Body

Long-term follow-up of the London patient suggests no detectable active HIV virus remains in the patient.

Although the treatment is high-risk and only suitable for certain patients, the results provide evidence that this patient is the second to be cured of the virus - replicating the finding that HIV cure is possible through stem cell transplantation. [1]

A study of the second HIV patient to undergo successful stem cell transplantation from donors with a HIV-resistant gene, finds that there was no active viral infection in the patient's blood 30 months after they stopped anti-retroviral therapy, according to a case report published in The Lancet HIV journal and presented at CROI (Conference on Retroviruses and Opportunistic Infections).

Although there was no active viral infection in the patient's body, remnants of integrated HIV-1 DNA remained in tissue samples, which were also found in the first patient to be cured of HIV. The authors suggest that these can be regarded as so-called 'fossils', as they are unlikely to be capable of reproducing the virus.

Lead author on the study, Professor Ravindra Kumar Gupta, University of Cambridge, UK, says: "We propose that these results represent the second ever case of a patient to be cured of HIV. Our findings show that the success of stem cell transplantation as a cure for HIV, first reported nine years ago in the Berlin patient, can be replicated." [1,2]

He cautions: "It is important to note that this curative treatment is high-risk, and only used as a last resort for patients with HIV who also have life-threatening haematological malignancies. Therefore, this is not a treatment that would be offered widely to patients with HIV who are on successful antiretroviral treatment. [2]

While most HIV patients can manage the virus with current treatment options and have the possibility of living a long and healthy life, experimental research of this kind following patients who have undergone high-risk, last-resort curative treatments, can provide insight into how a more widely applicable cure might be developed in the future.

In 2011, another patient based in Berlin (the 'Berlin patient') was the first HIV patient to be reported cured of the virus three and half years after undergoing similar treatment. Their treatment included total body irradiation, two rounds of stem cell transplant from a donor who carried a gene (CCR5Δ32/Δ32) that is resistant to HIV, and a chemotherapy drug regimen. [2] The transplant aims to make the virus unable to replicate in the patient's body by replacing the patient's immune cells with those of the donors, whilst the body irradiation and chemotherapy targets any residual HIV virus.

The patient reported in this study (the 'London patient'), underwent one stem-cell transplantation, a reduced-intensity chemotherapy drug regimen, without whole body irradiation. In 2019, it was reported that their HIV was in remission, and this study provides follow-up viral load blood test results at 30-months and a modelling analysis to predict the chances of viral re-emergence.

Ultrasensitive viral load sampling from the London patient's cerebrospinal fluid, intestinal tissue, or lymphoid tissue was taken at 29 months after interruption of ART and viral load sampling of their blood at 30 months. At 29 months, CD4 cell count (indicators of immune system health and stem cell transplantation success) was measured, and the extent to which the patient's immune cells have been replaced by those derived from the transplant.

Results showed no active viral infection was detected in samples of the patient's blood at 30 months, or in their cerebrospinal fluid, semen, intestinal tissue, and lymphoid tissue 29 months after stopping ART.

The patient had a healthy CD4 cell count, suggesting they have recovered well from the transplant, with their CD4 cells replaced by cells derived from the HIV-resistant transplanted stem cells.

Furthermore, 99% of the patient's immune cells were derived from the donor's stem cells, indicating the stem-cell transplant had been successful.

Since it was not possible to measure proportion of cells derived from the donor's stem cells in all parts of the patient's body (i.e. measurement was not possible in some tissue cells like lymph nodes), the authors used a modelling analysis to predict the probability of cure based on two possible scenarios. If 80% of patient's cells are derived from the transplant, the probability of cure is predicted at 98%; whereas if they have 90% donor derived cells, they predict a 99% probability of cure.

Comparing to the treatment used on the Berlin patient, the authors highlight that their case study of the London patient represents a step towards a less intensive treatment approach, showing that the long-term remission of HIV can be achieved using reduced intensity drug regimens, with one stem cell transplant (rather than two) and without total body irradiation.

However, being only the second reported patient to undergo this experimental treatment successfully, the authors note that that the London patient will need continued, but much less frequent, monitoring for re-emergence of the virus.

Speculating on what their results might mean for future developments of HIV cures that utilise the CCR5 (HIV resistant) gene, co-author on the study, Dr Dimitra Peppa, University of Oxford, UK, says: "Gene editing using the CCR5 has received a lot of attention recently. The London and Berlin patient are examples of using the CCR5 gene in curative therapies outside of gene editing. There are still many ethical and technical barriers - e.g. gene editing, efficiency and robust safety data - to overcome before any approach using CCR5 gene editing can be considered as a scalable cure strategy for HIV." [2]

Writing in a linked Comment, lead author Professor Sharon R Lewin, University of Melbourne, Australia, (who was not involved in the study), says, "The finding of no intact virus can be reassuring for a patient who might face significant anxiety and uncertainty about whether and when viral rebound off ART might occur, which in other settings has been completely unpredictable. Given the large number of cells sampled here and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow up case report is certainly encouraging but unfortunately in the end, only time will tell."

A new study published in Circulation, a journal of the American Heart Association, shows that noncitizens in the United States are less likely to receive treatment for cardiovascular disease risk factors when compared with born or naturalized U.S. citizens.

Cardiovascular disease, or CVD, includes conditions such as heart attack and stroke. It is the leading cause of death among adults in the U.S., including immigrants, according to the U.S. Centers for Disease Control and Prevention and the U.S. Department of Health and Human Services.

The University of Illinois at Chicago researchers who conducted the study -- which used nationally representative data from the National Health and Nutrition Examination Survey, or NHANES -- found that treatment rates for CVD risk factors were lower among noncitizens when compared with citizens. These differences were primarily due to the lack of insurance coverage and a usual source of care, such as a clinic or doctor's office.

Nearly 17,000 U.S. adults over the age of 20 were included in the analysis, which looked at three categories: U.S.-born citizens (82.1%), foreign-born citizens (8.6%) and noncitizens (9.3%). For each category, the researchers examined the prevalence and treatment of three key CVD risk factors: high cholesterol, high blood pressure and diabetes.

They found that noncitizens had considerably lower treatment rates for high cholesterol compared with foreign-born citizens and U.S.-born citizens. Only 16.5% of noncitizens received treatment for their high cholesterol, compared with 43.3% of foreign-born citizens and 45.5% of U.S.-born citizens. Similar differences were found for high blood pressure treatment (60.3% vs. 79.6% and 81.1%) and diabetes treatment (51.2% vs. 66.6% and 69.5%).

These disparities by citizenship status remained after the researchers adjusted for sociodemographic factors, including age, gender, education, income and language preferences. But when the researchers adjusted for insurance coverage and access to a usual source of care, the differences between U.S. and foreign-born citizens and noncitizens lessened.

"Citizenship status acts as a structural barrier to health for noncitizens, where many are systematically excluded from the health care system," said first and corresponding author Jenny Guadamuz, a UIC Ph.D. candidate at the College of Pharmacy. "Yet, much of the current literature on immigrant health does not acknowledge citizenship status as a structural barrier that drives health disparities experienced by immigrants, regardless of ethnic, cultural or behavioral differences."

UIC's Dima Qato, senior author of the study and associate professor of pharmacy systems, outcomes and policy at the UIC College of Pharmacy, says findings from this study offer "strong evidence on the impact of immigration policy on health and health disparities in the U.S. and the importance of promoting health policies at the local, state or federal levels that ensure access to care, including insurance coverage, and protect the health of immigrants, particularly noncitizens."

A population-based analysis from England indicates that the incidence of colorectal cancer is increasing rapidly in young adults. The findings, which are published in BJS (British Journal of Surgery), suggest that colorectal cancer should no longer be considered a disease of older people.

For the analysis, investigators examined information on adults who were diagnosed with colorectal cancer in England between 1974 and 2015. Of the 1,145,639 new cases of colorectal cancer diagnosed between 1974 and 2015 in adults aged over 20 years, there were 2,594 in 20-29 year olds, 11,406 among 30-39 year olds and 42,134 in 40-49 year olds.

The most sustained increase in incidence rates was seen in adults aged 20-29 years. The magnitude of increases was similar in both sexes and across income levels. The most pronounced increases in incidence occurred in the southern regions of England.

Another article in BJS notes that young patients need more treatment to achieve similar outcomes to older patients.

A growth hormone called insulin-like growth factor-1 (IGF-1) is likely to play a role in the development of breast cancer, according to new research published in the leading cancer journal Annals of Oncology [1] today (Wednesday).

IGF-1 is already known to encourage the growth and proliferation of cancer cells. Now, two analyses of information from several hundred thousand women enrolled in the UK Biobank study have shown that not only is there an association between higher levels of IGF-1 circulating in the blood and the development of breast cancer, but also, for the first time, that IGF-1 is likely to be a cause of the disease.

Researchers from the International Agency for Research on Cancer (IARC), Lyon, France, and the Cancer Epidemiology Unit at the University of Oxford, UK, carried out two, complementary studies to investigate the role of IGF-1 in breast cancer development. The first looked at the associations between levels of IGF-1 in the blood and the chances of the disease developing in 206,263 women.

The second study used a technique called Mendelian randomisation to analyse data from 265 variants of genes (single nucleotide polymorphisms or "SNPs") known to be associated with IGF-1 concentrations in 122,977 cases of breast cancer and 105,974 women without cancer (the controls). In this analysis, the researchers also looked at four SNPs for insulin-like growth factor-binding protein-3 (IGFBP-3), which may modulate the availability of IGF-1.

Mendelian randomisation uses complex statistical analysis of data from large population studies, such as UK Biobank, to provide evidence for cause and effect, rather than just the existence of an association. Randomly inherited genetic variations that alter levels of IGF-1 and IGFBP-3 mimic the effect of a randomised trial and are unaffected by the disease process, so the researchers were able to use them to see whether people with a different genetic make-up had a different risk of breast cancer.

During an average of seven years of follow-up, 4,360 cases of breast cancer occurred. Among the 206,263 women included in the observational analysis, levels of IGF-1 ranged between an average of around 14 nanomoles per litre of blood (nmol/L) among participants with levels in the lowest 20% and 29 nmol/L in the top 20%.

In the observational study, the researchers found that women with IGF-1 concentrations in the top 20% had 1.24-fold increased chance of developing breast cancer compared to those in the bottom 20%, after adjustments for various factors that could affect the results, such as age, physical activity, body mass index, alcohol consumption, smoking, educational level and concentrations of other hormones and proteins in the blood, such as C-reactive protein, and testosterone. For every 1,000 women in the study who had the lowest IGF-1 concentrations, 21 were diagnosed with breast cancer over the study period, while 26 were diagnosed among those who had the highest concentrations. Every additional 5 nmol/L of IGF-1 concentrations was associated with a 1.11-fold increased risk. The results were consistent for both pre- and post-menopausal women.

Results from the Mendelian randomisation study were similar. For every additional genetically predicted 5 nmol/L of IGF-1, the risk of breast cancer increased by 1.05. However, when the researchers looked at oestrogen receptor positive (ER+) and negative (ER-) breast cancers [2] separately, IGF-1 was only associated with an increased risk of ER+ breast cancer. For every additional 5 nmol/L of IGF-1, there was a 1.06-fold increased risk of ER+ breast cancer. No association was found for IGFBP-3 concentrations and breast cancer risk.

Dr Neil Murphy, a scientist at IARC, said: "We found that higher levels of IGF-1 circulating in the blood, as determined by blood measurements and genetic markers, were related to higher breast cancer risk. These results support a probable causal role of the IGF pathway in breast cancer development."

Dr Marc Gunter, scientist and head of the nutrition and metabolism section at IARC, said: "To our knowledge, this is largest single study and the first Mendelian randomisation study to examine the relationship between IGF-1 and breast cancer. Importantly, our Mendelian randomisation analyses yielded strikingly similar positive associations between IGF-1 and breast cancer as those found in our observational analyses. Taken together, these results provide the strongest evidence to date for a causal role of the IGF-pathway in breast cancer development, and suggest that altering IGF-1 levels through diet and lifestyle or pharmacological means may be an effective strategy in the primary prevention of breast cancer. Our next step is to gain a fuller understanding of which lifestyle practices can alter IGF-1 concentrations and, in turn, the chances of breast cancer developing."

Dr Anika Knüppel, a nutritional epidemiologist at the University of Oxford, said: "The association between IGF-1 and breast cancer was first investigated in the 1980s and our findings are in line with various studies since then. But clarifying the direction of the association using Mendelian randomisation in our study leads the way for research into how the IGF-1 pathway can be harnessed in breast cancer prevention."

It may be possible to modify IGF-1 concentrations in the blood through changes to the amount and types of protein in a person's diet. In addition, drugs that target the IGF-1 system have been developed. There may be other, as yet unknown factors that can affect IGF-1 concentrations too.

Dr Murphy said: "Although levels of IGF-1 in the blood are potentially modifiable it is currently unknown how long an intervention aimed at altering IGF-1 concentrations would have to be applied in order to have a measurable effect or whether there could be other adverse impacts of such an intervention."

Limitations of the study include the possibility that a different biological pathway may be involved in the effect of IGF-1 on breast cancer, although the researchers conducted various analyses to test this.

A new genetic test could help doctors pick out patients with the bone marrow cancer multiple myeloma who are at 'ultra high risk' of their cancer progressing aggressively early on.

Researchers showed that patients whose cancers display particular genetic patterns have a much poorer survival than average and are unlikely to benefit from a drug called lenalidomide on its own.

Picking out patients whose cancers have high-risk genetic features could therefore help clinicians realise sooner if they're unlikely to respond to treatment, enabling them to find alternative options as early as possible.

Scientists at The Institute of Cancer Research, London, studied 329 patients across UK hospitals from the phase III Cancer Research UK Myeloma XI trial, which looked at the effectiveness of a range of targeted drugs, including lenalidomide, in people with newly diagnosed with multiple myeloma.

Their study is published in the journal Leukemia and was funded by Myeloma UK and the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research (ICR), with further support from Cancer Research UK and through the Jacquelin Forbes-Nixon Fellowship.

Researchers looked for people at ultra high risk by analysing patterns of abnormal gene activity and genetic mutations of their cancers - with the aim of finding out if these 'signatures' could provide clues as to how aggressive their cancer is, how quickly it spreads and if it is likely to respond to treatment with lenalidomide on its own.

One quarter of the patients, 81 in total, had cancers with the so-called SKY92 signature - a pattern of gene activity involving 92 genes linked to high-risk status.

On average patients with cancers that had the SKY92 high-risk gene expression signature had an up to three-fold increased risk of their cancer returning early. Those with heavily genetically mutated - so called 'double-hit' cancers - had a two-fold increased risk of death.

Combining information about these two risk features, which had before been regarded as an 'either or' test, improved the researcher's ability to predict disease outcome.

Around 10 per cent of the total patient group had both the SKY92 signature and double-hit genetic features. People in this group were at ultra high risk of early, aggressive disease relapse, with all cancers in this group progressing within four years with current standard therapies - as opposed to much longer responses in other groups. Patients with ultra high risk disease had an 11-fold increased risk of death compared with other patients.

The ICR researchers found that patients in this ultra high risk group were highly unlikely to benefit from lenalidomide as ongoing or maintenance therapy - a treatment that can help very efficiently to keep myeloma from coming back after it has responded to initial therapy in cancers with only few or no genetic high risk features.

People with ultra high risk myeloma have a high unmet need for new treatment approaches, including cocktails of novel immunotherapy drugs in combination with chemotherapy. The researchers will be testing different drug combinations in a new clinical trial, OPTIMUM.

Next, the researchers plan to combine the insights from this study with the ongoing OPTIMUM trial, which will look at 470 patients, in order to find alternative treatment options for people with high-risk myeloma.

Study leader Dr Martin Kaiser, Team Leader in Myeloma Molecular Therapy at The Institute of Cancer Research, London, and Consultant Haematologist at The Royal Marsden NHS Foundation Trust, said:

"Our study shows that people whose tumours have an 'ultra high risk' combination of genetic features have particularly aggressive disease which doesn't respond sufficiently to standard treatment to keep their cancer at bay.

"Testing for high-risk genetic features could help target myeloma treatment, focusing on the specific needs of each patient. Not all patients with myeloma are the same, and we know that by better understanding their cancer's genetic and molecular features, we can tailor their treatment much more effectively.

"The next step is to combine our results for this study with the ongoing OPTIMUM trial, which will provide us with more information on how to tailor treatment for patients at ultra high risk based on genetic information."

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

"This exciting new research shows how it is possible to use genetic information to divide patients with bone marrow cancer into different disease sub-types, and to plan treatment accordingly. It will be exciting to see whether targeting these highest-risk patients with an intensive new treatment can improve survival."

Sarah McDonald, Director of Research at Myeloma UK, said:

"We are aware that myeloma isn't a 'one size fits all' cancer and treatment needs to become more personalised. This paper on the innovative research undertaken by the ICR team is a huge step forward. The ability to identify high-risk patients means they can receive the intensive treatment they need sooner and enables further study of this cohort to develop new treatment approaches which can improve patient survival."

Less than 8 percent of people who suffer from cardiac arrest outside of the hospital survive the incident, according to the American Heart Association. To improve survivorship and better administer life-saving cardiopulmonary resuscitation (CPR), researchers and physicians at The Feinstein Institutes for Medical Research and North Shore University Hospital developed a novel approach called Mechanical, Team-Focused, Video-Reviewed Cardiopulmonary Resuscitation (MTV-CPR) to video record, review and reform practices to improve performance. Their research results published today in the Journal of the American Heart Association.

The first-of-its-kind study to be conducted nationally began in 2018 when emergency department (ED) staff at North Shore University Hospital (NSUH) began video recording the process and use of the mechanical chest compression device (MCCD) for cardiac arrest patients. The goal of the study was to increase the return of spontaneous circulation (ROSC) rate pre- and post- MTV-CPR intervention.

A new team-focused strategy was developed with nurse-led Advanced Cardiac Life Support (ACLS) and biweekly, multidisciplinary video review of the cardiac arrests were conducted. The research is spearheaded by Lance Becker, MD, professor in the Institute of Bioelectronic Medicine at the Feinstein Institutes, and Daniel Rolston, MD, MSHPM an Emergency Medicine and Critical Care physician at NSUH.

"It was a simple, yet powerful idea; use overhead video cameras to record and then later review the process of our staff administering mechanical CPR in our emergency rooms to improve outcomes," said Dr. Becker, who is also the ED chair at Long Island Jewish Medical Center and NSUH. "Our data support the benefit of actively reviewing and improving on real-world CPR techniques to save peoples' lives. When we saw a problem we developed new protocols to overcome each challenge."

Four resuscitation rooms in the ED equipped with video review technology which monitored 151 cardiac arrest patients for the ROSC rate. Patients achieving ROSC improved from 26 percent before MTV-CPR intervention to 41 percent afterward.

Dr. Becker and his team of physicians, nurses and technicians gathered to watch video of the resuscitation and review processes, trying to find ways to make each incidence better. Through their analysis, the team implemented personalized feedback for those placing MCCD on patients, reduced chest compression interruptions, developed new assignment roles for an eight-person response team, and created new coordinated transition methods for technicians to go from manual to mechanical CPR.

"Dr. Becker and his team have led early, national efforts to put defibrillators in public spaces," said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes. "Now they are leading this new effort to prevent sudden cardiac deaths in hospital emergency departments."

A worldwide collaborative study led by scientists at the University of Sussex has proposed a new treatment strategy for patients with a rare but aggressive subtype of cancer known as triple negative breast cancer.

The treatment targets healthy cells using drugs that are already available and currently in use for patients with leukaemia and lymphoma.

Around 15% of breast cancer cases are diagnosed as triple negative breast cancer - a form of solid cancer where cells don't have receptors for the oestrogen (ΕRα) and progesterone hormones (PR), or a protein known as HER2. Current treatments involve surgery or chemotherapy, however prognosis still remains poor.

A new study led by Georgios Giamas, Professor of Cancer Cell Signalling at the University of Sussex, has provided strong evidence for the development of a new type of treatment to halt progression of the disease by using existing drugs to target the surrounding healthy tissues of cancerous cells, known as fibroblasts.

Prof Giamas said: "Cancer is a systemic disease so instead of only focusing on cancer cells to find a cure, sometimes we need to step back and look at the bigger picture known as the tumour microenvironment'. This means looking at the surrounding cell types - the 'normal cells' - that can actually contribute either positively or negatively to the progression of the disease."

Using samples from triple negative breast cancer patients, researchers found that overall survival was markedly worse when levels of the protein PIK3Cδ were high in surrounding healthy tissue. Interestingly, this was not the case for the other two subtypes of breast cancer(ΕRα+ and HER2+).

PIK3Cδ inhibitors were tested in two different breast cancer mouse models with results showing a reduction in tumour growth. As PIK3Cδ is mainly expressed in white blood cells, scientists believe that these drugs acted predominantly on the immune system. The findings suggest that if treatments could control levels of PIK3Cδ in the surrounding normal cells, then survival outcomes for patients would improve.

Prof Giamas said: "The lack of effective therapies for triple negative breast cancer is well-established, despite the emergence of approaches like immunotherapy.

"Our results suggest that repurposing already available drugs which act as inhibitors for PIK3Cδ could stop the progression of the disease. As the drugs are already available and FDA approved, clinical trials could begin immediately to further investigate the use of these inhibitors for triple negative breast cancer treatment."

Dr. Teresa Gagliano, first author of the study and currently Senior Scientist at the University of Zurich, said: "If we had focused only on the cancer cells, we would have never identified PIK3Cδ, and the possibility of an alternative therapy. Sometimes it's fundamental to think outside the box."

The study, funded by Action Against Cancer, involved scientists from across three continents and six different countries and was published in the Journal of Clinical Investigation.

The findings will be of interest to oncologists who may decide to take this forward to clinical trial, if the Medicines and Healthcare products Regulatory Agency (MHRA) review and authorise the drug.

Researchers at the University of Campinas (UNICAMP) in São Paulo State, Brazil, have developed a computer program that analyzes molecules in blood plasma to search for biomarkers that identify individuals who are at risk of becoming overweight and developing obesity-related diseases.

The project was supported by FAPESP. The principal investigator was Professor Rodrigo Ramos Catharino, head of UNICAMP’s Innovare Biomarker Laboratory. The results are described in the journal Frontiers in Bioengineering and Biotechnology.

“The test is 90% accurate in detecting whether the subject will gain weight without any kind of intervention,” Catharino told Agência FAPESP. “It also shows whether there’s a risk of developing diseases such as diabetes, high blood pressure and dyslipidemia [abnormally elevated levels of fat in the blood]. It’s an important tool because health professionals can use it to recommend lifestyle changes before a problem materializes.”

The test consists of a mass spectrometer analysis to detect all the metabolites present in the patient’s blood and produce a profile of the various metabolic processes at work in the organism. The data obtained by mass spectrometry are processed by the new software.

The program was written as part of Flávia Luísa Dias-Audibert’s PhD research, in partnership with researcher Luiz Cláudio Navarro. Dias-Audibert’s thesis advisor is Professor Anderson Rezende Rocha of UNICAMP’s Computer Science Institute.

The group was supported by the Obesity and Comorbidities Research Center (OCRC), a Research, Innovation and Dissemination Center (RIDC) funded by FAPESP and hosted by UNICAMP.

“The program screens the blood sample for five metabolites that function as biomarkers with the potential to predict weight gain,” Catharino said. “When one of these biomarkers is present in the sample, the patient will tend to develop diabetes if he or she becomes obese.”

The software files are open-source and can be downloaded free of charge from the internet. According to Catharino, any health service with access to a mass spectrometer can apply the methodology.

“It’s an inexpensive technique and affordable even for the SUS [Brazil’s national health system]. All you need is one mass spectrometer for a network of hospitals and outpatient clinics,” Catharino said.

Machine learning

The methodology developed at UNICAMP combines metabolomics (the analysis of all the metabolites in a biological sample) with machine learning, a subdiscipline of artificial intelligence. The researchers used data obtained from the analysis of blood samples supplied by 180 people to “teach” the program to recognize a pattern associated with weight gain.

Half the volunteers included in the study were within the body mass index (BMI) range deemed healthy, while the rest were overweight to varying degrees or obese.

“Anthropometric measurements [weight, height and body mass] were taken for all participants, who also completed a questionnaire on family history of chronic disease, as well as age and gender,” Catharino said. “We used some of the patients to train the software and the others to validate it by comparing its results with their own anthropometrics and health history. The random forest machine learning algorithm was used for the training part.”

The researchers found that 18 metabolites can serve as biomarkers of metabolic processes relating to fat accumulation, five of which have the potential to predict weight gain.

“Prostaglandin B2 and carboxy-leukotriene B4 are metabolites of arachidonic acid [a fatty acid in the omega-6 family] known to participate in inflammatory processes, in the recruiting of cells to the site of inflammation, and in the production of reactive oxygen species [an excess of which impairs cell functioning],” Dias-Audibert said. “Two other molecules we identified were argininosuccinate and dihydrobiopterin, both of which are involved in the nitric oxide cycle and can be considered markers of free radical production.”

According to Dias-Audibert, the combination of these biomarkers suggests that feedback from the inflammatory cascade occurs in overweight individuals. “This finding matches those of several studies that describe low-grade chronic inflammation as one of the active deleterious processes in the overweight condition,” she said.

The fifth biomarker found to be a potential predictor of weight gain was carboxy-methyl-propyl-furanpropanoic acid (CMPF), a metabolite associated with dysfunction of the insulin-producing cells in the pancreas and the development of diabetes. “Considering there were diabetics in the study group, this biomarker could be the link between weight gain and diabetes,” Dias-Audibert said.

Catharino said the computer program can also be used by health professionals to assess the effectiveness of a treatment prescribed to reduce a patient’s percentage of body fat.

“Even before the subject loses weight, it’s possible to know whether the intervention is working well. If the metabolic processes that lead to fat accumulation are interrupted, the 18 metabolites we identified will tend to disappear from blood plasma,” he said.

Researchers from the Center for Health, Work and Environment (CHWE) at the Colorado School of Public Health have published a paper in PLoS-ONE, studying the decline in kidney function for young, first-time sugarcane workers in Guatemala. The study, led by University of Colorado Instructor Miranda Dally, is the first to examine kidney function decline in workers starting their first day on a job with a high risk of developing Chronic Kidney Disease of Unknown Origin (CKDu), a rising epidemic in rural workers in Central and South America.

The study found that workers who entered the sugarcane workforce with even slightly lower than average kidney function were at a greater risk for a rapid onset of kidney injury once they start work. 47% of all first-time workers entered the workforce with mild hypertension, another significant risk factor. Additionally, those workers who live in coastal communities were found to be a high risk compared to seasonal migrant workers from the mountainous highlands.

"Our work establishes that there is a subgroup of people for whom their occupation can make them more susceptible and more vulnerable to reduced kidney function," said Dally. "Previous research on CKDu has looked at this health crisis as an occupational disease. While occupation plays a role in contributing to the disease, it does not tell the full story."

Until now, most research on this international epidemic has examined how working conditions contribute to the disease. The Center's research is one of the first studies to consider how community health risks factors may impact the health and safety of workers.

"Researchers have mostly focused on workers' exposures on the job in the search for the causes of this epidemic," said Dr. Newman, Professor and director of the Center's research program addressing the health of workers in Latin America. "This study provides the first direct evidence that we need to step back and consider what else is contributing to kidney disease in communities--even before people join the workforce."

Based on this study, the research team recommends that blood pressure and renal function screenings become a routine part of health monitoring for workers and community members at risk of CKDu, specifically those performing intense labor in hot environments. The Center for Health, Work & Environment is conducting additional research projects exploring other potential risk factors contributing to CKDu as part of its mission of promoting the health, safety and well-being of all workers.

Unnecessary prostate cancer biopsies could be reduced by 60 per cent thanks to new research from the University of East Anglia.

Researchers have developed new methods to identify biomarkers for prostate cancer by combining information from multiple parts of urine samples.

It is hoped that the breakthrough could help large numbers of men avoid an unnecessary initial biopsy.

Prostate cancer is the most common cancer in men in the UK. It usually develops slowly and the majority of cancers will not require treatment in a man's lifetime.

The most commonly used tests for prostate cancer include blood tests, a physical examination known as a digital rectal examination (DRE), an MRI scan or a biopsy.

Lead author Shea Connell from UEA's Norwich Medical School, said: "Prostate cancer is more commonly a disease men die with rather than from.

"Current practice assesses a patient's disease using a PSA blood test, prostate biopsy and MRI. But up to 60 per cent of men with a raised PSA level are negative for prostate cancer on biopsy.

"So it is clear that there is a considerable need for additional, more accurate, tests.

Last year, the same team unveiled an experimental new test called 'PUR' (Prostate Urine Risk) which diagnoses aggressive prostate cancer and predicts whether patients will require treatment up to five years earlier than standard clinical methods.

The latest research combines information from two different components in urine which further improves its use for diagnosis.

Shea Connell said: "We wanted to see if other biological information from urine could be integrated together with clinical information to create a new predictive test with even greater potential."

The team developed the ExoMeth test by studying urine samples collected from 197 patients. They used machine learning techniques to find which specific combination of biological markers could be useful for predicting the presence of prostate cancer.

ExoMeth takes a 'holistic view' of urine for biomarkers by considering much more than a single fraction of the urine. By integrating cell-free RNA, cellular methylation and clinical factors all together, the research team can now much more accurately discriminate the disease status of a patient without the need for an invasive biopsy.

It provides good evidence that multiple aspects of urine can be combined to determine a patient's disease status.

Senior author Dr Daniel Brewer, from UEA's Norwich Medical School, said: "It's still very early days for this research, but if ExoMeth were validated in a future study with many more patients, we could see an approximate 60 per cent reduction in unnecessary biopsies in around five years."

The research was led by UEA, in collaboration with the Norfolk and Norwich University Hospital, the Earlham Institute, University College Dublin, and the University of Toronto.

It was funded by Movember, the Masonic Charitable Foundation, the Bob Champion Cancer Trust, the King Family, the Andy Ripley Memorial Fund, the Hargrave Foundation, the US Prostate Cancer Foundation, the Science Foundation Ireland, the Royal Irish Academy and the Irish Cancer Society.

Dr Mark Buzza, global director of biomedical research programs at men's health charity Movember, said: "Despite advances in recent years, prostate cancer remains very difficult to diagnose and treat. That's why we're so excited about the Exometh test. One of the major advantages of the test is that it could remove the need for 60 per cent of invasive biopsies.

"We are delighted to have supported this project under Movember's Global Action Plan (GAP1) Biomarker project which fosters collaboration between researchers across the globe. Bringing researchers together to collaborate rather than compete for funding allows research findings to be fast-tracked."

In the first study of its kind, researchers from the University of Surrey and Princess Alice Hospice investigated the bereavement support provided to children before and after a parent's death. Ensuring children receive adequate support is vital in safeguarding their psychological wellbeing, as previous research in this area has found that approximately half of children who lose a parent through a prolonged illness continue to experience unresolved grief up to nine years later.

Hospices in the UK provide palliative and end-of-life care either in the community or at in-patient units to more than 200,000 people with terminal and life-limiting conditions each year. Up to 10 per cent of hospice patients have children under the age of 18, but little is known across the sector about the range of support provided for families before and/or after the death of a parent.

Surveying 130 adult hospices, representing two-thirds of those in the UK, researchers identified that all provide some form of support before and after parental death, but the type and timing of the support available varies widely. The most common forms, offered by the majority of hospices, are written materials, signposting to external agencies, online resources and face to face sessions. Specialist counsellors are the professionals most likely to provide support whilst psychologists and psychiatrists are the least likely to be involved. Further, volunteers are more likely to be involved after than before a death, the findings revealed.

Researchers also found that a greater range of support is provided after a parental death than before, suggesting that proactive support when a parent is dying is less resourced.

More than three-quarters of hospices said they formally ask and record whether patients in their care have dependent children under the age of 18. Of those that do have formal processes in place, most report providing training for their staff to deliver support to children but many describe this to be 'generic' and 'ad hoc.' Many cite funding difficulties in training and maintaining staff for bereavement support services to be a barrier in delivering this vital service.

Lead author Jane Cockle-Hearne, Research Fellow at the University of Surrey, said: "Without appropriate support, a parent's death can have long lasting and damaging effects on a child's schooling, relationships, independence and emotional wellbeing. But it can be challenging for hospices to provide this needed support in the context of increasing demand and financial pressures. This is despite national guidelines which acknowledge that when a parent is dying, tailored support for dependent children should be available."

Dr Jennifer Todd of Princess Alice Hospice, co-author of the paper, stated: "The finding that virtually all responding hospices provide some form of support to families before and after parental death is reassuring, and demonstrates that this important support is valued throughout adult hospices in the UK.

"That said, there appears room for improvement in terms of the use of formal processes to record the number of dependent children of dying patients, to ensure no one falls through the net. While better recording should improve the support provided to dependent children of dying patients, the report acknowledges that one of the key challenges for hospices is the shortfall in resources and skills training, predominantly down to lack of funding."

Professor Emma Ream, Director of Health Sciences Research at the University of Surrey, said: "Findings from this important study show that palliative care services vary enormously. Consequently, children and their needs may go under the radar.

"We should be more proactive in seeking to support parents and children to prepare them for a parent's death; we should not wait for problems to develop."

The economic and ecological impact of nature on humans have long been established with prevalent environmental issues such as climate change and over-exploitation of natural resources being the first to cross one's mind. On the other hand, much less attention has been paid to the cultural and social values nature brings to humans. Even though natural wonders such as the Great Barrier Reef and the Swiss Alps have been named some of the top holiday destinations, the intangible benefits people gain from experiencing nature are still difficult to quantify, and such studies typically require resource-intensive surveys and interviews.

In order to evaluate the benefits of nature experiences more efficiently and effectively, a team of researchers from the National University of Singapore (NUS) turned to social media and artificial intelligence (AI) in a study published in Scientific Reports on 5 March 2020.

Led by Associate Professor Roman Carrasco and Dr Chang Chia-chen from the Department of Biological Sciences at NUS Faculty of Science, the research team analysed over 31,500 photographs across 185 countries on social media with the help of an automated image recognition technology.

"Integrating social media data and AI opens up a unique opportunity for us to carry out unprecedented large-scale global studies such as this to better understand our interactions with nature in our daily lives," said Dr Chang, Research Fellow at the Department of Biological Sciences at NUS Faculty of Science and first author of the study.

The team's analysis of the photographs uploaded on social media revealed that photographs tagged as #fun, #vacations and #honeymoons are more likely to contain elements of nature such as plants, water and natural landscape as compared to photographs tagged #daily or #routines. This finding, which is consistent across different countries, provides global evidence of biophilia hypothesis -- human's innate tendency to seek connection with nature -- and implies a positive association between nature and fond memories in memorable events like honeymoons.

The team also found that the amount of nature experiences in a country is linked to the life satisfaction of its residents. Countries which have more elements of nature in photographs tagged as #fun such as Costa Rica and Finland, for instance, possess higher llfe national satisfaction scores according to scores reported in the World Happiness Report 2019. Collectively, the findings suggest the importance of nature in contributing to emotional happiness, relaxation and life satisfaction in communities worldwide.

Assoc Prof Carrasco said, "Our study brings to light the cultural and social values that nature brings to humans. It further emphasises the importance of preserving our natural environment for the loss of nature may mean more than losing quantifiable economic and ecological benefits; it could also mean losing the background to our fondest memories."

"Our next step is therefore to establish how nature experiences may benefit human well-being such as how it improves our satisfaction in life, hence enabling the development of constructive solutions to better environmental conservation," he added.

Scientists at UCL have invented a new test to identify the earliest genetic changes of prostate cancer in blood: a process which could allow doctors to see if cancers have spread, monitor tumour behaviour and enable better treatment selection.

In the study, published in The Journal of Clinical Investigation, researchers at UCL Cancer Institute used Next Generation Sequencing (NGS) to establish if they could identify prostate cancer DNA in blood plasma. Previous studies have focused on tissue samples, however this requires an invasive biopsy.

Researchers say their successful discovery in blood represents a prostate tissue "fingerprint", or early circulating biomarker, and when detected identifies that cancer is active and spreading. As this can be detected in a simple blood test, commonly known as a liquid biopsy, physicians could monitor cancer response to treatment regularly and in real-time.

Moving forward researchers will see if this test could complement or replace the existing prostate specific antigen test, which is used for prostate cancer diagnosis and treatment monitoring.

Lead author, Dr Anjui Wu (UCL Cancer Institute), said: "Metastatic prostate cancer - the most dangerous late stage of the disease - can vary substantially in its treatment response and clinical progression.

"We urgently need biomarkers that will help us determine how far along each patient's cancer is, to determine the best course of treatment.

"With tumour biopsies difficult to obtain, being able to identify prostate cancer DNA signatures at the earliest opportunity in blood, will help monitor patients better and assist more effective treatment selection and combination."

In this proof of concept study, the researchers set out to investigate a process called DNA methylation - that is, a chemical change in DNA molecules that can affect gene function and has been studied in tissues.

To do this, the methylation and genome profiles of circulating-cell free DNA (degraded DNA fragments released to the blood plasma) from 25 metastatic prostate cancer patients were concurrently profiled using NGS. As a control, four healthy blood plasma samples were also analysed.

The research group interrogated the molecular profiles to identify circulating tumour DNA (ctDNA) methylations, which can be used to sensitively track tumour content change.

Traditionally, the amount and quality of circulating cell-free DNA extracted from blood can be limited: surprisingly, researchers discovered 1,000s of methylation changes specific to the prostate gland in blood samples from men with prostate cancer. Using this finding, they developed these changes into a signature (a blood test that can be used in the clinic) for tracking prostate genetic material in blood to monitor cancer activity.

Corresponding author, Professor Gert Attard (UCL Cancer Institute), said:

"We are now testing our new technique in trial patients to see if it can complement or substitute the traditional serum prostate specific antigen (PSA) for diagnosis, risk assignment and monitoring how well a treatment is working.

"We believe the increased sensitivity and additional information we derive, will significantly improve the outcomes of men with advanced prostate cancer."

Professor Mark Emberton, Dean of the Faculty of Medical Sciences at UCL, said "The field of liquid biopsies has shown great potential recently to improve the diagnosis and management of cancer patients.

"This test could be the first to tell us cancer has got into blood before the spread is large enough to see on imaging. This could allow targeting of treatment for men at the highest risk of prostate cancer spread."

Barth syndrome is a rare metabolic disease in boys caused by mutation of a gene called tafazzin or TAZ. It can cause life-threatening heart failure and also weakens the skeletal muscles, undercuts the immune response, and impairs overall growth. There is no cure or specific treatment, but new research at Boston Children's Hospital suggests that gene therapy could prevent or reverse cardiac dysfunction.

The findings, involving new mouse models of Barth syndrome, were published today "Online First" by the journal Circulation Research.

In 2014, to get a better understanding of Barth syndrome, William Pu, MD, and colleagues at Boston Children's Hospital collaborated with the Wyss Institute to create a beating "heart on a chip" model of Barth syndrome. The model used heart-muscle cells with the TAZ mutation, derived from patients' own skin cells. It showed that TAZ is truly at the heart of cardiac dysfunction: the heart muscle cells did not assemble normally, mitochondria inside the cells were disorganized, and heart tissue contracted weakly. Adding a healthy TAZ gene normalized these features.

But to truly capture Barth syndrome and its whole-body effects, Pu and colleagues needed an animal model. "The animal model was a hurdle in the field for a long time," says Pu, director of Basic and Translational Cardiovascular Research at Boston Children's and a member of the Harvard Stem Cell Institute. "Efforts to make a mouse model using traditional methods had been unsuccessful."

Modeling Barth syndrome in mice

Recently, however, the lab of Douglas Strathdee's group at the Beatson Institute for Cancer Research in the U.K. overcame the challenge and created animal models of Barth syndrome. In new work, Pu, research fellow Suya Wang, PhD, and colleagues characterized these "knockout" mice, which came in two types. In one, the TAZ gene was deleted in cells throughout the body; in the other, just in the heart.

Most mice with the whole-body TAZ deletion died before birth, apparently because of skeletal muscle weakness. But some survived, and these mice developed progressive cardiomyopathy, in which the heart muscle enlarges and loses pumping capacity. Their hearts also showed scarring, and, similar to human patients with dilated cardiomyopathy, the heart's left ventricle was dilated and thin-walled.

Mice lacking TAZ just in their cardiac tissue, which all survived to birth, showed the same features. Electron microscopy showed heart muscle tissue to be poorly organized, as were the mitochondria within the cells.

Pu, Wang, and colleagues then used gene therapy to replace TAZ, injecting an engineered virus under the skin (in newborn mice) or intravenously (in older mice). Treated mice with whole-body TAZ deletions were able to survive to adulthood. TAZ gene therapy also prevented cardiac dysfunction and scarring when given to newborn mice, and reversed established cardiac dysfunction in older mice -- whether the mice had whole-body or heart-only TAZ deletions.

Getting the gene in

Further tests showed that TAZ gene therapy provided durable treatment of the animals' cardiomyocytes and skeletal muscle cells, but only when at least 70 percent of heart muscle cells had taken up the gene.

That's where the challenge will lie in translating the results to humans. Simply scaling up the dose of gene therapy won't work: In large animals like us, large doses risk a dangerous inflammatory immune response. Giving multiple doses of gene therapy won't work either.

"The problem is that neutralizing antibodies to the virus develop after the first dose," says Pu. "Getting enough of the muscle cells corrected in humans may be a challenge."

Maintaining populations of gene-corrected cells is another challenge. While levels of the corrected TAZ gene remained fairly stable in the hearts of the treated mice, they gradually declined in skeletal muscles.

"The biggest takeaway was that the gene therapy was highly effective," says Pu. "We have some things to think about to maximize the percentage of muscle cell transduction, and to make sure the gene therapy is durable, particularly in skeletal muscle."

Among African adolescent girls and young women who took HIV pre-exposure prophylaxis (PrEP) daily, levels of the PrEP drug tenofovir were more than 30% lower in those who were pregnant than in those who had recently given birth. All 40 study participants took PrEP under direct observation, confirming their near-perfect adherence. PrEP drug levels were lower to a similar degree in the pregnant African adolescent girls and young women compared to American men and non-pregnant, non-lactating women who took PrEP daily under direct observation in an earlier study. These findings from the NIH-funded IMPAACT 2009 study were reported today at the Conference on Retroviruses and Opportunistic Infections (CROI).

The study investigators suggest that nonetheless, daily PrEP may provide substantial protection for pregnant African adolescents and young women as part of a comprehensive HIV prevention program.

"Adolescent girls and young women in sub-Saharan Africa, including those who are pregnant or have recently given birth, urgently need safe, desirable and effective HIV prevention tools," said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID) at NIH. "While taking PrEP daily as directed is important for everyone who receives it, these new data suggest daily adherence to PrEP will be especially critical for pregnant adolescents and young women. Additional research is needed to determine the level of protection that daily PrEP can provide this population."

NIAID is a co-funder of IMPAACT 2009.

The substantially lower drug concentration found in dried blood spots from pregnant African adolescents and young women in the study does not necessarily indicate a lower PrEP efficacy for this group, according to the IMPAACT 2009 investigators. The response to any drug follows a curve that rises from zero as the dose increases until the curve reaches a plateau where a range of doses achieves a sufficient biological response to have the desired effect--in this case, preventing HIV infection. Based on available data, the study investigators believe the drug concentration in the target cells of pregnant adolescents and women who take PrEP daily will fall near this plateau. However, further research is required to establish whether this is the case.

During pregnancy, the kidneys clear drugs from the blood faster than at other times and the concentration of red blood cells in plasma decreases. These physiological changes help explain the lower concentration of PrEP drug observed in the dried blood spots from pregnant study participants. A goal of IMPAACT 2009 was to determine how much lower the drug concentration in pregnant adolescents and young women would be.

In sub-Saharan Africa, adolescent girls and young women bear the brunt of new HIV cases. Girls account for four in five new HIV cases among adolescents ages 15 to 19 years, and adolescent girls and women ages 15 to 24 years are twice as likely to be living with HIV than men. In addition, the risk for acquiring HIV more than doubles for this population during pregnancy and the six months after giving birth, also known as the postpartum period.

PrEP is a powerful HIV prevention strategy that could potentially protect pregnant and postpartum adolescent girls and young women from acquiring the virus. It involves taking a daily oral tablet containing two anti-HIV drugs. Studies have shown that PrEP reduces the risk of sexual HIV acquisition by more than 90% in men and women when taken daily. Additional studies have found that women must take PrEP tablets six to seven days per week for drug concentrations to reach protective levels in the female genital tract.

In two large clinical trials of PrEP in African women, VOICE and Fem-PrEP, the daily dosing regimen did not suit study participants' needs, and therefore the HIV prevention strategy did not work. Consequently, scientists are researching ways to introduce PrEP to African women and support their adherence to the medication so that this HIV prevention tool is a desirable and effective option for them.

The findings reported today are from the first phase of the NIH-funded IMPAACT 2009 clinical trial. The study is designed to assess whether pregnant and postpartum adolescent girls and young women in southern and eastern Africa are willing and able to consistently take daily PrEP when given enhanced support, and whether PrEP is safe for them and their infants. Investigators hypothesize that pregnant and breastfeeding women may be uniquely motivated to start PrEP and take it consistently to protect themselves and their babies. A recent review of studies on the safety of PrEP for pregnant and breastfeeding women concluded that the benefits clearly outweigh potential risks.

In this first phase of the trial, investigators measured the concentration of tenofovir in the red blood cells of pregnant and postpartum adolescents and young women who took PrEP daily or nearly so under the direct observation of a study team member for 12 weeks. These data will serve as a reference for accurately determining whether study participants are taking PrEP daily during the second phase of the trial, if conducted, and in future studies of this PrEP medication in similar populations.

The study team enrolled 40 adolescent girls and young women ages 16 to 24 years in Malawi, South Africa, Uganda and Zimbabwe. Half of the participants were pregnant at 14 to 24 weeks gestation, and half had given birth 6 to 12 weeks before enrollment. With intense support from highly trained and experienced study staff, the women and adolescents collectively took more than 99% of their required PrEP doses daily under direct observation. Observation was primarily in person and occasionally by real-time video phone call. This ensured that investigators could reliably confirm near-perfect adherence. The PrEP medication used in the study contains two drugs, tenofovir and emtricitabine.

The study team collected blood samples from study participants weekly by blotting a drop of blood on filter paper, where it dried. Scientists then took a hole punch of each dried blood spot and measured the concentration of tenofovir there. The investigators found that the median steady-state concentration of tenofovir was 965 femtomoles (fmol) per punch during pregnancy and 1,406 fmol/punch postpartum, a 31% difference. Using a model that estimates how fast tenofovir is cleared from the blood for each participant, the predicted median steady-state concentrations of tenofovir were similar: 890 fmol/punch in pregnancy and 1,418 fmol/punch postpartum, a 37% difference.