Body

If you have just had knee, shoulder or hip surgery, you may want to take anti-inflammatories in the morning or at noon, but not at night. A McGill-led study shows, for the first time, that circadian clock genes are involved in healing from surgery. Indeed, the researchers demonstrated that anti-inflammatory medications are most effective in promoting post-operative healing and recovery when taken during the active periods of our biological clocks.

The study, recently published in Scientific Reports, also suggests that if anti-inflammatories are taken either in the afternoon or at night, during the resting phases of the circadian rhythm, they can severely deter healing and bone repair following surgery. That's because these are the periods when cells known as osteoblasts are rebuilding bone.

Circadian clock genes involved in healing from surgery

Although prior research has shown that circadian clock genes play a role in diseases such as cancer, Alzheimer's, arthritis and Parkinson's, this is the first study to see the effect of the circadian rhythm in any type of surgery or injury. Faleh Tamimi Marino, the Canada Research Chair for Translational Cranofacial Research is the senior co-author on the article, along with Belinda Nicolau and Laura Stone. All are McGill's Faculty of Dentistry.

Inflammation, following surgery, is crucial to healing since part of the process involves both destroying any bacteria that may be in the area, and signaling to attract the cells that will rebuild the tissues. But the process is not a constant.

"There are periods of inflammation that are actually very destructive, and there are periods that are constructive and important for healing," said Faleh Tamimi. "So many pharmaceutical companies have been trying to develop drugs that will inhibit the destructive processes during inflammation but not interfere with the helpful ones."

He adds, "The idea that I came up with in the shower one morning is that we could perhaps use the circadian variations in inflammation to our advantage. The destructive component of the circadian rhythm as it relates to bone healing occurs during the day, when cells known as osteoclasts break down bones. The constructive cells, known as osteoblasts that rebuild bones are active at night. By limiting the use of anti-inflammatories to the mornings and giving analgesics at night for the pain, I thought we might get better results in terms of bone healing than if anti-inflammatories are given throughout the day."

Significant differences in rates of healing and in genes

The researchers compared pain and bone healing in two different groups of mice with fractured tibia. One group was given constant doses of anti-inflammatories over a twenty-four hour period, while the others were given anti-inflammatories only in the morning - during the active phases of the circadian rhythm - and analgesics at night. The researchers found that the second group recovered from the pain of the injury, and regained bone strength more quickly and more fully. Surprisingly, they also noticed differences between the groups in the expression of over 500 genes specifically related to bone healing processes. "Its almost as if morning anti-inflammatories and evening anti inflammatories were two different drugs" adds Faleh Tamimi.

The rhythm of the body's own healing

"When I was a child, and I cut myself, my mother would say to me, don't worry, go to sleep and tomorrow you will be better," said Haider El-Waeli, the first author on the study, who wrote the paper while working on his PhD at McGill and is now a clinical resident at Dalhousie University. "It turns out she was right because most of the healing happens at night."

"The body has a rhythm," adds Tamimi. "And if you give anti-inflammatories in the morning you are working with the rhythm of the body and when you give them at night, you are working against it so you disrupt the healing."

As a next step, the researchers are collecting preliminary data from a clinical trial monitoring pain and healing related to extraction of wisdom teeth, using two different drug treatments - one involving exclusive use of anti-inflammatories, and the other administering anti-inflammatory medications only in the morning and at noon, and analgesics in the afternoon and evening. The preliminary results are promising.

Bethesda, Maryland (Jan. 21, 2020) -- Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD) associated with an increased risk of colorectal cancer, can be life-altering for patients with moderate to severe disease activity.

An increasing number of drugs are available for long-term management of moderate to severe UC, leading to questions about treatment strategies for optimal patient care. A new clinical guideline from the American Gastroenterological Association, published in Gastroenterology, the official journal of the AGA Institute, provides recommendations for the management of adult outpatients with moderate to severe UC as well as adult hospitalized patients with acute severe ulcerative colitis (ASUC). The guideline focuses on immunomodulators, biologics, and small molecules to bring on and maintain remission for patients with moderate to severe UC and to decrease the risk of colectomy.

"While there is no cure for ulcerative colitis, currently available therapies can help patients into remission, which means the patient feels well and does not show signs of inflammation. With so many drugs available, the question for many gastroenterologists is what is the right drug for my patient? This guideline takes a comprehensive and evidence-based look at available therapies to provide the most trusted guidance to-date on treatment options to ultimately improve the care of patients with moderate-to-severe UC," said lead guideline author Joseph D. Feuerstein, MD, Division of Gastroenterology and Center for Inflammatory Bowel Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Here are 5 of the most important guideline recommendations. For all 15 recommendations, review the full guideline.

1. In adult outpatients with moderate to severe UC, AGA recommends using infliximab, adalimumab, golimumab, vedolizumab, tofacitinib or ustekinumab over no treatment. (Strong recommendation: moderate quality evidence)

2. In adult outpatients with moderate to severe UC who are new to biologics, AGA suggests using infliximab or vedolizumab rather than adalimumab for induction of remission. (Conditional recommendation: moderate quality evidence)

Comment: Patients, particularly those with less severe disease, who place higher value on the convenience of self-administered subcutaneous injection, and a lower value on the relative efficacy of medications, may reasonably chose adalimumab as an alternative.

3. In adult outpatients with moderate to severe UC who have been exposed to infliximab, particularly those who were not responsive, AGA suggests using ustekinumab or tofacitinib, rather than vedolizumab or adalimumab, for induction of remission. (Conditional recommendation: low quality evidence)

Comment: Patients, particularly those with less severe disease who place higher value on the potential safety of medications, and a lower value on the relative efficacy of medications, may reasonably chose vedolizumab as an alternative.

4. In adult outpatients with moderate to severe UC, AGA suggests early use of biologics with or without immunomodulator therapy, rather than gradual step up after failure of 5-aminosalicylates. (Conditional recommendation: very low quality evidence)

Comment: Patients, particularly those with less severe disease, who place higher value on the safety of 5-ASA therapy, and lower value on the efficacy of biologic agents, may reasonably choose gradual step therapy with 5-ASA therapy.

This recommendation supports AGA's ongoing fight against step therapy treatment where insurers require patients to try and fail medications before agreeing to cover the initial therapy prescribed by their health care provider. AGA believes that patients should be given a clear, equitable and transparent appeals process when subjected to step therapy protocols. Learn more and take action on this issue.

5. In hospitalized adult patients with acute severe UC refractory to intravenous corticosteroids, AGA suggests using infliximab or cyclosporine. (Conditional recommendation: low quality evidence)

For all 15 recommendations, review the full guideline.

WHAT IS ULCERATIVE COLITIS?

Ulcerative colitis is an inflammatory bowel disease (IBD) that affects the large intestine. In a person with UC, the lining of the colon becomes inflamed and swollen. Untreated UC can lead to problems or other chronic conditions, such as bleeding in the stool, diarrhea, severe dehydration and anemia due to blood loss. UC is associated with an elevated risk of colorectal cancer. Learn more about ulcerative colitis in the AGA GI Patient Center.

A little over a year ago, Caltech's Lihong Wang developed the world's fastest camera, a device capable of taking 10 trillion pictures per second. It is so fast that it can even capture light traveling in slow motion.

But sometimes just being quick is not enough. Indeed, not even the fastest camera can take pictures of things it cannot see. To that end, Wang, Bren Professor of Medical Engineering and Electrical Engineering, has developed a new camera that can take up to 1 trillion pictures per second of transparent objects. A paper about the camera appears in the January 17 issue of the journal Science Advances.

The camera technology, which Wang calls phase-sensitive compressed ultrafast photography (pCUP), can take video not just of transparent objects but also of more ephemeral things like shockwaves and possibly even of the signals that travel through neurons.

Wang explains that his new imaging system combines the high-speed photography system he previously developed with an old technology, phase-contrast microscopy, that was designed to allow better imaging of objects that are mostly transparent such as cells, which are mostly water.

Phase-contrast microscopy, invented nearly 100 years ago by Dutch physicist Frits Zernike, works by taking advantage of the way that light waves slow down and speed up as they enter different materials. For example, if a beam of light passes through a piece of glass, it will slow down as it enters the glass and then speed up again as it exits. Those changes in speed alter the timing of the waves. With the use of some optical tricks it is possible to distinguish light that passed through the glass from light that did not, and the glass, though transparent, becomes much easier to see.

"What we've done is to adapt standard phase-contrast microscopy so that it provides very fast imaging, which allows us to image ultrafast phenomena in transparent materials," Wang says.

The fast-imaging portion of the system consists of something Wang calls lossless encoding compressed ultrafast technology (LLE-CUP). Unlike most other ultrafast video-imaging technologies that take a series of images in succession while repeating the events, the LLE-CUP system takes a single shot, capturing all the motion that occurs during the time that shot takes to complete. Since it is much quicker to take a single shot than multiple shots, LLE-CUP is capable of capturing motion, such as the movement of light itself, that is far too fast to be imaged by more typical camera technology.

In the new paper, Wang and his fellow researchers demonstrate the capabilities of pCUP by imaging the spread of a shockwave through water and of a laser pulse traveling through a piece of crystalline material.

Wang says the technology, though still early in its development, may ultimately have uses in many fields, including physics, biology, or chemistry.

"As signals travel through neurons, there is a minute dilation of nerve fibers that we hope to see. If we have a network of neurons, maybe we can see their communication in real time," Wang says. In addition, he says, because temperature is known to change phase contrast, the system "may be able to image how a flame front spreads in a combustion chamber."

CORVALLIS, Ore. - Oregon's unique health care delivery system for low-income patients is resulting in fewer infant deaths, according to a recent study by Oregon State University researchers.

The study found that Oregon's implementation of Coordinated Care Organizations (CCOs) in 2012 was associated with infant mortality rates falling significantly among Medicaid patients relative to non-Medicaid patients, who are not managed by the new delivery system.

Researchers say this is a good indication that CCOs' aim of provider integration and caring for the whole patient is on the right track. CCOs help catch patients who might otherwise fall through the cracks and miss important care by using an integrated care model, where medical providers work together with behavioral health specialists, dentists, nutritionists and social workers. This approach allows them to address social determinants of health outside conventional medical services, such as housing and access to transportation.

"This is good news, that CCOs appear to be addressing the needs of this at-risk population in such a way that it has a significant impact on infant mortality," said health economist and associate professor Jangho Yoon of OSU'S College of Public Health and Human Services.

Led by Linh Bui, a recent Ph.D. student in health policy at OSU, with co-authors Yoon, Marie Harvey and Jeff Luck, the study is the latest from an ongoing six-year project funded by the Centers for Disease Control and Prevention. OSU researchers in the College of Public Health and Human Sciences have used the same dataset to examine the impact of Oregon's 2012 CCO implementation on birth outcomes and prenatal care, as well as the statewide expansion of Medicaid in 2014.

The infant mortality study looked at nearly 300,000 births to compare infant mortality rates between non-Medicaid and Medicaid patients in the three-year periods before and after CCO implementation.

Over the study period, infant mortality dropped much more steeply in the Medicaid population than in the non-Medicaid population, which includes uninsured people and privately insured people, who do not receive care under the CCO structure.

Among Medicaid patients in the pre-CCO period, 266 of 77,850 infants died, compared with 235 of 57,903 infants in the non-Medicaid population. Post-CCOs, only 193 out of 88,683 Medicaid infants died, compared with 233 of the 59,967 in the non-Medicaid population.

The decline was most significant among preterm births - babies born at or before 37 weeks gestation, who face greater risk of health problems than full-term babies and as a result, incur higher health care costs, Yoon said. As CCOs reduce infant mortality and help mothers and babies get the care they need, the state will save money on Medicaid.

Another recently published study using the same health claims dataset found that Oregon's expansion of Medicaid in 2014 improved access to reproductive health services.

Researchers examined access to preventive reproductive care, comparing medical claims data from before and after the expansion. They focused on well-woman visits, contraceptive counseling and services, cervical cancer screening and screening for sexually transmitted infections.

Prior to expansion, pregnant women were already fairly well covered by Medicaid, said Susannah Gibbs, a post-doctoral fellow and health policy researcher at OSU. By expanding Medicaid, she said, Oregon ensured that women could get those vital preventive reproductive health services whether they were pregnant or not.

From an initial bump in the amount of services used, researchers surmise there was a pent-up demand for care among the newly expanded Medicaid population. But visits soon leveled off, and researchers concluded that the expansion population is now using preventive reproductive health care in much the same way that the existing Medicaid population did.

Their results also showed no significant drop in access for the existing Medicaid population, suggesting that the sudden increase in Medicaid patients did not overwhelm providers, as some had feared.

Access to preventive reproductive care is crucial in avoiding costly future chronic health problems, Gibbs said, as well as ensuring that women who do get pregnant experience healthier pregnancies.

Breast cancer progression can vary significantly between patients. Even within the same tumor, different areas may be composed of different types of cells and characterized by different tumor structures. This heterogeneity makes it challenging to ascertain the severity of a tumor and assess its molecular subtype, thereby affecting the precision of diagnosis and the choice of the most effective treatment approach. More detailed characterization of a breast cancer tissue could help improve a treatment's chances of success and may decrease the risk of relapse.

High-dimension biomarkers reveal differences in breast cancer survival

The research group headed by Bernd Bodenmiller, professor of quantitative biology at UZH, has been able to refine the pathological classification of breast cancer using imaging mass cytometry. This method enables scientists to simultaneously visualize and analyze multiple biomarkers to generate information-rich digital images of tissue sections. In their study, the researchers quantified 35 protein biomarkers in breast cancer patients. "This created an unprecedented view of a tumor's cellular landscape and the surrounding tissue, which enabled us to determine whether more complex biomarkers exist for clinical outcome," explains Jana Fischer, co-first author of the study.

The team of researchers analyzed hundreds of tissue sections from 350 breast cancer patients and categorized the many cell components and how they are organized in cellular communities and form tumor tissues. "Four categories of breast cancer are routinely classified in the clinic, but our new analysis allows us to go further and identify multiple detailed subcategories of breast cancer. The danger from these diverse tumors can be very different, and each type could respond to therapy in its own way," explains co-first author Hartland Jackson.

Potential impact on breast cancer precision medicine

This finding has the potential to change clinical practice. The new subgroups of breast cancer patients vary in their molecular profiles. Bernd Bodenmiller and his research team are now working on finding out which drugs are best able to combat tumor cells with a specific molecular profile. "By improving our ability to describe cellular features and categories as well as our ability to precisely identify patients that have high or low risk breast cancer, we're opening up new possibilities for precision medicine," says Bodenmiller.

Boston, MA -- For most patients, melanoma begins with a small, pigmented spot on their skin that they notice starts to change. Many primary melanomas can be cured by having this lesion removed, but melanoma can also recur and spread; an analysis of the removed lesion can offer some information on the likelihood that the cancer will come back. Today, lesions are analyzed in much the same way that they were 100 years ago. Despite advances in molecular diagnostics for other forms of cancer, analysis of a skin cancer lesion is surprisingly simplistic. The lesion's thickness -- patients with thinner melanomas tend to do better -- and microscopic features, such as ulcerations, are considered, and a T stage of 1 through 4 is assigned. In a paper published in Nature Cancer, investigators from Brigham and Women's Hospital, in collaboration with international colleagues, present a new, quantitative technique that leverages DNA sequencing to make more sophisticated and accurate predictions about which primary melanomas are likely to recur and spread.

"As recently as 10 years ago the outlook for metastatic melanoma was dismal, but we now have treatments to offer patients with metastatic disease and may also be able to apply these treatments when primary disease hasn't metastasized," said corresponding author Thomas Kupper, MD, chair of the Department of Dermatology at the Brigham. "Because of the advent of these new immunotherapy treatments, it's important to have a clear idea of which patients are likely to progress so that we can tailor treatment accordingly."

Immune checkpoint inhibitors, which can reawaken T cells to mount an immune response against cancer cells, have radically changed outcomes and options available to patients whose skin cancer has spread. In some patients, they can elicit dramatic responses, including long-term remission, essentially curing a patient. But identifying patients at greatest risk for disease progression has remained an unmet need.

To address this, Kupper and colleagues sought to determine if certain measurable features of T cells could predict recurrence in patients whose primary melanoma had been removed and were free of disease. T1 melanomas (4mm) primary melanomas. The research team faced a unique hurdle in acquiring enough samples to conduct a robust study. Unlike most tumors, which are removed by a surgeon at a hospital, skin lesions can be removed in private practices and ambulatory clinics, which means that specimens are not concentrated in hospital settings. In addition, specimens must be kept for several years after removal, delaying their availability for research studies. To collect enough samples, investigators from the Brigham collaborated with colleagues at the Melanoma Institute of Australia and the Zealand University Hospital in Denmark to share resources. The current analysis includes more than 300 samples from patients across these sites.

The team compared samples from patients whose primary melanoma progressed to metastatic disease to patients whose primary melanoma did not. They used high-throughput DNA sequencing, performed by Adaptive Biotechnologies, to analyze the T cell repertoire of the tumors. The investigators found that of all variables identified, the T-cell fraction (TCFr; or proportion of cells in the lesion that were T cells) was a powerful, independent predictor of which patients would progress. Even for patients whose lesion thickness (T) was the same, TCFr was able to predict which patients were more likely to have metastatic disease. Patients with a TCFr of lower than 20 percent were more at risk of disease progression than patients with a TCFr of higher than 20 percent. For example, for patients with T3 melanoma (2-4mm thickness), five years after having their primary lesion removed, 51 percent of those with lower TCFr experienced recurrence, compared to 24 percent with higher TCFr.

The test used in this work is commercially available for research use only and is not currently yet available in the clinic. The authors also note that the current study is retrospective, looking at samples from patients whose outcomes are already known. Prospective studies of patients whose outcomes are not yet known will be needed to further validate the test. If brought to the clinic, Kupper and colleagues envision that the test could strengthen current prediction models and improve patient care.

"This is a simple, elegant test. It's quantitative rather than subjective, and it may be able to add value to predictions about disease progression," said Kupper. "In the future, such a test could help us tailor treatment; patients with high TCFr may further benefit from checkpoint inhibitor therapy, while low TCFr patients may need additional intervention."

A University of Liverpool research paper, published in American Psychologist, provides new evidence for using a humane, respectful and compassionate approach to interrogating High-Value Detainees (HVDs - i.e. terrorist suspects) to encourage co-operation and disclosure of information.

Motivational interviewing (MI) is a counselling method that helps people resolve ambivalent feelings and insecurities to find the internal motivation they need to change their behaviour.

Carl Rogers and Abraham Maslow, two humanistic psychologists, who rejected the approach to therapy that suggested there was something repressed or wrong with the individual that needed a therapist to 'fix, originally developed this style of interviewing.

This alternative approach empowers patients by helping to create an environment in which they have their own autonomy over whether and how they would approach their substance misuse / health related problems.

In clinical contexts, this method is often used to address addiction and the management of physical health conditions such as diabetes, heart disease, and asthma. This intervention helps people become motivated to change the behaviours that are preventing them from making healthier choices.

Engagement and information yield

Currently, LE interviewers do use skills consistent with four principles of MI (reflective listening, summaries, rolling with resistance and developing discrepancies) and five Global MI strategies relating to MI 'spirit' (acceptance, empathy, evocation, adaptation and autonomy) when interviewing HVDs.

However, there has been no clear evidence relating to which specific MI skills and approaches can increase or decrease HVD engagement and information provided.

Researchers from the University's Centre for Critical and Major Incident Psychology, led by Centre Director Professor Laurence Alison, conducted a study to examine the relationship between LE interviewers' use of these four skills consistent with the principles of MI, the five Global MI strategies relating to MI 'spirit', detainee engagement, and information yield.

The researchers analysed 804 tapes of law enforcement interviews with 75 terrorism suspects in the U.K using the Observing Rapport Based Techniques (ORBIT) coding Manual.

Professor Alison and his team have worked for over 15 years on the ORBIT approach to interviewing which includes managing difficult behaviours (the interpersonal element) and extracting information (the rapport skills element).

Reactance, choice and mind set

The researchers found that MI Skills encouraged detainee engagement and subsequent information gain.

It also revealed that any approach antithetical to MI had a profoundly negative impact on detainee engagement and subsequent information gain - through the creation of 'reactance'.

Professor Alison, said: "An interviewer can create resistance when there previously was none i.e. a suspect could be considering talking but when the interviewer states, "It is in your best interest to talk" it creates 'reactance'.

"To prevent reactance an interviewer must provide choice and freedom - the freedom to talk or not talk - it is up to the interviewee.

"The more an interviewer pressures an interviewee to talk, the less likely they are to. Personal control and a feeling of autonomy is exactly what a therapist in counselling seeks to create in clients (whether that be substance misuse or health related behaviours) and it should be what interviewers should do with suspects too."

PhD candidate Frances Surmon-Böhr, First author of the study, adds: "The key to success is creating the right mind set for the interviewer not an 'off the peg' tactic they can deploy. Our research provides unique evidence for the use of specific skills and approaches that can increase or decrease HVD engagement and information provided.

"These findings have potential to improve methods of national security whilst promoting fair treatment of detainees."

Researchers at Cardiff University have discovered a new type of killer T-cell that offers hope of a "one-size-fits-all" cancer therapy.

T-cell therapies for cancer - where immune cells are removed, modified and returned to the patient's blood to seek and destroy cancer cells - are the latest paradigm in cancer treatments.

The most widely-used therapy, known as CAR-T, is personalised to each patient but targets only a few types of cancers and has not been successful for solid tumours, which make up the vast majority of cancers.

Cardiff researchers have now discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognises and kills most human cancer types, while ignoring healthy cells.

This TCR recognises a molecule present on the surface of a wide range of cancer cells as well as in many of the body's normal cells but, remarkably, is able to distinguish between healthy cells and cancerous ones, killing only the latter.

The researchers said this meant it offered "exciting opportunities for pan-cancer, pan-population" immunotherapies not previously thought possible.

How does this new TCR work?

Conventional T-cells scan the surface of other cells to find anomalies and eliminate cancerous cells - which express abnormal proteins - but ignore cells that contain only "normal" proteins.

The scanning system recognises small parts of cellular proteins that are bound to cell-surface molecules called human leukocyte antigen (HLA), allowing killer T-cells to see what's occurring inside cells by scanning their surface.

HLA varies widely between individuals, which has previously prevented scientists from creating a single T-cell-based treatment that targets most cancers in all people.

But the Cardiff study, published today in Nature Immunology, describes a unique TCR that can recognise many types of cancer via a single HLA-like molecule called MR1.

Unlike HLA, MR1 is does not vary in the human population - meaning it is a hugely attractive new target for immunotherapies.

What did the researchers show?

T-cells equipped with the new TCR were shown, in the lab, to kill lung, skin, blood, colon, breast, bone, prostate, ovarian, kidney and cervical cancer cells, while ignoring healthy cells.

To test the therapeutic potential of these cells in vivo, the researchers injected T-cells able to recognise MR1 into mice bearing human cancer and with a human immune system.

This showed "encouraging" cancer-clearing results which the researchers said was comparable to the now NHS-approved CAR-T therapy in a similar animal model.

The Cardiff group were further able to show that T-cells of melanoma patients modified to express this new TCR could destroy not only the patient's own cancer cells, but also other patients' cancer cells in the laboratory, regardless of the patient's HLA type.

Professor Andrew Sewell, lead author on the study and an expert in T-cells from Cardiff University's School of Medicine, said it was "highly unusual" to find a TCR with such broad cancer specificity and this raised the prospect of "universal" cancer therapy.

"We hope this new TCR may provide us with a different route to target and destroy a wide range of cancers in all individuals," he said.

"Current TCR-based therapies can only be used in a minority of patients with a minority of cancers.

"Cancer-targeting via MR1-restricted T-cells is an exciting new frontier - it raises the prospect of a 'one-size-fits-all' cancer treatment; a single type of T-cell that could be capable of destroying many different types of cancers across the population.

"Previously nobody believed this could be possible."

What happens next?

Experiments are under way to determine the precise molecular mechanism by which the new TCR distinguishes between healthy cells and cancer.

The researchers believe it may work by sensing changes in cellular metabolism which causes different metabolic intermediates to be presented at the cancer cell surface by MR1.

The Cardiff group hope to trial this new approach in patients towards the end of this year following further safety testing.

Professor Sewell said a vital aspect of this ongoing safety testing was to further ensure killer T-cells modified with the new TCR recognise cancer cells only.

"There are plenty of hurdles to overcome however if this testing is successful, then I would hope this new treatment could be in use in patients in a few years' time," he said.

Professor Oliver Ottmann, Cardiff University's Head of Haematology, whose department delivers CAR-T therapy, said: "This new type of T-cell therapy has enormous potential to overcome current limitations of CAR-T, which has been struggling to identify suitable and safe targets for more than a few cancer types."

Professor Awen Gallimore, of the University's division of infection and immunity and cancer immunology lead for the Wales Cancer Research Centre, said: "If this transformative new finding holds up, it will lay the foundation for a 'universal' T-cell medicine, mitigating against the tremendous costs associated with the identification, generation and manufacture of personalised T-cells.

"This is truly exciting and potentially a great step forward for the accessibility of cancer immunotherapy."

A method for finding genes that spur tumor growth takes advantage of machine learning algorithms to sift through reams of molecular data collected from studies of cancer cell lines, mouse models and human patients.

By teaching the artificial intelligence system to link certain DNA mutations to altered functionality, a team led by Robert Hoehndorf from KAUST's Computational Bioscience Research Center showed that they could identify genes with a known causative role in cancer and pick out dozens of putative new ones for 20 different tumor types.

The prediction method--described in Scientific Reports and freely available online--could help clinicians tailor medicines to the molecular subtypes of patients. It could also be used by drug companies in the hunt for new therapeutic targets.

"Our method can be used as a framework to predict and validate cancer-driver genes in any database or real population sample," says Sara Althubaiti, a Ph.D. student in Hoehndorf's lab and the first author of the study.

Traditionally, scientists have approached the search for genes with a causal role in cancer by starting with DNA sequence data. By extensively cataloging tumor mutations shared among patients with a common type of cancer, the research community has documented hundreds of genes with a causal impact on tumor development. Experimental follow up is then used to functionally associate these genes with the hallmarks of cancer.

"Our method turns this approach on its head," Althubaiti explains. "Essentially, our approach is knowledge-driven and we use tumor sequencing data as validation. This is unlike most approaches, which are data-driven combined with interpretation of the findings with respect to established knowledge."

The rate of discovery for new cancer-driving genes has been declining rapidly in recent years, leading the KAUST team to seek a new computational strategy. Instead of relying on sequence data, Althubaiti and Hoehndorf built a machine learning model that takes into account many biological features of genes and pathways involved in tumor formation.

The researchers designed the algorithm to recognize functional and phenotypic patterns that predispose a gene toward playing a role in driving tumor development. They validated the model using a publicly available database of some 27,000 different tumor variants as well as functional and sequence data--showing that the algorithm could accurately categorize known cancer-driving genes and detect more than 100 other likely culprits, many with specific roles in particular tumor types.

The KAUST investigators then further tested the algorithm's performance on molecular data gathered from two cohorts of cancer patients. The first was from King Abdulaziz University Hospital in Saudi Arabia, comprising 26 tumor samples from individuals with a rare type of head and neck cancer called nasopharyngeal carcinoma. The other cohort comprised 114 colorectal cancer samples from patients treated at the University of Birmingham Hospital in the United Kingdom. In both patient groups, the model singled out candidate driver genes that were frequently mutated and shared pathogenic features of other cancer-causing genes.

Hoehndorf emphasizes the importance of the team effort involved. "This work is a good example for scientific collaboration within Saudi Arabia," he says, "but it also demonstrates the need for multidisciplinary collaborations between computer scientists, clinical researchers and biologists."

Only since a few years, malignant melanoma has been treatable with immunotherapy. However, in every second patient strong autoimmune reactions such as skin rash or diarrhea occur after immunotherapy. Researchers from the Medical Center - University of Freiburg and Swiss colleagues have now shown that these reactions can be stopped with a specific light therapy. They treated a 29-year-old cancer patient with severe inflammation of the intestinal mucosa very successfully using extracorporeal photopheresis (ECP). In this method, immune cells outside the body are mixed with a light-reactive drug, irradiated with UV light and returned to the body. The procedure presumably activates immune cells which stop the inflammation. The photopheresis therapy led to a complete resolution of the patient's symptoms, while the ongoing cancer therapy successfully treated skin cancer. Previous, established treatment approaches had been unsuccessful. The case description was published in the renowned New England Journal of Medicine on 15 January 2020.

"The patient responded incredibly well to our new therapeutic approach. With extracorporeal photopheresis, we have found an important therapeutic option for him and hopefully for many other patients," said study leader Prof. Dr. Robert Zeiser, head of the Department of Tumour Immunology at the Hospital of Internal Medicine I of the Medical Center - University of Freiburg. "In principle, the therapeutic approach is also conceivable for immune-mediated side effects of other cancer therapies," said Zeiser. The research group led by Zeiser in cooperation with Dr. Frank Meiß and Prof. Dr. Dagmar von Bubnoff, both senior physicians at the Department of Dermatology and Venerology at the Medical Center - University of Freiburg, together with Prof. Dr. Burkhard Becher from the Institute of Experimental Immunology at the University of Zurich, were able to show the effectiveness of ECP.

Replacement for cortisone therapy with its many side effects

In the treatment of malignant melanoma and many other types of cancer, so-called immunocheckpoint inhibitors are used. "Cancer cells often have a kind of cloak that makes them invisible to the body's own immune response. Immunocheckpoint inhibitors snatch this cloak from them and thus enable the immune system to attack the cancer cells," explains Zeiser. However, the immune system often also starts to destroy the body's own structures. These side effects can affect different organs such as the intestines, skin, thyroid gland, liver or brain. "Until now, patients with such side effects of cancer immunotherapy have usually been treated with cortisone or other immunomodulating agents for a longer period of time. But this does not always work or can have severe side effects," said Zeiser. In addition, cortisone is suspected of blocking the immune response to the tumor and thus torpedoing cancer treatment.

The ECP treatment was repeated every two to four weeks for eight months. Shortly after the start of therapy, there was a complete reduction in the severe diarrhoea caused by inflammation. As the researchers found, during ECP therapy a certain type of immune cells became larger and more active. "We assume that these enlarged immune cells act on other parts of the immune system and thus slow down the inflammation," explains Zeiser. The therapeutic approach also proved to be safe in the preclinical animal model. "It was very important for the accompanying therapy that the ECP treatment did not have a negative effect on the anti-tumour effect of the immune drugs," said Zeiser.

An adapted form of 'low intensity' cognitive behavioural therapy (CBT) could offer help to autistic adults living with depression, according to a new study funded by NIHR.

Autism Spectrum Disorder (ASD) affects around 1% of the UK adult population. Approximately one-third of autistic people experience depression at some point in their lives, however to date surprisingly little research into treatments for depression within the autistic community has been conducted.

Co-occurring autism and mental health conditions, including depression, present particular challenges for psychologists and healthcare professionals. While there is strong evidence of effective treatments for depression for the population as a whole, including CBT, accessing mainstream therapies can be difficult for autistic people due to communication and neurocognitive differences, and many therapists are not trained to work with autistic people.

The researchers suggest that autism can exacerbate mental health challenges such as depression. Barriers to rewarding employment and social isolation can make life difficult and adjusting and adapting behaviours and activities because of autism are also challenges. For the latest study, published in the journal Autism, the team at the University of Bath's Centre for Applied Autism Research tested the feasibility and uptake for a form of low intensity CBT called Guided Self-Help, which is based on Behavioural Activation.

Behavioural Activation aims to reduce depression by helping individuals to better schedule activities that help boost positive mood, whilst also giving them techniques to become more aware of triggers for low mood. The researchers split 70 participants into two groups: a Guided Self-Help group (35), who received the new materials and sessions with a low-intensity psychological therapist; and a treatment as usual group (35), who received the treatment that is ordinarily available.

Measuring outcomes at 10-, 16- and 24- week windows, the researchers found the adapted intervention to be both well received and promising in terms of helping people to make change. 86% of participants attended five of nine Guided Self-Help sessions, with 71% attending all treatment sessions.

The authors of the study acknowledge the fact that when depressed, autistic people can struggle more than most to generate shifts in routines, behaviours and thought patterns. Acknowledging this, they suggest that Behavioural Activation coupled with new training for psychological therapists, to recognise and adapt their approach to meet the needs of autistic people, offers new opportunities to help individuals get the benefits of depression treatment.

Dr Ailsa Russell of the Centre for Applied Autism Research at the University led the study working with colleagues at the University of Bristol, Newcastle University and service providers including Avon & Wiltshire Mental Health Partnership NHS Trust and Cumbria, Newcastle,Tyne & Wear NHS Foundation.

She explained: "We know that people with autism face depression in disproportionate numbers, yet that too often traditional treatment plans fail to meet their specific needs.

"Co-occurring autism and depression is a particular challenge both in terms of helping individuals' access support, but crucially in accessing the right kind of support to help them change their thinking and get back on a healthier and happier course.

"This study focused on Behavioural Activation which shows promising signs in helping individuals to break out of negative thought cycles and our findings are positive. With new funding, we need to scale-up this work with a larger study to better inform future mental health guidance."

The team behind the study now want more evidence from a larger-scale trial to inform guidance as to whether low intensity psychological intervention is an effective treatment for autistic adults with co-occurring depression.

Children born to mothers who both drank and smoked beyond the first trimester of pregnancy have a 12-fold increased risk for Sudden Infant Death Syndrome (SIDS) compared to those unexposed or only exposed in the first trimester of pregnancy, according to a new study supported by the National Institutes of Health.

SIDS is the sudden, unexplained, death of an infant under one year of age. Many studies have shown that the risk of SIDS is increased by maternal smoking during pregnancy. Some studies have also found that prenatal alcohol exposure, particularly from heavy drinking during pregnancy, can increase SIDS risk. Now, the NIH-funded Safe Passage Study provides a look at how SIDS risk is influenced by the timing and amount of prenatal exposure to tobacco and alcohol. A report of the study appears in EclinicalMedicine, an online journal published by The Lancet.

"Ours is the first large-scale prospective study to closely investigate the association between prenatal alcohol and tobacco exposure and the risk of SIDS," said first author Amy J. Elliott, Ph.D., of the Avera Health Center for Pediatric & Community Research in Sioux Falls, South Dakota. "Our findings suggest that combined exposures to alcohol and tobacco have a synergistic effect on SIDS risk, given that dual exposure was associated with substantially higher risk than either exposure alone."

To conduct the study, a multi-center team of scientists from throughout the U.S. and in South Africa formed the Prenatal Alcohol in SIDS and Stillbirth (PASS) Network. From 2007 until 2015, PASS Network researchers followed the outcomes of nearly 12,000 pregnancies among women from two residential areas in Cape Town, South Africa; and five sites in the U.S., including two American Indian Reservations in South Dakota and North Dakota. The study sites were selected for their high rates of prenatal alcohol use and SIDS, and to include populations where the ethnic and socioeconomic disparities in SIDS remains understudied.

The researchers determined one-year outcomes for about 94 percent of the pregnancies. They found that 66 infants died during that time, including 28 SIDS deaths and 38 deaths from known causes. In addition to the almost 12-fold increased SIDS risk from combined smoking and drinking beyond the first trimester of pregnancy, they determined that the risk of SIDS was increased five-fold in infants whose mothers reported they continued smoking beyond the first trimester, and four-fold in infants whose mothers reported they continued drinking beyond the first trimester. These risks were in comparison to infants who were either not exposed to tobacco or alcohol during gestation or whose mothers quit tobacco or alcohol use by the end of the first trimester.

"The Safe Passage Study provides important new information about the role of dual exposures to prenatal smoking and drinking as risk factors for SIDS," said co-first author Hannah C. Kinney, M.D., of the Department of Pathology at Boston Children's Hospital and Harvard School of Medicine. "Our findings support the current recommendation of the U.S. Centers for Disease Control and Prevention, the U.S. Surgeon General, and the World Health Organization that women not drink or smoke during pregnancy, and emphasizes the significance of dual exposure, which provides the greatest risk for infant mortality."

In a joint statement, the leaders of the NIH Institutes that provide primary funding for the Safe Passage Study said:

"These findings provide still more evidence of the vital importance of the early prenatal environment to healthy postnatal outcomes. Insofar as many women quit drinking and smoking only after they learn that they are pregnant, this study argues strongly for screening for substance use early in pregnancy and intervening as soon as possible. It also calls for stronger public health messaging regarding the dangers of drinking and smoking during pregnancy, and among women who plan to become pregnant."

Women who experience premature menopause are almost three times more likely to develop multiple, chronic medical problems in their 60s compared to women who went through the menopause at the age of 50 or 51.

These are the findings from a study of 5107 women who were part of a national study of 11,258 Australian women, aged 45-50 years in 1996 and who were followed until 2016. The study is published today (Monday) in Human Reproduction [1], one of the world's leading reproductive medicine journals.

As life expectancy is now more than 80 years for women in high income countries, a third of a woman's life is spent after the menopause. It is known already that premature menopause, occurring at the age of 40 or younger, is linked to a number of individual medical problems in later life, such as cardiovascular disease and diabetes. However, there is little information about whether there is also an association between the time of natural menopause and the development of multiple medical conditions - known as multimorbidity.

Researchers at the Centre for Longitudinal and Life Course Research at The University of Queensland, Brisbane (Australia) used data on women who had joined the prospective Australian Longitudinal Study on Women's Health between 1946 and 1951. The women responded to the first survey in 1996 and then answered questionnaires every three years (apart from a two-year interval between the first and second survey) until 2016. The women reported whether they had been diagnosed with or treated for any of 11 health problems in the past three years: diabetes, high blood pressure, heart disease, stroke, arthritis, osteoporosis, asthma, chronic obstructive pulmonary disease, depression, anxiety or breast cancer. Women were considered to have multimorbidity if they had two or more of these conditions.

The women's age at natural menopause was defined as at least 12 months without monthly bleeding, where this was not the result of a surgical intervention such as removal of the ovaries or hysterectomy.

During the 20 years of follow-up, 2.3% of women experienced premature menopause and 55% developed multimorbidity. Compared with women who experienced menopause at the age of 50-51 years, women with premature menopause were twice as likely to develop multimorbidity by the age of 60, and three times as likely to develop multimorbidity from the age of 60 onwards.

Dr Xiaolin Xu, who conducted the research as part of his PhD thesis at the University of Queensland and who is now a research professor at Zhejiang University, China, said: "We found that 71% of women with premature menopause had developed multimorbidity by the age of 60 compared with 55% of women who experienced menopause at the age of 50-51. In addition, 45% of women with premature menopause had developed multimorbidity in their 60s compared with 40% of women who experienced menopause at the age of 50-51."

Professor Gita Mishra, director of the Centre and senior author of the paper, said: "Our findings indicate that multimorbidity is common in mid-aged and early-elderly women. Premature menopause is associated with an increased risk of developing multimorbidity, even after adjusting for previous chronic conditions and for possible factors that could affect the results, such as whether or not the women had children, how many, education, body mass index, smoking and physical activity."

Dr Xu added: "We also found that premature menopause is associated with a higher incidence of individual chronic conditions."

The researchers say they believe that this is the first study to assess the link between premature menopause and the development of multimorbidity in a large group of women and with long-term, prospective follow-up.

"Our findings suggest that health professionals should consider providing comprehensive screening and assessment of risk factors when treating women who experience natural premature menopause in order to assess their risk of multimorbidity," said Prof Mishra. "Our findings also highlight that multimorbidity should be considered as a clinical and public health priority when policy-makers are considering how to control and prevent chronic health problems in women."

The study does not show that premature menopause causes the development of multimorbidity, only that there is an association. A limitation of the study is that the researchers relied on self-reported information from the women.

The researchers are now investigating what risk factors could be targeted in order to prevent or slow down the development of health problems in women who experience premature menopause. These include improving diet and exercise, not smoking, controlling body weight, engaging in mentally stimulating activity and regular screening for cancer and other medical problems related to the reproductive system.

Scientists at UCL have shown a blood test could predict the onset of tuberculosis three to six months before people become unwell, a finding which could help better target antibiotics and save countless lives.

In the study, published in The Lancet Respiratory Medicine, researchers sought to identify which, if any, gene expression signatures in blood could be used to predict the disease at a very early stage and before symptoms arise.

Gene expression signatures are single or combined measurements of levels of specific gene products and are being tested in a range of diseases to aid diagnosis, prognosis or prediction of the response to treatment. Some are already being used to support the management of cancers, but none have reached the clinic in infectious diseases, such as tuberculosis (TB).

For this study, researchers initially conducted a systematic review of published gene signatures found to be present in blood samples from people with TB, compared to healthy individuals.

From this, 17 candidate gene expression signatures for TB were identified, and tested in more than 1,100 blood samples in published data sets from South Africa, Ethiopia, The Gambia, and the UK. Scientists analysed samples from people who had no TB symptoms at the time they gave blood. Those people were then followed up to identify which participants developed TB in the subsequent months.

Researchers found that eight of these signatures, including measurement of expression of a single gene, could predict the diagnosis of TB within three to six months, which falls within the accuracy required by the World Health Organisation (WHO) for new diagnostic tests*. This accuracy was achieved, by revealing the patients' immune responses to bacteria before the symptoms of the disease develop.

Lead author Dr Rishi Gupta (UCL Institute for Global Health) said: "The emergence of gene expression signature tests, which can aid diagnosis and early treatment, provides real hope for the management of infectious diseases. In this study we identify multiple signatures to identify the onset of tuberculosis, which is extremely encouraging, potentially providing multiple targets for early detection.

"Further development of these tests could help identify people who will benefit most from preventative antibiotic treatment, in order to reduce the occurrence of tuberculosis - a disease which causes the greatest number of deaths worldwide due to any single infection. The availability of multiple signatures will help to broaden access to these tests."

Tuberculosis is a disease caused by a bacteria (Mycobacterium tuberculosis) that most often affects the lungs. TB is spread from person to person through the air. When people with lung TB cough, sneeze or spit, they propel the TB germs into the air. Another person needs to inhale only a few of these germs to become infected. Worldwide, TB is one of the top 10 causes of death and in 2018 1.5 million people died from the disease.

Corresponding author, Professor Mahdad Noursadeghi (UCL Infection & Immunity), said: "About one-quarter of the world's population is thought to have been infected with the bacteria that cause TB. The majority of these individuals remain well and cannot transmit the disease.

"However, we currently do not know which people are most likely to develop TB disease after being infected. If we can identify these individuals, we can treat their infection more easily and prevent it from spreading to others.

"Our findings establish the gene signatures in blood which show most promise for identifying people who are at risk of disease. Future development of a blood test based on these findings could make an important contribution to efforts to reduce the impact and spread of this deadly infection."

What The Study Did: In this randomized clinical trial of about 200 patients with septic shock, combination treatment with intravenous vitamin C, hydrocortisone and thiamine compared with intravenous hydrocortisone alone didn't significantly improve the amount of time patients were alive and free of medicines that raise blood pressure (vasopressors) over seven days. The study findings are being released to coincide with presentation at the Critical Care Reviews Meeting 2020 in Belfast, Northern Ireland.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Authors: Rinaldo Bellomo, M.D., Ph.D., of Monash University in Melbourne, Australia, is the corresponding author.

(doi:10.1001/jama.2019.22176)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.