increased cancer-related mortality risk by 12 percent. The systematic review largely corroborated our findings. Overall, higher proportions of dietary energy from animal protein, combined with low energy intake from either carbohydrate sub-types or dietary fats, increases all-cause and cardiovascular mortality risks, but not cancer-related mortality.

IGF-1 and Risk of Morbidity and Mortality From Cancer, Cardiovascular Diseases, and All Causes in EPIC-Heidelberg.

CONTEXT: The functional status of organs, such as the liver, involved in IGF-1 signaling pathways influences circulating levels of IGF-1 and hence its relationship to risk of chronic disease and mortality, yet this has received limited attention. OBJECTIVE: To examine the relationship between IGF-1 and risk of morbidity and mortality from cancer, cardiovascular diseases (CVD), and all causes, accounting for liver function. METHODS: This study was a case-cohort design nested within EPIC-Heidelberg. IGF-1 was measured in 7461 stored serum samples collected from 1994 to 1998. Median follow-up for incident mortality events was 17.5 years. The case-cohort included a subcohort of 1810 men and 1890 women, in addition to 1668 incident cases of cancer (623 breast, 577 prostate, 202 lung, and 268 colorectal), and 1428 cases of CVD (707 myocardial infarctions and 723 strokes) and 2441 cases of death. RESULTS: Higher IGF-1 levels showed direct associations with risks of breast (1.25; 95% CI [1.06-1.47]) and prostate (1.31; [1.09-1.57]) cancers. Restricted cubic splines plots and models including IGF-1 as quintiles revealed a U-shaped relationship between the biomarker and mortality. Participants with the lowest and the highest levels of IGF-1 experienced higher hazards of mortality from cancer, CVD, and all causes. The U-shaped form of the relationship persisted but was attenuated in analyses including only participants without any indications of liver dysfunction. CONCLUSION: This large population-based prospective study showed that both individuals with lowest and highest levels of circulating IGF-1 were at increased risk of deaths from cancer, CVD, and all causes. For individuals with low IGF-1, the excess risks of death were more pronounced among individuals with liver cancer and cirrhosis but were also present among individuals without elevated liver enzymes.

Short- and long-term reproducibility of the COMET assay for measuring DNA damage biomarkers in frozen blood samples of the EPIC-Heidelberg cohort.

The comet assay is widely used for quantification of genomic damage in humans. Peripheral blood derived mononuclear cells (PBMCs) are the most often used cell type for this purpose. Since the comet assay can be performed in an enhanced throughput format, it can be applied to large sample collections such as biobanks. The European Prospective Investigation into Cancer and Nutrition (EPIC) study is one of the largest existing prospective cohort studies, and the German Cancer Research Institute (DKFZ) in Heidelberg is a participating center with 25.000 frozen blood samples stored from around 25 years ago, enabling retrospective assessment of disease risk factors. However, experience with decades long frozen samples in the comet assay is so far missing. In Heidelberg, 800 study participants were re-invited twice between 2010 and 2012 to donate further blood samples. Here, we analyzed 299 Heidelberg-EPIC samples, compiled from frozen PBMC and buffy coat preparations selected from the different sampling time points. In addition, 47 frozen PBMC samples from morbidly obese individuals were included. For buffy coat samples, we observed a poor correlation between DNA damage in the same donors assessed at two sampling time points. Additionally, no correlation between DNA damage in buffy coat samples and PBMCs was found. For PBMCs, a good correlation was observed between samples of the same donors at the two time points. DNA damage was not affected by age and smoking status, but high BMI (>30; obesity) was associated with increased DNA damage in PBMCs. There was no indication for a threshold of a certain BMI for increased DNA damage. In conclusion, while 25 year-long stored buffy coat preparations may require adaptation of certain experimental parameters such as cell density and electrophoresis conditions, frozen PBMC biobank samples can be analyzed in the comet assay even after a decade of storage.

Systolic blood pressure and six-year mortality in South Africa: Evidence from a country-wide population-based cohort study.

Background: Improving hypertension control is an important global health priority yet, to our knowledge, there is no direct evidence on the blood pressure (BP)-mortality relationship in sub-Saharan Africa. We investigate the BP-mortality relationship in South Africa and assess the comparative effectiveness of different care targets for clinical care and population-wide hypertension management efforts. Methods: We use country-wide population-based longitudinal data from five waves (2008 - 2017) of the South African National Income Dynamics Study (N = 4,993). We estimate the relationship between systolic BP (SBP) and six-year all-cause mortality and compare the mortality reductions associated with lowering SBP to different targets. We then estimate the number needed to treat to avert one death (NNT) under different hypothetical population-wide scale up scenarios. Findings: We found a weak, nonlinear, SBP-mortality relationship with larger incremental mortality benefits at higher SBP values: reducing SBP from 160 to 150 mmHg was associated with a mortality risk ratio of 0.95 (95% CI: 0.90, 0.99, p = 0.033), incrementally reducing SBP from 150 to 140 mmHg a risk ratio of 0.96 (95% CI: 0.91, 1.01, p = 0.12), with no evidence of incremental benefits of reducing BP below 140 mmHg. At the population level, reducing SBP to 150 mmHg among all those with an SBP > 150 mmHg had the lowest NNT (50) at 3.3 deaths averted (95% CI: -0.6, 0.3) per 1,000 population while requiring BP management for 16% (95% CI: 15.2, 17.3) of individuals. Interpretation: The SBP-mortality association is weaker in South Africa than in high-income and many low- and middle-income countries. As such, we do not find compelling evidence in support of targets below 140 mmHg and find that scaling up management based on a 150 mmHg target is more efficient in terms of the NNT compared to strategies to reduce SBP to lower values.

Risk-tailored starting age of breast cancer screening based on women's reproductive profile: A nationwide cohort study.

BACKGROUND: Although reproductive history is recognised to affect the risk of breast cancer, current breast cancer screening guidelines do not consider risk differences by this important factor. As there is a need for an earlier screening in women at increased risk of breast cancer, we provided evidence-based risk-adapted starting age of screening based on different reproductive profiles. MATERIAL AND METHODS: We conducted a nationwide cohort study including 5,099,172 Swedish women born after 1931. Records of study participants in Swedish Cancer Registry, Multi-generation Register, Cause of Death Register, and national censuses (follow-up, 1958-2015) have been linked. We used 10-year cumulative risk of breast cancer curves to determine the age at which women with different reproductive factors attained the risk level at which breast screening is usually recommended. RESULTS: The 10-year cumulative risk of breast cancer at age 40, 45 and 50 years in the general population, at which current screening guidelines recommend screening was calculated. We found that women with various reproductive factors (defined by parity and age at first birth) obtained this level of risk at different ages. The difference was between nine years later and three years earlier. CONCLUSIONS: This study provides the age at which women with particular reproductive profile could start risk-adapted breast cancer screening. This supplies novel information for clinicians and women about when to start breast cancer screening and is an important step towards a personalised screening.

Risk-Adapted Starting Age of Screening for Relatives of Patients With Breast Cancer.

IMPORTANCE: Breast cancer screening guidelines acknowledge the need for earlier screening for women at increased risk but provide limited guidance for women with a family history of breast cancer. A risk-adapted starting age of screening for relatives of patients with breast cancer may help supplement current screening guidelines. OBJECTIVE: To identify the risk-adapted starting age of breast cancer screening on the basis of a woman's detailed family history. DESIGN, SETTING, AND PARTICIPANTS: This nationwide cohort study analyzed data recorded in the Swedish family-cancer data sets. All women born from 1932 onward and with at least 1 known first-degree relative (FDR) were included (N = 5 099 172). Data from January 1, 1958, to December 31, 2015, were collected. Data were analyzed from October 1, 2017, to March 31, 2019. EXPOSURES: Family history of breast cancer in FDRs and second-degree relatives (SDRs). MAIN OUTCOMES AND MEASURES: Primary invasive breast cancer diagnosis and the age at which women with different constellations of family history attained the risk level at which breast screening is usually recommended. RESULTS: Of the 5 099 172 women included in the study, 118 953 (2.3%) received a diagnosis of primary invasive breast cancer. A total of 102 751 women (86.4%; mean [SD] age at diagnosis, 55.9 [11.1] years) did not have family history of breast cancer in FDRs and SDRs at the time of their diagnosis. Risk-adapted starting age of breast cancer screening varied by number of FDRs and SDRs with breast cancer diagnosis and the age at diagnosis of the FDRs. For example, for screening recommendation at age 50 years for the general population (2.2% 10-year cumulative risk), women with multiple affected FDRs, with the youngest affected relative receiving a diagnosis before age 50 years, reached the benchmark risk level at age 27 years. When the youngest relative received a diagnosis after age 50 years, however, this risk level was attained at age 36 years. CONCLUSIONS AND RELEVANCE: This study identifies possible risk-based starting ages for breast cancer screening based on population-based registers. These results may serve as high-quality evidence to supplement current screening guidelines for relatives of patients with breast cancer.