Culture

Researchers recently conducted the largest study to date to evaluate the effectiveness of weight loss surgery in a Chinese population of individuals with obesity and type 2 diabetes.

In the study, which is published in Diabetes/Metabolism Research and Reviews, surgery provided substantial and sustainable effects on weight, blood sugar, and cholesterol over five years.

"The effectiveness of restrictive and bypass surgeries was similar at the end of follow-up, though restrictive surgeries were slightly more effective in type 2 diabetes remission," the authors wrote. (Restrictive surgeries reduce the size of the stomach.)

A new Points to Consider document from the ACMG aims to assist referring physicians, laboratory geneticists, genetic counselors and other medical professionals in understanding the complexity and implications of exome sequencing (ES) in prenatal care. Published in ACMG's official journal Genetics in Medicine, the document, "The Use of Fetal Exome Sequencing in Prenatal Diagnosis: A Points to Consider Document of the American College of Medical Genetics and Genomics (ACMG)," is also intended to guide clinical laboratories in the development of protocols and policies related to the increasing use of prenatal exome sequencing.

ACMG President Anthony R. Gregg, MD, MBA, FACOG, FACMG said, "In May 2012, the ACMG Board approved "Points to Consider in the Clinical Application of Genomic Sequencing" and, at that time, they did not recommend fetal genomic sequencing. New data speaks to ACMG's concerns raised at that time. Among these are turnaround time and guidance on identifying and reporting variants of unknown clinical significance. "The Use of Fetal Exome Sequencing in Prenatal Diagnosis: A Points to Consider Document of the American College of Medical Genetics and Genomics (ACMG)" is the first ACMG document devoted exclusively to fetal genomic sequencing and the first to provide a framework that laboratories and clinicians can share. As new information emerges, ACMG creates new guidance, which translates to improved patient care."

Approximately 2-4% of pregnancies are complicated by significant fetal structural anomalies. Given respect for reproductive autonomy, the ACMG document states that "all patients diagnosed with a fetal anomaly should be offered genetic counseling, including review of options for genetic testing." A genetic diagnosis can assist in determining the fetal prognosis and help guide prenatal care, including decisions of reproductive choice, in utero therapy, delivery planning, and neonatal care, and will potentially decrease morbidity and mortality. A prenatal genetic diagnosis may lead to informed genetic counseling for future reproductive options including preimplantation genetic testing, diagnostic prenatal testing or the possible use of donor gametes. Exome sequencing may be considered when a diagnosis cannot be obtained using routine prenatal methods in a fetus with one or more significant structural anomalies. The utilization of exome sequencing is increasing in prenatal care and the new ACMG document provides an in-depth review of its application in the clinical setting for fetuses with sonographic anomalies. "As a trained pediatrician and medical geneticist, one of the most common questions I have heard from parents of a newborn with structural anomalies is: 'What does my child have? What does it mean for my baby? And can this happen again?' To questions regarding diagnosis, prognosis, and recurrence, it is of utmost importance to recognize the underlying cause for the combination of findings first. Fetal exome analysis is now available and has been shown to contribute to earlier diagnosis, which in turn can lead to earlier treatment and better counseling for the family," said ACMG Chief Executive Officer Maximilian Muenke, MD, FACMG.

The comprehensive Points to Consider document includes:

pre-test considerations;

considerations for reporting--including known disease genes, genes of uncertain significance, fetal incidental findings, parental incidental findings, ACMG secondary findings, misattributed parentage, and consanguinity;

post-test considerations;

consideration of cost;

re-analysis considerations;

consideration for targeted family testing; and

education of healthcare professionals.

The Points to Consider document concludes, "As a new diagnostic test in fetal medicine, ES may be considered when a diagnosis cannot be obtained using routine prenatal methods in a fetus with one or more significant anomalies.... Additional research is needed on patient perspectives of the consent process, effective and appropriate communication of uncertainty, return of results and reinterpretation, and health and economic outcomes."

Health research faces a crisis that could impact on patient care, says a new report led by 10 prominent figures in the NHS and academia.

The Academy of Medical Sciences' report raises the alarm about the number of research active NHS staff who are finding it increasingly difficult to find time for research. Support for research is not helped by the widening gap between universities and the NHS.

Released today (Wednesday 8 January) the report is calling for leaders in universities, the NHS and government to make urgent changes to protect and enhance research in the NHS. It sets out a powerful vision to enhance the NHS research culture and support provided by universities to make sure scientific discoveries boost the NHS and improve patient care.

The report calls for immediate action by giving NHS staff protected time to do research. This should begin by running an estimated £25 million pilot scheme to allow 1 in 5 consultants to have one day a week of their time protected for research in ten hospitals across the UK. It is expected that the scheme would become cost neutral or even save money in the longer term by improving recruitment and retention of NHS staff, reducing spending on agency staff, and increasing research funding from life sciences companies.

Professor Sir Robert Lechler PMedSci, President of the Academy of Medical Sciences, said:

"Protecting and strengthening research is a win-win situation for patients, the NHS, Universities and our economy. Research is the tonic the NHS needs right now.

"There is increasing evidence that shows that patients treated in research active hospitals get better quality of care, even if they are not taking part in a research project.

"Evidence also suggests that including research in medical roles makes it easier to attract and keep the best doctors. Research can also provide a coping mechanism to avoid burnout in NHS staff, so could make a dent in the £480 million yearly NHS spend on agency staff*."

The report also calls for:

All healthcare organisations, including hospitals and doctors' surgeries, to actively promote research, by valuing and measuring the health research they carry out.

All healthcare staff, including doctors and nurses, to be trained to understand research and know how to carry it out or put it into practice.

Universities to embrace NHS staff into their research teams by increasing the number of honorary positions they award to NHS staff.

The NHS is uniquely placed to be the engine of health research. The historic research discoveries made in the NHS over the last 70 years show how much is at stake for patients. Discoveries include the development of penicillin as a drug, the invention of Magnetic Resonance Imaging (MRI) scanners, the development of in vitro fertilisation (IVF), DNA sequencing and making advances in immunology to allow organ transplantation.

Rob Lester, a retired GP from Fife in Scotland, was diagnosed with advanced prostate cancer aged 55. He has been treated with abiraterone - a drug discovered by The Institute of Cancer Research, London, and first shown to be effective for advanced prostate cancer by research developed through a partnership between The Institute of Cancer Research (ICR) and the Royal Marsden NHS Foundation Trust.

Rob said of his treatment:

"I would call myself a lucky man - abiraterone has treated my cancer. Not only have I survived, but I am living my life and feeling better than I have in years. When I was first diagnosed with advanced prostate cancer, I hoped to survive 5 years - now I have already survived 7 years. I am alive simply because of research carried out in the NHS. We must do all we can to make sure that this type of research continues to happen in future."

Professor Sir Robert Lechler PMedSci, continued:

"We are enjoying an exciting era of unprecedented medical discovery. Patients need us to convert this progress into new cures and better care.

"You could ask whether, at a time of too few doctors and nurses and overstretched budgets, we can afford to give time and money to research. The Prime Minister has been absolutely clear that his Government will boost funding on the NHS. Whatever improvements are made to our health service, research is a critical priority. It is important to note that every pound spent on biomedical research returns about 25p every year, forever. So we can't afford not to do this both financially and more importantly for the health of us all.

"There is a lot at stake for the NHS and everyone treated by it. If we unite and act decisively we can boost the NHS and make sure that the breath taking scientific discoveries being made in the UK are converted into better patient care."

Despite the known benefits of research, the report highlights that many NHS Trusts see research as 'nice to have'. The number of medical clinical academics - NHS consultants employed by Universities to lead research - has decreased from 7.5% to 4.2% of NHS medical consultants from 2004 to 2017. Only 0.4% of GPs and 0.1% of nursing, midwifery and other health professionals had research as part of their role in 2017.

Early Stone Age populations living between 1.8 - 1.2 million years ago engineered their stone tools in complex ways to make optimised cutting tools, according to a new study by University of Kent and UCL.

The research, published in the Journal of Royal Society Interface, shows that Palaeolithic hominins selected different raw materials for different stone tools based on how sharp, durable and efficient those materials were. They made these decisions in conjunction with information about the length of time the tools would be used for and the force with which they could be applied. This reveals previously unseen complexity in the design and production of stone tools during this period.

The research was led by Dr Alastair Key, from Kent's School of Anthropology and Conservation, and is based on evidence from mechanical testing of the raw materials and artefacts found at Olduvai Gorge in Tanzania -- one of the world's most important sites for human origins research.

Dr Key collaborated with Dr Tomos Proffitt, from UCL Institute of Archaeology, and Professor Ignacio de la Torre of the CSIC-Centro de Ciencias Humanas y Sociales in Madrid, for the study.

Their research, which employed experimental methods more commonly used in modern engineering research, shows that hominins preferentially selected quartzite, the sharpest but least durable stone type at Olduvai for flake tools; a technology thought to have been used for expedient, short-lived cutting activities.

Chert, which was identified as being highly durable and nearly as sharp as quartzite, was only available to hominins for a short 200,000 year period. Whenever it was available, chert was favoured for a variety of stone tool types due to its ability to maximise cutting performance over extended tool-use durations. Other stone types, including highly durable lavas, were available at Olduvai, however their use varied according to factors such as how long a tool was intended to be used for, a tools potential to create high cutting forces, and the distance hominins had to travel to raw material sources.

The study reveals a level of complexity and flexibility in stone tool production previously unseen at this time. Earlier research had demonstrated Early Stone Age populations in Kenya to select highly durable stone types for tools, but this is the first time cutting edge sharpness has been able to be considered. By selecting the material best suited to specific functional needs, hominins optimised the performance of their tools and ensured a tools efficiency and 'ease-of-use' was maximised.

Dr Key said: 'Why Olduvai populations preferentially chose one raw material over another has puzzled archaeologists for more than 60 years. This has been made all the more intriguing given that some stone types, including lavas and quartzite, were always available.

'What we've been able to demonstrate is that our ancestors were making quite complex decisions about which raw materials to use, and were doing so in a way that produced tools optimised for specific circumstances. Although we knew that later hominin species, including our own, were capable of such decisions, it's amazing to think that populations 1.8 - 1.2 million years ago were also doing so.'

Dr Proffitt added: 'Early hominins during the Oldowan were probably using stone flakes for a variety of tasks. Mostly for butchering animals whilst scavenging, but also probably for cutting various plants and possibly even shaping wood. A durable cutting edge would have been an important factor when using these tools.

'There are many modern analytical techniques used in material sciences and engineering that can be used to interrogate the archaeological record, and may provide new insights into the mechanical properties of such tools and artefacts. By understanding the way that these tools work and their functional limits it allows archaeologists to build up a greater understanding of the capabilities of our earliest ancestors at the dawn of technology.'

The team now hopes that researchers at other archaeological sites will want to apply similar mechanical tests and techniques to help understand the behaviour of Stone Age populations.

A key immune signal has a previously unknown role in turning off the immune system's attack on pancreatic cancer cells, a new study finds.

Led by researchers at NYU Grossman School of Medicine, the study found that an immune signaling protein, interleukin-1β (IL-1β), is made and released by pancreatic tumor cells. This was shown to reduce anti-cancer immune responses, which promoted the growth of pancreatic ductal adenocarcinoma or PDA, a form of cancer that is usually deadly within two years.

Published online in Cancer Research, a journal of the American Association for Cancer Research, on January 8, the study found that blocking the action of IL-1β in mice with immune proteins called antibodies caused a 32 percent decrease in PDA tumor growth.

Other experiments combined the anti-IL-1β antibody, which gloms onto and neutralizes its target, with an already approved antibody treatment that shuts down the protein "checkpoint" called PD1. To spare normal cells from immune attack, the immune system uses "checkpoints" on immune cells that turn them off when they receive the right signal. Cancer cells hijack checkpoints to turn off the system, leading to immune suppression of CD8+ T cells that would otherwise kill cancer cells. Therapies called checkpoint inhibitors counter this effect.

While effective against many cancers, checkpoint inhibitors have failed in PDA, with the response rate in tumors as low as roughly three percent in some trials, and the limitations attributed to poor CD8+ T cell infiltration and immune suppression. In the current study, adding anti-IL-1β antibodies to anti-PD-1 antibody treatment doubled the infiltration of such T cells into PDA tumors and increased the anti-tumor activity of PD-1 blockade by 40 percent.

"By engineering mice with versions of PDA that lack the IL-1β gene, we found for the first time that pancreatic cancer cells produce IL-1β, and that it is essential for the continued growth of PDA tumors," says study senior author Dafna Bar-Sagi, PhD, Vice Dean for Science and Chief Science Officer for NYU Langone Health. "Blocking IL-1β with an antibody treatment may represent another way to make pancreatic tumors vulnerable to the immune system, with the potential to significantly increase the effectiveness of checkpoint inhibitors if combined."

Initial Trigger

The new finding is in line with past work in other labs that had described the microbiome, the mix of bacterial species in the pancreas, as being altered in the presence of PDA, and a factor in cancer growth. The field had traditionally assigned the production of IL-1β to immune cells, but the new work finds that pancreatic tumor cells can also make it in response to proteins given off by certain bacteria.

Bacterial products were found to activate proteins on the cancer cell surfaces called toll-like receptors, which set off chain reactions that were required for IL-1β production in cancer cells.

The research team also found that higher IL-1β production caused nearby pancreatic stellate cells to increase production of dense, structural proteins like collagen. Desmoplasia is the overgrowth of such fibrous tissue that often occurs near pancreatic tumors, and which has been linked to treatment resistance.

Active stellate cells were also found to trigger production of the signaling proteins that attract immune cells called macrophages into tumors and programs them to become the type (M2) that suppresses immune reactions. Experiments also confirmed that higher IL-1β and M2 macrophage levels, along with fibroblast-driven desmoplasia, reduced the ability of cancer-cell-killing CD8+ T cells to enter tumors.

"This work provides strong evidence that blocking the action of IL-1β enables T cells to better penetrate tumors and kill cancer cells, mechanisms with potential to overcome the limitation of currently available immunotherapies in the treatment of pancreatic cancer," says first author Shipra Das, who was a member of Bar-Sagi's lab at the time the study was done.

Bacterial exposure has been identified as a potential environmental risk factor in developing coeliac disease, a hereditary autoimmune-like condition that affects about one in 70 Australians.

It is estimated that half of all Australians are born with one of two genes that cause coeliac disease, and approximately one in 40 are likely to develop the condition.

People with coeliac disease must follow a lifelong gluten-free diet, as even small amounts of gluten can cause health problems.

While environmental factors are known to trigger Coeliac Disease in those with the genetic predisposition, exactly how that works has remained unclear.

Scientists from the Monash Biomedicine Discovery Institute (BDI) and ARC Centre of Excellence in Advanced Molecular Imaging, have now provided a molecular foundation for microbial exposure as a potential environmental factor in the development of coeliac disease.

The results of the study, done in collaboration with researchers at Leiden University Medical Centre and the Walter and Eliza Hall Institute of Medical Research, have been published in the journal Nature Structural and Molecular Biology.

Co-Lead researcher Dr Hugh Reid, from Monash University, said the team showed, at the molecular level, how receptors isolated from immune T cells from coeliac disease patients can recognise protein fragments from certain bacteria that mimic those fragments from gluten.

Exposure to such bacterial proteins may be involved in the generation of aberrant recognition of gluten by these same T cells when susceptible individuals eat cereals containing gluten, he said.

"In coeliac disease you get aberrant reactivity to gluten and we have provided a proof-of-principle that there's a link between gluten proteins and proteins that are found in some bacteria," he said.

"That is, it's possible that the immune system reacts to the bacterial proteins in a normal immune response and in so doing develops a reaction to gluten proteins because, to the immune system, they look indistinguishable - like a mimic."

Dr Reid said the findings could eventually lead to diagnostic or therapeutic approaches to coeliac disease.

About coeliac disease

Coeliac disease is caused by an aberrant reaction of the immune system to gluten, a protein which occurs naturally in grains such as wheat, rye, barley and oats, and therefore is typically found in bread, pastries and cakes. Immune system cells, known as T cells, regard gluten as a foreign substance, and initiate action against it.

In patients with CD, activation of these T cells leads to an inflammatory response in the small intestine causing a wide range of symptoms including diarrhoea, bloating and malabsorption of nutrients, to name a few.

People with coeliac disease must follow a lifelong gluten-free diet, as even small amounts of gluten can cause health problems. If left untreated, the disease can cause serious issues including malnutrition, osteoporosis, depression and infertility, and there is a small increased risk of certain forms of cancer, such as lymphoma of the small bowel.

Infectious diseases triggered by bacteria and other microbes are the most frequent cause of human mortality across the globe. Roughly half of the world's population carry the bacteria Helicobacter pylori (H. Pylori) in their stomach, known to be the most significant risk factor for ulcers, MALT lymphoma and adenocarcinoma in the stomach. The rapid spread of pathogens resistant to medication such as antibiotics is making it increasingly difficult to treat infections such as these using antimicrobial therapies. A research team from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) has now revealed a new mechanism which controls the causes of infection with H. Pylori, triggering the development of stomach diseases. It is hoped that these findings will lead in time to new therapies. The study was published in the journal Nature Communications.

A team of national and international scientists led by Prof. Dr. Steffen Backert from the Chair of Microbiology at FAU has investigated how the bacteria manipulate the host's immune system in order to ensure their long-term survival in the stomach. A chronic inflammation is the most common cause for stomach illnesses such as these. The researchers have identified a 'molecular switch' which uses a previously unknown mechanism to regulate the inflammation reaction in the stomach. The interaction between H. Pylori and stomach cells activates a syringe-like pilus structure referred to as a type IV secretion system. A protein, CagL, is presented at the surface of this structure which allows the bacterial toxin known as CagA protein to be delivered into the stomach cells. The injected CagA then re-programmes the host cell so that stomach cancer can develop. It now appears that CagL also has another important function, however. The protein is recognised by the immune system via the receptor TLR5. Experiments in mouse models have demonstrated that TLR5 controls the infection efficiently. CagL imitates a TLR5 recognition motif in the flagellin protein of other pathogens, thereby controlling the human immune response.

Interestingly, this signalling pathway can be both switched on and switched off by the type IV secretion system, which is not thought to be the case with other bacteria. Presumably, H. Pylori has exploited this signalling pathway over thousands of years of evolution to eliminate 'bothersome' bacterial competitors in the stomach. At the same time, CagL influences the congenital and adaptive immune system as well as the inflammation reaction in such a way that H. Pylori itself is not recognised and therefore cannot be eliminated - a mechanism which is crucial for long-term infections with H. Pylori in the stomach and triggering stomach disease. Researchers also observed that TLR5 is no longer produced in healthy stomach cells and once an infection has been resolved. This indicates that the expression of this protein is a new indicator for stomach disease in humans triggered by H. Pylori.

New approach for treating stomach disease

Prof. Backert hopes that these findings will help develop significant new approaches for anti-bacterial treatment, as CagL, CagA and TLR5 lend themselves well to treatment. The participating researchers have already started to test appropriate substances. 'We hope that specific inhibitors can paralyse the function of the type IV secretion system, or partially or entirely prevent infection,' reports Prof. Backert.

The cow can only process grass in its rumen with the help of billions of microorganisms. An entire zoo of bacteria, archaea and protozoa works there like on a production line: First of all, these single-cell organisms break down the cellulose, a polysaccharide. Other bacteria ferment the sugars released into fatty acids, alcohols and gases, such as hydrogen and carbon dioxide. Finally, methanogenic archaea transform these two gases into methane.

An average cow produces about 110 liters of methane per day. It escapes from its mouth through rumination, but also mixes again with partly digested food. As a result, the sodium content of the grass pulp can fluctuate to a considerable degree (between 60 and 800 millimoles of sodium chloride (NaCl) per liter).

A German-American research team has now discovered how the ruminal bacteria adapt to these extreme fluctuations in sodium content: "Bioinformatic analyses of the genome of ruminal bacteria led our American colleague Tim Hackmann to assume that some ruminal bacteria have two different respiratory circuits. One of them functions with sodium ions and the other without," explains Professor Volker Müller from the Department of Molecular Microbiology and Bioenergetics at Goethe University. That is why Müller suggested to his doctoral researcher Marie Schölmerich that she study a typical representative in the microbiome of ruminants: the bacterium Pseudobutyrivibrio ruminis.

Together with undergraduate student Judith Dönig and Master's student Alexander Katsyv, Marie Schölmerich cultivated the bacterium. Indeed, they were able to corroborate both respiratory circuits. As the researchers report in the current issue of the Proceedings of the National Academy of Sciences (PNAS), the electron carrier ferredoxin (Fd) is reduced during sugar oxidation. Reduced ferredoxin drives both respiratory circuits.

The one respiratory circuit comprises the enzyme complex Fd:NAD+ oxidoreductase (Rnf complex). It uses energy to transport sodium ions out of the cell. When they re-enter the cell, the sodium ions trigger an ATP synthase, so that ATP is produced. This respiratory circuit only works in the presence of sodium ions.

In the absence of sodium ions, the bacterium forms an alternative respiratory circuit with another enzyme complex: The Ech hydrogenase (synonymous: Fd:H+ oxidoreductase) produces hydrogen and pumps protons out of the cell. If these re-enter the cell via a second ATP synthase that accepts protons but not sodium ions, ATP is also produced.

"This is the first bacterium so far in which these two simple, completely different respiratory circuits have been corroborated, but our bioinformatic analyses suggest that they are also found in other bacteria," explains Marie Schölmerich. "It seems, therefore, that this adaptation strategy is more widespread," she assumes.

Interestingly, both enzyme complexes (Rnf and Ech) were also discovered in bacteria which are old in terms of evolutionary biology. Professor Müller's research group has examined them in depth, but always only found one of the two enzyme complexes and never both together. "We're now going to use synthetic microbiology methods to produce hybrids of bacteria that contain both complexes in order to optimize them for biotechnological processes. In this way, we can raise the cellular ATP content, which will make it possible to produce products of a higher quality," explains Professor Müller. The intention is to use the respiratory circuits to recover valuable substances through the fermentation of synthesis gas. This is the subject of the trials being conducted in the framework of a project sponsored by the Federal Ministry of Education and Research.

Researchers at Karolinska Institutet in Sweden and Tampere University in Finland have developed a method based on artificial intelligence (AI) for histopathological diagnosis and grading of prostate cancer. The AI-system has the potential to solve one of the bottlenecks in today's prostate cancer histopathology by providing more accurate diagnosis and better treatment decisions. The study, presented in the scientific journal The Lancet Oncology, shows that the AI-system is as good at identifying and grading prostate cancer as world-leading uro-pathologists.

"Our results show that it is possible to train an AI-system to detect and grade prostate cancer on the same level as leading experts," says Martin Eklund, associate professor at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet who led the study. "This has the potential to significantly reduce the workload of uro-pathologists and allow them to focus on the most difficult cases."

A problem in today's prostate pathology is that there is a certain degree of subjectivity in the assessments of the biopsies. Different pathologists can reach different conclusions even though they are studying the same samples. This leads to a clinical problem where the doctors must pick treatment based on ambiguous information. In this context, the researchers see significant potential to use the AI-technology to increase the reproducibility of the pathological assessments.

To train and test the AI system, the researchers digitized more than 8,000 biopsies taken from some 1,200 Swedish men in the ages of 50-69 to high-resolution images using digital pathology scanners. About 6,600 of the samples were used to train the AI system to spot the difference between biopsies with or without cancer. The remaining samples, and additional sets of samples collected from other labs, were used to test the AI system. Its results were also compared against the assessments of 23 world-leading uro-pathologists.

The findings showed that the AI-system was almost near-perfect in determining whether a sample contained cancer or not, as well as in estimating the length of the cancer tumor in the biopsy. When it comes to determining the severity of the prostate cancer, the so-called Gleason score, the AI system was on par with the international experts.

"When it comes to grading the severity of the prostate cancer, the AI is in the same range as international experts, which is very impressive, and when it comes to diagnostics, to determine whether or not it is cancer, the AI is simply outstanding," says Lars Egevad, professor in pathology at Karolinska Institutet and co-author of the study.

The initial findings are promising but more validation is needed before the AI system may be rolled out broadly in clinical practice, according to the researchers. That is why a multicenter study spanning nine European countries is currently underway with completion slated by the end of 2020. That study aims to train the AI-system to recognize cancer in biopsies taken from different laboratories, with different types of digital scanners and with very rare growth patterns. In addition, a randomized study starting in 2020 will examine how the AI-model may be implemented in Sweden's health care system.

"AI-based evaluation of prostate cancer biopsies could revolutionize future health care," says Henrik Grönberg, professor in cancer epidemiology at Karolinska Institutet and head of the Prostate Cancer Center at S:t Göran Hospital in Stockholm. "It has the potential to improve the diagnostic quality, and thereby secure a more equitable care at a lower cost."

"The idea is not that AI should replace the human involvement, but rather act as a safety net to ensure that pathologists don't miss some cancers, and assist in standardization of grading," says Martin Eklund. "It could also serve as an alternative in parts of the world where there is a complete lack of pathological expertise today."

The new health care practice of "hotspotting" -- in which providers identify very high-cost patients and attempt to reduce their medical spending while improving care -- has virtually no impact on patient outcomes, according to a new study led by MIT economists.

The finding underscores the challenge of reducing spending on "superutilizers" of health care, the roughly 5 percent of patients in the U.S. who account for half the nation's health care costs. The concept of hotspotting, a little more than a decade old, consists of programs that give at-risk patients sustained contact with doctors, other caregivers, and social service providers, in an attempt to prevent rehospitalizations and other intensive, expensive forms of care.

The MIT study was developed in cooperation with the Camden Coalition of Healthcare Providers, which runs one of the nation's best-known hotspotting programs. The researchers conducted a four-year analysis of the program and found that being enrolled in it makes no significant difference to patients' health care use.

"This intervention had no impact in reducing hospital readmissions," says Amy Finkelstein, an MIT health care economist who led the study.

Significantly, the new study was a randomized, controlled trial, in which two otherwise similar groups of patients in Camden were separated by one large factor: Some were randomly selected to be part of the hotspotting program, and an equal number of randomly selected patients were not. The two groups generated virtually the same results over time.

"The reason it was so important we did a randomized, controlled trial," Finkelstein says, "is that if you just look at the individuals in the intervention group, it would look like the program caused a huge reduction in readmissions. But when you look at the individuals in the control group -- who were eligible for the program but were not randomly selected to get it -- you see the exact same pattern."

The paper, "Health Care Hotspotting -- A Randomized, Controlled Trial" is being published today in the New England Journal of Medicine. The co-authors are Finkelstein, the John and Jennie S. MacDonald Professor Economics at MIT, who is the paper's corresponding author; Joseph Doyle, an economist who is the Erwin H. Schell Professor of Management at the MIT Sloan School of Management; Sarah Taubman, a research scientist at J-PAL North America, part of MIT's Abdul Latif Jameel Poverty Action Lab; and Annetta Zhou, a postdoc at the National Bureau of Economic Research.

Camden Coalition "fabulous partners" in seeking answers

To conduct the study, the MIT-led research team evaluated 800 patients enrolled in the Camden Coalition of Healthcare Providers program from 2014 to 2017. The patients in the study had been hospitalized at least once in the six months prior to admission and had at least two chronic medical conditions, among other health care issues. The study was constructed after extensive consultation with the coalition.

"They were fabulous partners," Finkelstein says about the coalition. "Because they're so data-driven, they had the data infrastructure in place, which made this possible."

Finkelstein particularly cites the founder of the Camden Coalition of Healthcare Providers, Jeffrey Brenner, who served as executive director of the organization from 2006 through 2017, and whose development of "hotspotting" concepts has received substantial public attention. In Camden, where 2 percent of patients represent 33 percent of medical expenses, preventing the need for acute care is a pressing concern.

"Dr. Brenner is a really extraordinary person, and he's trying to solve a very hard problem," Finkelstein says, crediting Brenner for actively seeking data about his organization's results without knowing what those outcome would be.

Half of the study's 800 patients were placed in a group that used the program's services, and half were in a control group that did not take part in the program. The Camden hotspotting program includes extensive home care visits, coordinated follow-up care, and medical monitoring -- all designed to help stabilize the health of patients after hospitalization. It also helps patients apply for social services and behavioral health programs.

Overall, the study found that the 180-day hospital readmission rate was 62.3 percent for people in the program and 61.7 percent for people not in the program.

Additional measurements in the study -- such as the number of hospital readmissions for patients, aggregate number of days spent in the hospital, and multiple financial statistics -- also showed very similar outcomes between the two groups.

The study shows that while the overall number of people in hotspotting programs who need rehospitalization declines over the course of the program, it does not decline by a larger amount than it would if those people were outside the program's reach.

In short, people in hotspotting programs require fewer rehospitalizations because any group of patients currently using a lot of health care resources will tend to have lower health care use in the future. Previous reports about hotspotting programs had focused on the roughly 40 percent decline in six-month hospital readmissions -- while not comparing that to the rate for comparable patient groups outside such programs.

"If you think about health care interventions, almost by definition they're occurring at a time of unusually poor health or unusually high cost," Finkelstein says. "That's why you're intervening. So they're almost by construction going to be plagued by the issue of regression to[ward] the mean. I think that's a really important lesson as we continue to try to figure out how to improve health care delivery, especially as so much of the work focuses on these high-cost patients."

"We're not going to give up"

To be sure, as Finkelstein notes, the new study is a local one, and hotspotting programs exist in many locations. It also examines the four-year results of the program, which underwent some evolution during the study period; if the program had made a breakthrough change in, say, 2016, that would only partially be reflected in the four-year data. As it happens, however, the study found no such large changes over time.

Brenner's perspective about studying the effectiveness of his own initiative, Finkelstein says, was that, by analogy, "if you have a new medication to try to cure cancer, and you run a clinical trial on it and it doesn't work, you don't just say, 'I guess that's it, we're stuck with cancer.' You keep trying other things. ... We're not going to give up on improving the efficiency of health care delivery and the well-being of this incredibly under-served population. We need to continue to develop potential solutions and rigorously evaluate them."

Finkelstein also notes that the current study is just one piece of research in the complicated area of improving health care and reducing costs for people in need of extensive treatment, and says she welcomes additional research in this area.

"I hope it inspires more research and that more organizations will partner with us to study [these issues]," Finkelstein says.

Finkelstein also serves as the scientific director of J-PAL North America at MIT, which backs randomized controlled trials on a variety of social issues.

Each encounter is like a single shard in a mosaic that, taken as a whole, presents a picture of amazing optimism despite myriad challenges.

Alexandra M. Sims, M.D., FAAP, a General Academics Pediatric Fellow at Children's National Hospital, captured the anonymized vignettes in her journal, using writing as a way to help process both the unbounded joy and sobering trauma experienced by her young patients.

Dr. Sims distilled the snippets into a 27-line poem that will be published Jan. 7, 2020, in JAMA, as part of "Poetry and Medicine," poems penned by artists and physicians to explore the meaning of healing and illness.

One of the vignettes collapses eye-opening comments she heard during a number of clinical encounters, including a childhood immunization session for a 4-year-old: Doesn't flinch with the vaccines, but tells me not to call them 'shots' / His classmate was shot last year / And she died

"When I'm talking about a 'shot,' the first thing that comes to my mind - because of what I do for a living and how my life has unfolded - is a vaccination," Dr. Sims explains. "That caught me off guard. Even though I have been doing this job for a while, I can always learn from patients and families. It really made me shift the language I use, avoiding words that I might think are innocuous that can be translated in ways that can be scary for a child."

And the poem's title, "Keep That Same Energy," was inspired by a young man who, like many patients, calls her Dr. Seuss, and ended his visit by doing 10 pushups: Keep that same energy, sweet Black boy, I silently pray / That agency, that confidence / When the world tries to tell you who you are

During each clinical encounter, Dr. Sims says she tries to instill a sense of pride and competence in the hopes it helps her patients continue to persevere in the face of adversity.

"The patients we see here experience trauma in a lot of big and small ways," she says. "I'm blown away by their positivity and resilience and ability to deal with a lot of things life is throwing at them. My worry is when - and if - the resiliency will wear down and what things we should be doing as providers to build up that self-efficacy and resiliency so it will last a lifetime."

When Stanford physicians Donna Zulman, MD, and Abraham Verghese, MD, set out more than two years ago to lead a team in finding ways to heal a growing fracture in doctor-patient relationships, they knew the task would be complicated.

In recent surveys, clinicians have reported that the current climate of medicine -- with limits on the amount of time they can spend with patients during appointments, an explosion of biomedical knowledge and increased demands to update and review electronic health records -- translates into less time for meaningful interactions with patients.

That, Stanford researchers contend in a paper to be published Jan. 7 in JAMA, isn't good for patients -- or for clinicians who are feeling increasingly disconnected from the reasons they got into medicine.

The goal of their research, which began 2½ years ago, was to identify evidence-based measures that clinicians can take to be fully engaged with patients and understand their perspectives, life circumstances and priorities. Ultimately, researchers wanted to generate a brief list of highly effective practices that clinicians could easily incorporate into their interactions with patients, Zulman said.

In their paper, researchers describe five evidence-based recommendations:

Prepare with intention: Familiarize yourself with the patient you are about to meet; create a ritual to focus your attention before a visit.

Listen intently and completely: Sit down, lean forward and position yourself to listen; don't interrupt; your patient is your most valuable source of information.

Agree on what matters most: Find out what your patient cares about and incorporate these priorities into the visit agenda.

Connect with the patient's story: Consider the circumstances that influence your patient's health; acknowledge your patient's efforts, and celebrate successes.

Explore emotional cues: Tune in, notice, name and validate your patient's emotions to become a trusted partner.

The research was conducted in conjunction with Presence, an interdisciplinary center at Stanford that promotes the art and science of human connection in medicine. The objective of the research project was to revise the critical moment when physicians and patients meet, shifting the emphasis from institutional procedure to an interaction focused on meaningful human interaction.

"We were looking for practices that would improve the experience of patients and lead to better care for them, but would also improve the experience of clinicians and help them to rediscover the joy of medicine," said Zulman, an assistant professor of medicine and the director of Stanford Presence 5, one of several Presence initiatives.

"As physicians, we are privileged to work with people in their most vulnerable moments," she said. "And in today's climate, particularly in primary care, it's easy to lose sight of that with all of the administrative demands, time pressures and technology distractions."

Zulman, a health services researcher at Stanford and the Veterans Affairs Health Care System, is the lead author of the paper. Verghese, an advocate for the importance of bedside medicine and physical exams, is senior author of the paper, which includes links to podcast interviews with him and Zulman.

Identifying strategies

The Presence 5 practices, as they are known, were identified through a systematic review of 73 studies of interpersonal interventions published between January 1997 and August 2017, as well as through observations of clinician-patient encounters, and interviews with clinicians and patients at Stanford internal medicine and family medicine clinics, the Ravenswood Family Health Center in East Palo Alto and the Veterans Affairs Palo Alto Health Care System. The team also interviewed professionals outside the field of medicine to learn about cross-cutting themes related to clinician presence and human connection.

The published studies were analyzed to measure how interventions improved health outcomes, costs and patient and physician experiences. The interviews and observations provided insights into best practices at the clinical level.

The information researchers gleaned from the studies, interviews and observations generated 31 ideas for practices physicians could implement, which were reviewed, rated and culled to five with input from a group of experts: physicians, researchers, a patient advocate, a caregiver advocate and health care leaders.

Zulman said the team's next step is to evaluate how using the five practices affects the experiences of patients and clinicians, with new research being conducted at Stanford primary care clinics, the MayView Community Health Center in Mountain View and the San Jose VA Clinic, which is part of the VA Palo Alto Health Care System.

Researchers are holding workshops to share their findings, as well as developing a curriculum for training medical students and residents. The team is also working to validate their findings with international collaborators and to determine whether the practices can be adapted for different clinical settings and models.

"The Presence 5 practices resonate because they speak to something that is timeless and central to medicine," said Verghese, the Linda R. Meier and John F. Lane Provostial Professor and director of the Presence Center. "Patients want us to be more present. And we as physicians want to be more present with our patients, because without that contact, our professional life loses much of its meaning."

Systematic change is needed

Zulman said the researchers see the Presence 5 measures as just one step to address frustrations with modern-day medicine.

"While we might not be able to change the system overnight, our study suggests there are some concrete, evidence-based strategies that we, as physicians, can use that will help preserve and foster the connections that are most healing for patients and for us as physicians," she said.

What The Study Did: Researchers pooled data from four large study groups with 250,000 women to estimate the association between using body powder in the genital area and risk of ovarian cancer.

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

Authors: Katie M. O'Brien, of the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, is the corresponding author.

(doi:10.1001/jama.2019.20079)

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.

WASHINGTON, D.C., January 7, 2020 -- Doctors have used focused ultrasound to destroy tumors without invasive surgery for some time. However, the therapeutic ultrasound used in clinics today indiscriminately damages cancer and healthy cells alike.

Most forms of ultrasound-based therapies either use high-intensity beams to heat and destroy cells or special contrast agents that are injected prior to ultrasound, which can shatter nearby cells. Heat can harm healthy cells as well as cancer cells, and contrast agents only work for a minority of tumors.

Researchers at the California Institute of Technology and City of Hope Beckman Research Institute have developed a low-intensity ultrasound approach that exploits the unique physical and structural properties of tumor cells to target them and provide a more selective, safer option. By scaling down the intensity and carefully tuning the frequency to match the target cells, the group was able to break apart several types of cancer cells without harming healthy blood cells.

Their findings, reported in Applied Physics Letters, from AIP Publishing, are a new step in the emerging field called oncotripsy, the singling out and killing of cancer cells based on their physical properties.

"This project shows that ultrasound can be used to target cancer cells based on their mechanical properties," said David Mittelstein, lead author on the paper. "This is an exciting proof of concept for a new kind of cancer therapy that doesn't require the cancer to have unique molecular markers or to be located separately from healthy cells to be targeted."

A solid mechanics lab at Caltech first developed the theory of oncotripsy, based on the idea that cells are vulnerable to ultrasound at specific frequencies -- like how a trained singer can shatter a wine glass by singing a specific note.

The Caltech team found at certain frequencies, low-intensity ultrasound caused the cellular skeleton of cancer cells to break down, while nearby healthy cells were unscathed.

"Just by tuning the frequency of stimulation, we saw a dramatic difference in how cancer and healthy cells responded," Mittelstein said. "There are many questions left to investigate about the precise mechanism, but our findings are very encouraging."

The researchers hope their work will inspire others to explore oncotripsy as a treatment that could one day be used alongside chemotherapy, immunotherapy, radiation and surgery. They plan to gain a better understanding of what specifically occurs in a cell impacted by this form of ultrasound.