“This is a big step in providing actionable data for regulatory agencies and clinicians in terms of making sense of the state of the literature on this hugely important health topic. The results can be used by organizations like the Environmental Protection Agency, which is currently considering strengthening limits on PM2.5 exposure,” said lead author Marc Weisskopf, Cecil K. and Philip Drinker Professor of Environmental Epidemiology and Physiology. “Our findings support the public health importance of such a measure.”

The study is the first systematic review and meta-analysis to use the new Risk of Bias In Non-Randomized Studies of Exposure (ROBINS-E) tool, which addresses bias in environmental studies in greater detail than other assessment approaches. It also is the first to include newer studies that used “active case ascertainment,” a method that involved screening of entire study populations followed by in-person evaluation for dementia among individuals who did not have dementia at baseline.

The study will be published online April 5, 2023, in The BMJ.

More than 57 million people worldwide are currently living with dementia, and estimates suggest that number will increase to 153 million by 2050. Up to 40% of these cases are thought to be linked to potentially modifiable risk factors, such as exposure to air pollutants.

Weisskopf and his co-authors, Elissa Wilker, researcher in the Harvard Chan-NIEHS Center for Environmental Health, and Marwa Osman, a doctoral student in the Biological Science in Public Health program, scanned more than 2,000 studies and identified 51 that evaluated an association between ambient air pollution and clinical dementia, all published within the last 10 years. Those studies were assessed for bias using ROBINS-E, and 16 of them met the criteria for the meta-analysis. The majority of the research was about PM2.5, with nitrogen dioxide and nitrogen oxide being the next most common pollutants studied. Of the studies used in the meta-analysis, nine used active case ascertainment.

The researchers found consistent evidence of an association between PM2.5 and dementia, even when annual exposure was less than the current EPA annual standard of 12 micrograms per cubic meter of air (μg/m3). In particular, among the studies using active case ascertainment, the researchers found a 17% increase in risk for developing dementia for every 2 μg/m3 increase in average annual exposure to PM2.5. They also found evidence suggesting associations between dementia and nitrogen oxide (5% increase in risk for every 10 μg/m3 increase in annual exposure) and nitrogen dioxide (2% increase in risk for every 10 μg/m3 increase in annual exposure), though the data was more limited.

The researchers noted that air pollution’s estimated association with risk of dementia is smaller than that of other risk factors, such as education and smoking. However, because of the number of people exposed to air pollution, the population-level health implications could be substantial.

“Given the massive numbers of dementia cases, identifying actionable modifiable risk factors to reduce the burden of disease would have tremendous personal and societal impact,” Weisskopf said. “Exposure to PM2.5 and other air pollutants is modifiable to some extent by personal behaviors — but more importantly through regulation.”

Funding for the study came from Biogen and from National Institutes of Health grants P30 ES000002 and T32 HL007118.

Empowering survivors with the numbers

Despite the finding of excess mortality in survivors, the investigators found that patients’ health behaviors had an impact on their risk. Maintaining a healthy lifestyle (defined as having a healthy weight, not drinking more than moderate amount of alcohol, not smoking and exercising at or above the intensity recommended by the Centers for Disease Control guidelines) was associated with a 20% reduction in the risk of mortality, compared to those who did not.

“These findings provide important evidence that the high-risk for mortality that this population faces may be able to be reduced through changes in their health behaviors,” said senior author Greg Armstrong, M.D., M.S.C.E., St. Jude Department of Epidemiology and Cancer Control chair. “This is important because our goal is to extend the lifespan of survivors and to improve their healthspan as well.”

In addition to lifestyle, several major risk factors for heart disease and related issues were associated with mortality risk. Survivors with hypertension or diabetes had a significantly higher mortality rate than survivors without those conditions. However, these conditions are modifiable — patients can improve or prevent them, and physicians can provide treatments effective against these diseases.

“Much research has demonstrated that survivors are vulnerable to early onset of chronic disease and mortality,” said co-author Melissa Hudson, M.D., St. Jude Cancer Survivorship Division director. “The study highlights the importance of encouraging survivors to practice healthy behaviors and maintain good control of cardiovascular disease risk factors to improve their healthspan and lifespan.”

Excess mortality and cause of death in survivors

In addition to the importance of potentially modifiable risk factors, this report is the first to detail that the specific primary causes of death in long term survivors are similar to the leading causes of death in the U.S. population, occurring earlier in survivors.

“We identified that long-term survivors of childhood cancer are experiencing a large number of deaths in excess of what would be expected for the general, aging population,” said the first and corresponding author Stephanie Dixon, M.D., MPH, St. Jude Department of Oncology. “We were the first to find that decades after treatment, these excess deaths are predominantly due to the same leading causes of death as in the general population, including second cancers, heart disease, cerebrovascular disease/stroke, chronic liver and kidney disease and infectious causes of death, experienced at a younger age and higher rate, in childhood cancer survivors,” Dixon said.

Treatments for childhood cancers have improved to the point where over 85% of U.S. patients are effectively cured of their primary tumor after frontline treatment. As more patients survive their childhood cancer, there is a growing population of adult survivors. By comparing the CCSS cohort to the public, the researchers found that decades after treatment survivors still experience four times the expected risk of death.

The largest cancer survivor cohort feeds discovery

The researchers were able to understand the problems affecting survivors using detailed health data from thousands of CCSS participants. The CCSS is the largest cohort of cancer survivors in North America, representing an estimated 20% of all childhood cancer survivors in that region. The scientists were able to take this vast swath of data to statistically isolate variables affecting survivor mortality. The group showed that even when common confounders, such as sociodemographic features, were controlled for, the gap in mortality between survivors and the general public persisted, but so did the protective effects of a healthy life.

“What was most exciting to see was that, independent of prior treatment exposures and sociodemographic factors, a healthy lifestyle and absence of hypertension or diabetes were each associated with a reduced risk of health-related mortality,” Dixon said. “This suggests that while continued efforts to reduce treatment intensity while maintaining (or improving) 5-year survival are needed, future research should also focus on interventions for modifiable lifestyle and cardiovascular risk factors which may need to be specifically tailored to survivors with the goal of reducing chronic disease development and extending the lifespan of survivors of childhood cancer.”

Intensive treatments continue to tax childhood cancer survivors

Patients treated with more intensive therapies continued to experience higher mortality than other survivors. Much research has focused on minimizing the harms of therapy, but many survivors in the CCSS were treated before improved techniques were widely available. This study showed that physicians and researchers need to consider interventions that can decrease risk for the vulnerable population of survivors that were treated with aggressive therapies in their youth.

“The Childhood Cancer Survivors Study continues to provide important insights into the long-term outcomes of the growing number of children successfully treated for cancer,” said co-author Leslie Robison, emeritus St. Jude Department of Epidemiology and Cancer Control chair. “The findings from the current analysis further emphasize the need to expand our efforts to reduce acute, chronic and late-onset toxicities of treatment, particularly those toxicities that can directly or indirectly result in premature mortality.”

Approximately one in six people worldwide is affected by infertility, according to the World Health Organization, and one in every 22 children in Australia is born via assisted reproduction. With a 78% failure rate, each IVF cycle can be an emotional rollercoaster that often ends in heartbreak.

“Male infertility plays a role in around 30% of cases, due to problems such as low sperm count, reduced motility or movement or poor sperm quality,” says Professor Majid Warkiani from the School of Biomedical Engineering at the University of Technology Sydney (UTS).

“While much work has been done around selecting eggs and embryos to boost the success rates of IVF, sperm selection, an essential component in assisted reproduction, is by far the most neglected step in regard to technological innovation,” he says.

To tackle this problem, researchers from UTS and NeoGenix Biosciences, a UTS-born start-up, have created and tested a new microfluidic sperm selection device that provides a more reliable process for selecting high-quality sperm.

Traditional sperm selection methods, such as density gradient centrifugation and swim-up, can cause DNA fragmentation and cell death, leading to unsuccessful IVF cycles.

“This new technology is a 3D printed, biologically inspired microfluidic sperm selection device, which replicates the female reproductive tract and the natural sperm selection process, where only a small percentage of total sperm reach the egg,” Professor Warkiani said.

“We conducted extensive testing against conventional IVF selection methods, with the new method showing an 85% improvement in DNA integrity and an average 90% reduction in sperm cell death. The sperm selected by our method also demonstrated better recovery after freezing than traditional methods,” he said.

The study results were recently published in Nature: Microsystems & Nanoengineering.

The researchers have partnered with Monash University and Australian IVF clinics to implement the technology into clinical practice. They hope the device will provide help for those struggling with infertility and reduce the number of unsuccessful IVF cycles.