Body

A research team led by Professor Hongzhe SUN, Chair Professor from the Department of Chemistry, Faculty of Science, in collaboration with Dr Pak-Leung HO, Director of the HKU Carol Yu Centre for Infection from the Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong (HKU) discovers that by repurposing an antirheumatic gold drug, auranofin (AUR), "last-resort" antibiotics can be resensitized for treatment of infections caused by multidrug-resistant superbugs including bloodstream infections, pneumonia and wound infections.

The findings provide insights into development of inorganic pharmaceutics and new therapeutic approach for superbug infections. The ground-breaking findings on antimicrobial resistance (AMR) are now published in a leading multidisciplinary science journal, Nature Communications and a related patent has been filed in the US.

Background

Antibiotics are medicines designed to kill bacteria and treat bacterial infections. Antibiotic resistance occurs when bacteria adjust in response to the misuse or overuse of these medicines and it has become one of the biggest public health challenges in this era. At least 2.8 million people get an antibiotic-resistant infection annually in the US, and more than 35,000 people die from it.

The most commonly used antibiotics to treat bacterial infections are β-lactams antibiotics, such as cephalosporins and carbapenems. However, their clinical efficacies have been greatly challenged as bacteria produce a resistant determinant that are capable of hydrolysing nearly all β-lactams antibiotics, named metallo-β-lactamases (MBLs). Therefore, the "last-line" antibiotic colistin (COL) has re-emerged as a therapeutic option in response to the outbreak of infections caused by extensively multidrug-resistant Gram-negative pathogens since the mid-1990s. Unfortunately, the efficacy of COL has also been seriously compromised in the regular treatment of lethal bacterial infections, owing to the emergence of another resistant determinant, mobilized colistin resistance (MCR) enzyme in 2015. Owing to the vast structural difference and mode of mechanisms between the two enzymes, it remains an extreme difficulty of adopting a general therapy for infections caused by MBL(s) and MCR(s) co-producing pathogens. As said by Dr Tedros ADHANOM GHEBREYESUS, Director-Genera of World Health Organization (WHO), "As we gather more evidence, we see more clearly and more worryingly how fast we are losing critically important antimicrobial medicines all over the world." Thus, in clinic context, common infections with these "superbugs" may soon be untreatable, which will severely endanger public health system and leave clinicians with virtually no therapeutic options.

Key findings

With little remission from the therapeutic reliance on the current pipeline of β-lactam antibiotics and COL, the combination therapy consisting of an antibiotic resistance and an antibiotic-resistance breaker offers promising options to narrow the gap between multidrug-resistant bacteria and the development of new antibiotics. The research team previously discovered an anti-peptic ulcer bismuth drug, colloidal bismuth subcitrate, potently inhibits MBL activity and re-sensitize MBL-positive bacteria to β-lactam antibiotics. The related works were published in Nature Communication in 2018 and it was ranked as Highly cited paper in this area.

Their new findings follow this widely-recognized discovery, and identifies AUR serves to revive the potency of both carbapenem such as meropenem (MER), and COL through a series of screening on an Escherichia coli (denoted as E. coli CKE), clinically collected by Dr Ho Pak Leung in Queen Mary Hospital in Hong Kong, that co-produces two key resistant determinants, MBLs and MCRs. They found that AUR could entirely inhibit the hydrolytic activity of MBL through targeting crucial cysteine residue in the enzyme active site and functionally disrupt MCR-1 by targeting phosphorylated Thr285 residue via a distinct metal displacement route. Significantly, the novel combinatorial therapy allows the dose of either MER or COL to be lowered by 32~64 folds to achieve the same level of effectiveness against superbug E. coli CKE, and the development of level of resistant determinant to be significantly slowed down, which will dramatically extend the life cycle of currently used antibiotics.

In the mouse model, combination therapy comprising AUR and COL is highly effective in eradicating multidrug-resistant bacteria in peritonitis infection model. Co-administration with AUR restored the in vivo efficacy of COL, with over 10-fold reduction in MCR-1-producing Klebsiella pneumoniae loads in mouse liver and spleen in comparison to antibiotic alone. More significantly, all the mice that were systemically infected by superbug E. coli CKE were saved after 5-day treatment of AUR-COL combination.

"Considering the well-recorded safety of in human, AUR as well as related gold drugs as a dual-inhibitor of MBLs and MCRs would largely broaden the therapeutic options in treating the infections caused by multidrug-resistant superbugs," said Professor Sun.

UNIVERSITY PARK, Pa. -- Strength training is an important part of any exercise routine, but some women may not be getting the recommended hours. New Penn State research discovered some of the barriers preventing women from strength training, as well as some solutions to overcoming those obstacles.

In a study of college students, researchers found that women were less likely than men to participate in muscle-strengthening activities and use weight areas in campus recreation facilities. But, the researchers also found that women were more likely to feel uncomfortable using campus recreation facilities -- and weight areas in particular.

Oliver Wilson, graduate student in kinesiology, said the study suggests that there are gender differences in both physical exercise habits and campus facility use. He added that there may be opportunities for school administrators, policy makers and others to help provide equal opportunities for everyone.

"Ideally, all students -- regardless of gender identity, race and ethnicity, sexual orientation, religion, and/or socio-economic status -- should participate in muscle-strengthening activities," Wilson said. "Implementation and enforcement of policies, facility design and equipment layout, supportive social environments, and other opportunities for students to build the skills and confidence to participate in muscle-strengthening activities are necessary to provide equitable opportunities for all."

According to the researchers, previous research has consistently found disparities in physical activity between men and women. Additionally, prior work has found certain areas of campus recreational facilities to be highly gendered spaces.

For example, the researchers said women may feel constrained from using the free weights section of some facilities due to a lack of knowledge or confidence, crowded spaces, or unsolicited advice from male peers.

Melissa Bopp, associate professor of kinesiology, said that because a person's college-age years are an important period for establishing good exercise habits, they wanted to investigate potential reasons and solutions for these disparities.

"It was important to ask these questions because we know that physical activity participation typically declines across students' time in college despite the access they may have to facilities," Bopp said. "It's important to understand why this decline happens before we can create strategies for promoting physical activity."

The researchers recruited 319 college students for the study. The participants were asked to complete a survey designed to measure physical activity and their use and comfort in using campus recreational facilities, as well as their reasons and potential solutions for feeling uncomfortable using the facilities.

According to Wilson, meaningful differences in physical activity behaviors, facility use, and comfort levels in using facilities between male and female students appeared once the data were analyzed.

"Women reported less muscle-strengthening activity, lower frequency of both weight use and informal sport participation, and higher frequency of cardio and group exercise participation," Wilson said. "Women also reported lower comfort using facilities in general -- as well as machine weights, free weights, and indoor running tracks -- compared to men."

The researchers found that the presence and behaviors of men, feeling like they don't know how to properly use the equipment, and feeling self-consciousness emerged as common themes women gave for not using weight equipment.

"It is uncomfortable using certain parts of the recreational facilities because it is often divided into mostly women using the cardio machines and men in the weight section," according to one anonymous participant quoted in the study. "So, even though I like using weights, it can be a little intimidating going into a room full of guys by myself to work out with weights."

The participants also provided potential solutions that could help them feel more comfortable participating in muscle strengthening activities. Themes included the addition of women's-only sections or hours, as well as implementing sexual harassment policies.

Bopp said the study -- recently published in the Journal of American College Health -- suggests that making campus recreational facilities more open and welcoming to all students may be key to ensuring equitable opportunities for all to get the exercise they need.

"I think that it's important to understand that despite the fact that we have wonderful resources for physical activity on our campus, they sometimes don't feel accessible to everyone," Bopp said. "Whether it's the culture or policies that need to be changed to create a welcoming environment remains to be seen, but it also informs us that physical activity behavior is complex -- just having a place to be active doesn't ensure exercise participation."

National Institutes of Health researchers have discovered a gene in mice that controls the craving for fatty and sugary foods and the desire to exercise. The gene, Prkar2a, is highly expressed in the habenula, a tiny brain region involved in responses to pain, stress, anxiety, sleep and reward. The findings could inform future research to prevent obesity and its accompanying risks for cardiovascular disease and diabetes. The study was conducted by Edra London, Ph.D., a staff scientist in the section on endocrinology and genetics at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and colleagues. It appears in JCI Insight.

Prkar2a contains the information needed to make two subunits--molecular components--of the enzyme protein kinase A. Enzymes speed up chemical reactions, either helping to combine smaller molecules into larger molecules, or to break down larger molecules into smaller ones. Protein kinase A is the central enzyme that speeds reactions inside cells in many species. In a previous study, the NICHD team found that despite being fed a high fat diet, mice lacking functioning copies of Prkar2a were less likely to become obese than wild type mice with normally functioning Prkar2a.

The researchers determined that Prkar2a-negative mice ate less high-fat food than their counterparts, not only when given unlimited access to the food, but also after a fast. Similarly, the Prkar2a negative mice also drank less of a sugar solution than the wild type mice. The Prkar2a-negative mice were also more inclined to exercise, running 2-3 times longer than wild type mice on a treadmill. Female Prkar2a-negative mice were less inclined to consume high fat foods than Prkar2-negative males, while Prkar2-negative males showed less preference for the sugar solution than Prkar2-negative females.

Pancreatic cancer is highly lethal: according to the National Cancer Institute, only about 10 percent of patients remain alive five years after diagnosis. Now, a preclinical study from the lab of Marsha Moses, PhD at Boston Children's Hospital, reports marked and lasting tumor regression in a mouse model, using a highly selective, potent, engineered antibody-drug combination.

The findings, published November 3 in the journal Advanced Science, provide the basis for further pre-clinical studies to advance this approach to the clinic, the researchers say.

Pancreatic cancer has proven very difficult to treat with drugs. Not only do the tumors have a limited blood supply, making it hard to deliver drugs, they are also surrounded by stroma (a dense connective tissue) and tumor cells are protected by an extracellular matrix (a meshwork of proteins and carbohydrates).

"It can be difficult to get drugs into these tumors," says Moses, who directs the Vascular Biology Program at Boston Children's. "We developed a novel chemo-immunotherapy agent that selectively recognizes and penetrates pancreatic tumors better than other therapeutics."

Led by Jing Huang, PhD, the Moses lab developed an antibody-drug conjugate, or ADC, consisting of two parts: an antibody that selectively homes to a molecule on the surface of pancreatic cancer cells, known as ICAM1, and a drug toxic to cancer cells. Cells bearing ICAM1 on their surface are killed by the drug, while normal cells are spared.

"The size of the ADC is similar to the size of a single antibody: less than 10 nanometers," says Peng Guo, PhD, of the Moses Lab, co-corresponding author on the paper with Moses. "Because of this ultra-small diameter, it can penetrate the stroma and reach pancreatic tumor cells better than other novel treatments such as T-cell immunotherapy or nanomedicines."

Rational selection of antibody and drug

The team chose ICAM1 as a target for the ADC antibodies after screening the tumor surface for dozens of different proteins. In 2014, the Moses lab showed high levels of ICAM1 on triple-negative breast cancers, and it is abundant on melanoma and thyroid cancers as well.

The team performed similarly unbiased screening to select the best drug to include in the ADC. from a pool of drugs already used clinically. They tested four candidate ADCs in two human pancreatic cancer cell lines as well as in normal pancreatic cells. ADCs combining ICAM1 antibodies with the cytotoxic drug DM1 (mertansine), used clinically in HER2-positive breast cancer, were the most effective in killing tumor cells, working better than other ADC drugs. The DM1-ICAM1 antibody combination did not harm non-cancerous pancreatic cells which do not produce ICAM-1.

Shrinking pancreatic tumors

The team next randomized mice with pancreatic tumors to receive one of four treatments, given as systemic injections: the DM1-ICAM1 antibody conjugate, DM1 bound to a non-targeting antibody (IgG), gemcitabine (a first-line chemotherapy drug used in pancreatic cancer), or a sham treatment.

Compared with the other groups, mice receiving the DM1-ICAM1 antibody conjugate had a significant reduction in tumor size that persisted during the 14-week study, even after just two doses. The treatment also effectively inhibited metastasis to normal organs including lung, liver, and spleen. There was no observed toxicity, assessed by weighing the animals and through pathology analysis of their organs.

Noninvasive tumor monitoring

Finally, Huang developed an MRI-based molecular tumor imaging technique to complement ICAM1 ADC therapy, confirming the presence of ICAM1 on the tumor without the need for an invasive biopsy. This could potentially help to predict the treatment's effect and monitor changes over time. Eventually, Moses hopes to be able to monitor the treatment effect using two non-invasive urinary biomarkers previously reported by the team.

While other ADCs have been tested in pancreatic cancer, none have shown sufficient efficacy in the clinic and have also resulted in off-target toxicity, says Moses. "The precision of our approach comes from both the specific targeting and the ability to monitor that targeting with MRI," she says.

The ICAM1-DM1 ADC is part of a portfolio of targeted, patented cancer drug delivery systems being developed in the Moses lab; others include nanolipogels, liposomes, and exosomes.

Predicting the course of a COVID-19 patient's disease after hospital admission is essential to improving treatment. Brigham and Women's Hospital researchers analyzed patients' levels of inflammation, known to be associated with severity of illness, by looking at C-reactive protein (CRP) trends in 100 COVID-19 patients admitted to the hospital. They found that a rapid rise in CRP levels during the first 48-to-72 hours of hospitalization was predictive of subsequent respiratory deterioration and intubation, while steadier CRP levels were observed in patients whose condition remained stable. Findings were published in Cell Reports Medicine.

"We realized that whereas a single CRP lab value from hospital admission wasn't very practical as a predictor of who might get sicker, tracking the rate of change from Day 1 to Day 2 or 3 was a very powerful and very clinically predictive test," said corresponding author Edy Yong Kim, MD, PhD, of the Division of Pulmonary and Critical Care Medicine at the Brigham. "Even though all of these patients looked clinically similar upon admission, as early as 24 hours after hospitalization, the immune systems of patients who would go on to the ICU multiple days later were already inflamed, as measured by these biomarkers."

Inflammation is a broad term that describes the release of chemicals involved in immune responses. CRP tests integrate signals from a number of different proteins involved in inflammation, called cytokines, to provide physicians with a snapshot of a patient's inflammatory activity within a matter of hours. Other tests, like cytokine assays, can provide more specific information about which proteins may be active in inflammatory pathways, but these tests can take one to two days to process, and COVID-19 patients' conditions can worsen before the results are received. CRP tests can therefore serve as a practical addition to standard protocols for assessing the anticipated clinical trajectories of COVID-19 patients.

"Because of our findings, we changed our guidelines at the Brigham to mandate CRP tracking every day for the first three days of hospitalization so that we could try to identify vulnerable patients and keep a close eye on their inflammation," said Kim, who stressed the importance of putting findings into practice as early as possible amid the current uptick of positive cases.

The results, from a study population of 100 Brigham patients, also provide insight into the underlying mechanisms at play in COVID-19 infections. In particular, an increase in a cytokine called IL-6 during the first 24-48 hours was correlated to CRP levels and the progression of the disease. Fifteen patients treated during this acute period with the drug tocilizumab, an IL-6 receptor, had rapid, sustained reductions in their CRP levels. In larger, randomized trials, tocilizumab was not shown to provide benefits to COVID-19 patients, but Kim states that this could be because the drug was not administered early enough to the subset of patients who stand to benefit most. Alternatively, while CRP is associated with IL-6, CRP can reflect other inflammatory pathways besides IL-6, so targeting other inflammatory cytokines or pathways besides IL-6 could be considered.

"Even if you gave immunomodulatory drugs, which reduce rising inflammation, as early as Day 3 -- which is pretty early for a clinical trial -- that may already be too late," Kim said. "But here we have some evidence that a rise in inflammation directly drives respiratory failure, which implies that the immunomodulatory drugs might be able to prevent respiratory failure if given very, very early -- as early as hospital Day 1 and 2."

Ultimately, Kim hopes that the findings will help front-line workers better understand the volatility of COVID-19 patients' conditions. "Doctors' and nurses' clinical instincts about COVID-19 are not fully developed because the disease is still so new," Kim said. "But when we showed these results to frontline doctors and nurses at the Brigham, they felt like it matched what they intuitively saw in the spring. It's always nice to hear that what you do in the lab reflects what goes on in the real world, too."

MUSC Hollings Cancer Center researchers identified that blocking an alternative energy pathway for T-cells after hematopoietic stem cell transplant helps reduce graft-versus-host disease (GVHD) in an animal model of leukemia.

Xue-Zhong Yu, M.D., who also is associate director of Basic Science at Hollings, and collaborators at the Indiana University School of Medicine discovered that donor T-cells must have the key enzyme lysosomal acid lipase in order to induce GVHD.

The Yu laboratory focuses on understanding the biological balance between GVHD and graft-versus-leukemia effect. Hematopoietic stem cell transplantation is used as a treatment option for some leukemia patients. T-cells in stem cell grafts from a donor are given to a leukemia patient in order to kill the cancer and reboot the patient's immune system. GVHD is a big clinical challenge because the donor T-cells, which come from the bone marrow, can attack the patient's organs. Anywhere from 30% to 70% of patients develop acute GVHD after allogeneic bone marrow transplant and 15% die.

"When we deal with hematopoietic cell transplant, it is an important balance - blocking GVHD while still allowing T-cells to do their job and control the cancer," Yu said.

Each cell in our body has its own metabolic process. Cells convert the food that is eaten into energy in order to perform their intended functions. However, cellular metabolism is often altered in various diseases. Yu researches T-cell metabolism in order to understand the balance between graft-versus-host and graft-versus-leukemia responses.

Most cells in our body require oxygen to create energy efficiently. However, this research focused on lipid, or fat, metabolism. T-cells have special metabolic processes: Sometimes they multiply so rapidly that they need an extra source of energy from free fatty acids.

Lysosomal acid lipase is an enzyme that breaks the large lipids and cholesterol into individual free fatty acid building blocks. If that enzyme is missing, there are not enough free fatty acids for energy production. This changes the T-cell metabolism, which in turn changes T-cell function.

Clinically, broad spectrum immunosuppression drugs (steroids and rapamycin) are still used as the first line of care in patients with severe GVHD. However, Yu and collaborators hypothesized that changing T-cell metabolism could reduce GVHD after hematopoietic stem cell transplantation.

"We know that the gut is the primary organ affected by GVHD. Since the gut has less oxygen, the T-cells rely on free fatty acids and must use lysosomal acid lipase. We thought if we could remove or block the activity of that, we could reduce GVHD in the gut."

The Yu Laboratory collaborated with the Indiana University School of Medicine and used a lysosomal acid lipase-deficient mouse model. T-cells lacking lysosomal acid lipase were given to mice with leukemia. As a control, T-cells with lysosomal acid lipase from normal mice were given to another group of leukemia mice. Strikingly, the mice that received the T-cells without lysosomal acid lipase did not get severe GVHD. Additionally, the T-cells from the donor lysosomal acid lipase-deficient bone marrow still killed the leukemia cells.

To increase the clinical translational potential of the work, orlistat, the FDA-approved lysosomal acid lipase inhibitor was also tested in the leukemia model. Mice with leukemia were treated with orlistat every other day after receiving bone marrow from normal mouse donors. Similar to the first experiment with the lysosomal acid lipase-deficient bone marrow, blocking the activity of lysosomal acid lipase with orlistat greatly reduced GVHD while the graft-versus-leukemia effect was preserved.

Additionally, the researchers discovered that inhibiting the lysosomal acid lipase enzyme with orlistat reduced the number of pathogenic T-cells and increased the number of regulatory T-cells. The pathogenic T-cells are the ones that cause GVHD. Regulatory T-cells are one of the "braking mechanisms" of the immune system. They help to reduce the activity of the pathogenic T-cells and prevent GVHD damage.

Therefore, blocking lysosomal acid lipase activity with orlistat preferentially stopped the donor T-cells from damaging the gut but allowed the T-cells to function during circulation and kill the leukemia cells.

The researchers' future plan is to look deeper at the biological mechanisms. For example, it is not clear how the loss or inhibition of lysosomal acid lipase affects the other metabolites in T-cells. To move this finding closer to the clinic, Yu explained that human cells can be used in a special mouse model that recreates the human immune environment.

"Looking at the immune cells in the gut was technically challenging. However, the results were exciting because our hypothesis was validated. These results encourage us to continue studying this in order to provide better treatment options to patients."

Among U.S. patients with rheumatic disease and COVID-19, racial/ethnic minorities had higher risks of needing to be hospitalized and put on ventilators. The findings come from an analysis published in Arthritis & Rheumatology.

The analysis included data on all U.S. patients with rheumatic disease and COVID-19 entered into the COVID-19 Global Rheumatology Alliance physician registry from March 24 to August 26, 2020. A total of 1,324 patients were included, of whom 36% were hospitalized and 6% died; 26% of hospitalized patients required mechanical ventilation.

Compared with white patients, Black, Latinx, and Asian patients had 2.74-, 1.71-, and 2.69-times higher odds, respectively, of being hospitalized. Latinx patients also had three-fold increased odds of requiring mechanical ventilation. No differences in mortality based on race/ethnicity were found.

"Similar to the general population, Black, Latinx, and Asian individuals with rheumatic diseases are more likely to experience severe outcomes of COVID-19. These data suggest that the current pandemic will further exacerbate the health disparities that already exist for many patients with rheumatic disease," said senior author Jinoos Yazdany, MD, MPH, of the University of California, San Francisco.

A new analysis published in the Journal of the American Geriatrics Society indicates that fewer older adults may be experiencing certain symptoms that can restrict their activity at the end of life.

The analysis examined information on 665 individuals in Connecticut who were aged 70 years or older when they died between 1998 and 2019. Investigators assessed the occurrence of 16 restricting symptoms within 6 months of death during monthly interviews.

From 1998 to 2019, rates decreased for 5 restricting symptoms (difficulty sleeping; chest pain or tightness; shortness of breath; cold or flu symptoms; and nausea, vomiting, or diarrhea), increased for 3 (arm or leg weakness; urinary incontinence; and memory or thinking problem), and changed little for the other 8 (poor eyesight; anxiety; depression; musculoskeletal pain; fatigue; dizziness or unsteadiness; frequent or painful urination; and swelling in feet or ankles).

"Based on our results, the occurrence of most restricting symptoms at the end of life has been decreasing or stable over the past two decades," said lead author Thomas M. Gill, MD, of the Yale School of Medicine. "These results suggest that end-of-life care has been improving, although additional efforts will be needed to further reduce symptom burden at the end of life."

Human papilloma virus (HPV) is one of the most common sexually transmitted infections and cases various cancers in women and men. There are currently three vaccines available, and their efficacy and safely have been thoroughly assessed in females but not males. A new analysis published in the British Journal of Clinical Pharmacology shows that HPV vaccines are safe and well tolerated in the male population, and the side effects that may occur after immunization are similar in both sexes.

The analysis included all reports of adverse events following immunization present in the U.S. Vaccine Adverse Event Reporting System from January 1, 2006 to September 30, 2018.

"To the best of our knowledge, this is one of the first studies focused on the evaluation of the safety profile of HPV vaccines in males," the authors wrote.

Osteoporosis can be detected through low dose computed tomography (LDCT) imaging tests performed for lung cancer screening or other purposes. A study published in the Journal of Bone and Mineral Research found that such tests can identify large numbers of adults with low bone mineral density.

The study included 69,095 adults from 14 cities across China who received a chest LDCT scan for the purpose of lung cancer screening in 2018 and 2019. Analyses of these scans revealed that the prevalence of osteoporosis among individuals older than 50 years of age was 29.0% for women and 13.5% for men, equating to 49.0 million and 22.8 million Chinese citizens, respectively. In women, this rate is comparable to estimates from standard bone density scans, but in men, the prevalence was double.

"Our large scale, multi-center study of bone density measured from routine LDCT scans demonstrated the great potential of using LDCT for the opportunistic screening of osteoporosis as an alternative to standard DXA scans," said senior author Wei Tian, MD, of the Chinese Academy of Engineering and the Peking University School of Medicine. "Our study revealed the unexpectedly high prevalence of osteoporosis in men, which may impact on the management strategy of men in the future."

Sophia Antipolis, 5 November 2020: Offspring of mothers with heart healthy lifestyles live nearly a decade longer without cardiovascular disease than those whose mothers have unhealthy lifestyles. That's the finding of a study published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).1

"Our study suggests that mothers are the primary gatekeepers of their children's health," said study author Dr. James Muchira of Vanderbilt University, Nashville and the University of Massachusetts, Boston. "This maternal influence persists into the adulthood of their offspring."

Previous research has shown that parents pass on health to their offspring through both genes and shared environment/lifestyle.2,3 This was the first study to examine whether parents' heart health was associated with the age at which offspring develop cardiovascular disease. In addition, it investigated the influence of each parent separately.

The study was conducted in offspring-mother-father trios from the Framingham Heart Study - a total of 1,989 offspring, 1,989 mothers, and 1,989 fathers. Offspring were enrolled at an average age of 32 years and followed over 46 years (1971-2017) for the development of cardiovascular events. "Crucially, the study followed offspring into most of their adult life when heart attacks and strokes actually occur," explained Dr. Muchira.

Cardiovascular health of mothers and fathers was rated according to their attainment of seven factors: not smoking, healthy diet, physically active, and normal body mass index, blood pressure, blood cholesterol, and blood glucose. The three categories of cardiovascular health were: poor (0 to 2 factors achieved), intermediate (3 to 4), and ideal (5 to 7).

The researchers assessed the association between parental cardiovascular health and how long their offspring lived without cardiovascular disease. Links between each pair were assessed, i.e. mother-daughter, mother-son, father-daughter, and father-son.

Offspring of mothers with ideal cardiovascular health lived nine more years free of cardiovascular disease than offspring of mothers with poor cardiovascular health (27 versus 18 years, respectively). Poor maternal cardiovascular health was linked with twice the hazard of early onset cardiovascular disease compared with ideal maternal cardiovascular health. Fathers' heart health did not have a statistically significant effect on the length of time offspring lived without cardiovascular disease.

Dr. Muchira said the strong contribution of mothers was likely a combination of health status during pregnancy and environment in early life. He said: "If mothers have diabetes or hypertension during pregnancy, those risk factors get imprinted in their children at a very early age. In addition, women are often the primary caregivers and the main role model for behaviours."

Sons were more affected than daughters by the mother's unhealthy lifestyle. Dr. Muchira said: "This was because sons had more unfavourable lifestyle habits than daughters, making the situation even worse. It shows that individuals can take charge of their own health. People who inherit a high risk from their mother can reduce that risk by exercising and eating well. If they don't, the risk will be multiplied."

The authors state that optimising cardiovascular health among women of reproductive age and mothers with young children has the potential to break the intergenerational cycle of preventable cardiovascular disease.

"Family-based interventions should occur during pregnancy and very early in the child's life, so that the real impact of protective cardiovascular health tracks into adulthood," said Dr Muchira. "For example, pairing mothers and young children in an exercise or diet improvement programme. If children grow into healthy adults, they will not acquire the same cardiovascular risk as their parents, a situation that will raise the chances of having even healthier grandchildren."

OAK BROOK, Ill. - Artificial intelligence (AI) can enhance the performance of radiologists in reading breast cancer screening mammograms, according to a study published in Radiology: Artificial Intelligence.

Breast cancer screening with mammography has been shown to improve prognosis and reduce mortality by detecting disease at an earlier, more treatable stage. However, many cancers are missed on screening mammography, and suspicious findings often turn out to be benign. An earlier study from Radiology found that, on average, only 10% of women recalled from screening for additional diagnostic workup based on suspicious findings are ultimately found to have cancer.

AI-based algorithms represent a promising avenue for improving the accuracy of digital mammography. Developers "train" the AI on existing images, teaching it to recognize abnormalities associated with cancer and distinguish them from benign findings. The programs can then be tested on different sets of images. AI offers not only the possibility of better cancer detection but also improved efficiency for radiologists.

For the study, researchers used MammoScreen, an AI tool that can be applied with mammography to aid in cancer detection. The AI system is designed to identify regions suspicious for breast cancer on 2D digital mammograms and assess their likelihood of malignancy. The system takes as input the complete set of four views composing a mammogram and outputs a set of image positions with a related suspicion score.

Fourteen radiologists assessed a dataset of 240 2D digital mammography images acquired between 2013 and 2016 that included different types of abnormalities. Half of the dataset was read without AI and the other half with the help of AI during a first session and without during a second session.

Average sensitivity for cancer increased slightly when using AI support. AI also helped reduce the rate of false negatives, or findings that look normal even though cancer is present.

"The results show that MammoScreen may help to improve radiologists' performance in breast cancer detection," said Serena Pacilè, Ph.D., clinical research manager at Therapixel, where the software was developed.

The improved diagnostic performance of radiologists in the detection of breast cancer was achieved without prolonging their workflow. In cases with a low likelihood of malignancy, reading time decreased in the second reading session. This reduced reading time could increase overall radiologists' efficiency, allowing them to focus their attention on the more suspicious examinations, the researchers said.

In March, the U.S. Food and Drug Administration cleared MammoScreen for use in the clinic, where it could help reduce the workload of radiologists, according to Dr. Pacilè.

The researchers plan to explore the behavior of the AI tool on a large screening-based population and its ability to detect breast cancer earlier.

People whose treatment for cancer is delayed by even one month have in many cases a 6 to 13% higher risk of dying - a risk that keeps rising the longer their treatment does not begin - suggests research published online in The BMJ.

Canadian and UK researchers found there was a significant impact on a person's mortality if their treatment was delayed, whether that be surgical, systemic therapy (such as chemotherapy), or radiotherapy for seven types of cancer.

Globally, health systems have problems with cancer treatment delays and it is already widely accepted that such delays can have adverse consequences on a patient's outcome. But the precise impact of delays from diagnosis to receipt of treatment on mortality has not been thoroughly analysed.

The need for better understanding of the impact of treatment delay on outcomes has come into focus during the COVID-19 pandemic because many countries have experienced deferral of elective cancer surgery and radiotherapy as well as reductions in the use of systemic therapies, while health systems have directed resources to preparing for the pandemic.

Therefore, a team of researchers led by Timothy Hanna from Queen's University in Kingston, Canada, carried out a review and analysis of relevant studies into the subject published between January 2000 and April 2020.

These studies had data on surgical interventions, systemic therapy (such as chemotherapy), or radiotherapy for seven forms of cancer - bladder, breast, colon, rectum, lung, cervix, and head and neck - that together, represent 44% of all incident cancers globally.

Their main outcome measure was the risk to overall survival per four-week delay for each indication and delays were measured from diagnosis to first treatment, or from the completion of one treatment to the start of the next.

They found 34 suitable studies for 17 types of conditions that needed to be treated (indications) involving more than 1.2 million patients, collectively. The association between delay and increased mortality was significant for 13 of these 17 indications.

Analysis of the results showed that across all three treatment approaches, a treatment delay of four weeks was associated with an increase in the risk of death.

For surgery, this was a 6-8% increase in the risk of death for every four-week treatment delay whereas the impact was even more marked for some radiotherapy and systemic indications, with a 9% and 13% increased risk of death for definitive head and neck radiotherapy and adjuvant (follow-up) systemic treatment for colorectal cancer, respectively.

In addition, the researchers calculated that delays of up to eight weeks and 12 weeks further increased the risk of death and used the example of an eight week delay in breast cancer surgery which would increase the risk of death by 17%, and a 12 week delay that would increase the risk by 26%.

A surgical delay of 12 weeks for all patients with breast cancer for a year (for example during COVID-19 lockdown and recovery) would lead to 1,400 excess deaths in the UK, 6,100 in the United States, 700 in Canada, and 500 in Australia, assuming surgery was the first treatment in 83% of cases, and mortality without delay was 12%.

The researchers used an example from the UK's NHS, which at the beginning of the COVID-19 pandemic, created an algorithm to prioritise surgery.

A number of conditions had been considered safe to be delayed by 10 to 12 weeks with no predicted impact on outcome, including all colorectal surgery.

"Therefore, our results can help to directly inform policy--we found that increasing the wait to surgery from six weeks to 12 weeks would increase the risk of death in this setting by 9%," they said.

The authors acknowledged that their study had limitations such as the fact that it was based on data from observational research which cannot perfectly establish cause, and it was possible that patients with longer treatment delays were destined to have inferior outcomes for reasons of having multiple illnesses or treatment morbidity.

Nevertheless, their analysis was based on a large amount of data and they ensured that they only included high quality studies that had high validity, meaning they accurately measured what they were investigating.

Hanna concludes: "A four week delay in treatment is associated with an increase in mortality across all common forms of cancer treatment, with longer delays being increasingly detrimental.

"In light of these results, policies focused on minimising system level delays in cancer treatment initiation could improve population level survival outcomes."

Problems with the sense of smell appear to be an early indicator of cognitive decline in people with type 2 diabetes. However, it's unknown whether factors such as diet and obesity play a role in who develops these symptoms. Now, researchers reporting in ACS Chemical Neuroscience found that mice fed a moderate-fat, high-sugar chow (simulating a Western diet) showed a faster decline in their ability to learn and remember new odors.

Some people with type 2 diabetes (T2D) show signs of olfactory dysfunction, including problems with detecting, discriminating or recalling odors, or even a complete loss of smell. These symptoms are strongly associated with cognitive impairment, and evidence suggests they could be an early indicator of the condition in people with T2D. Obesity, which is the main risk factor for T2D, has also been associated with olfactory dysfunction, but the impact of obesity on the sense of smell specifically in these patients is unclear, as studies have produced conflicting results. Also, it's unknown whether certain nutrients in the diet, such as fat and sugar, affect the sense of smell. To find out, Grazyna Lietzau, Cesare Patrone and colleagues wanted to compare the effects of two diets on different olfactory functions in mice: a high-fat, moderate-sugar diet (HFD); and a moderate-fat, high-sugar diet (similar to a Western diet, WD). In mice, both diets cause obesity and T2D-like features.

At one, three and eight months, the team performed tests to assess different olfactory functions in the mice. By eight months, both the HFD- and WD-fed mice had impaired odor detection, odor-related learning and olfactory memory compared with the control mice. However, the WD-fed mice had a faster decline in the latter two abilities, showing olfactory dysfunction as early as 3 months after beginning the diet. These findings indicate that a high dietary sugar content, rather than hyperglycemia or weight gain, is linked with early deterioration of olfactory functions related to learning and memory, the researchers say. How sugar causes these effects, and whether they are also seen in humans, the researchers acknowledge, remains to be determined.

A University of Cincinnati researcher is recommending pediatric hospital emergency rooms consider screening for sexually transmitted infections (STI) teenage and young adult patients who visit for other acute care issues.

Mark Eckman, MD, professor and director of the UC Division of General Internal Medicine, conducted a computer analysis that simulated outcomes for screening pediatric emergency room patients ages 15-21 for sexually transmitted infections. It will add costs to hospital budgets but Eckman says it also helps combat future health complications of STIs for young people.

Using a hypothetical population that included 10,000 emergency room visits Eckman looked at a 3.6% prevalence of chlamydia and gonorrhea - the same amount generally found in the nation's young adult population - and the impact of targeted screening, universal screening and no screening.  Under the scenario 360 STI cases would be present.

Targeted screening resulted in the detection and successful treatment of 95 of 360 STI cases (26.4%) at a cost of $313,063 and universally offered screening identified and treated 112 of 360 STI cases at a cost of $515,503. If no screening were done, 76 of 360 cases (21.1%) would be found at a cost of $190,409. 

The study's results in its entirety were recently published in the Journal of American Medical Association Pediatrics.

"Untreated chlamydia or gonorrhea can in women lead to pelvic inflammatory disease and ectopic pregnancies because of scarring in the fallopian tubes, while men can face epididymitis," says Eckman, also a UC Health physician. "Women and men could face infertility if these sexually transmitted infections are not treated."

Nationally, adolescents and young adults represent 25% of the sexually active population, but comprise 50% of all diagnosed sexually transmitted infection cases.  Of the 20 million new cases of sexually transmitted infections each year 10 million occur among adolescents and young adults.