Lancet Commission calls for reform in Regenerative Medicine research

A Lancet commission of senior scientists has demanded root and branch reform of the way experimental therapies associated with Regenerative Medicine are carried out.

The commission, led by cell biologist Professor Giulio Cossu from The University of Manchester, says the specialism is held back by poor quality science, unrealistic hopes, unclear funding models and unscrupulous private clinics.

Professor Cossu said: “The Commission finds that a major rethink of the social contract that supports regenerative medicine is required if it is to shift from mostly small-scale bespoke experimental interventions into routine clinical practice”.

The past 10 years have seen an exponential growth in experimental therapies which include tissue engineering and cell and gene therapy.

However, though there has been some undeniable success in finding new ways to treat previously incurable diseases, such as gene therapy for congenital immune deficiencies, most therapies have had modest or no effect.

And products involving cells, genetically manipulated cells, viral vectors, or biomaterials with or without cells are costly and often produced in limited numbers.

The commission also argues that numbers of poorly controlled trials and poorly regulated clinics have grown in recent years.

Commission members include senior scientists from University College London, the University of Manchester, Oxford and Bristol Universities.

Although public investments in this field are massive internationally, they argue, they do not carry guaranteed commercial returns and follow a highly uncertain route to market.

The report argues: “New therapies expose patients to risks, some of which are difficult to predict even with inbuilt safeguards.

“Despite the relatively small number of clinical successes, there are gaps between people’s expectations, often inflated by media reports, and the realities of translating regenerative technologies into clinical practice.

“These ethical and governance issues pose a challenge to scientists in engaging with the public, the press, and decision- making bodies in different national health systems.

“In poorly regulated states, the authorization of a novel therapy might be politically attractive, even when efficacy is unconfirmed, and the burden for taxpayers could deprive other patients of established and effective therapies.”

The Commission recommends a coordinated strategy with four pillars: better science, better funding models, better governance, and better public engagement.

Dr Richard Horton, editor-in-chief of The Lancet, said: “Regenerative medicine offers transformative potential for the future of patient care. But that potential could be jeopardised by low quality research and a loss of public trust in stem cell science. This Lancet Commission sets out the societal opportunities of regenerative medicine. It also makes critical recommendations for protecting and strengthening both the quality of research and public confidence in this important and exciting new branch of medical science.”

Recommendations of the Commission include:

  • More investment to develop clinician scientists to facilitate the transition from preclinical to clinical work; more academic good medical practice facilities should be created to make trials more affordable
  • Prioritising research into how celland gene therapies can become cost-effective and scalable
  • An international register of cell and biological experimental interventions
  • Policy developed by the International Committee of Medical Journal Editors so that trials reporting results of cell and biological therapies will not be published unless trials have been registered in the proposed international register
  • Researchers and others involved in funding, publishing, and communicating stem cell research should integrate public dialogue into their research.
  • doi: 10.1016/S0140-6736(17)31366-1

US NIH completes atlas of human DNA differences that affect gene expression

Researchers funded by the US National Institutes of Health have completed a detailed atlas documenting the stretches of human DNA that influence gene expression – a key way in which a person’s genome gives rise to an observable trait, like hair colour or disease risk. This atlas is a critical resource for the scientific community interested in how individual genomic variation leads to biological differences, like healthy and diseased states, across human tissues and cell types.

The atlas is the culmination of work from the Genotype-Tissue Expression (GTEx) Consortium, established to catalogue how genomic variation influences how genes are turned off and on.

“GTEx was unique because its researchers explored how genomic variation affects the expression of genes in individual tissues, across many individuals, and even within an individual,” said Simona Volpi, Ph.D , program director for GTEx at the National Human Genome Research Institute (NHGRI), who oversaw various parts of the project.

According to Dr Volpi, there was previously no resource at the scale used by GTEx that enabled researchers to study how gene expression in the liver might be different than in the lung or heart, for example, and how those differences relate to the inherited genomic variation in an individual.

Researchers involved in the GTEx Consortium collected data from more than 53 different tissue types (including brain, liver and lung) from autopsy, organ donations and tissue transplant programs. These tissues came from approximately 960 donors in total.

“GTEx depended entirely on families choosing to donate biosamples for research after the death of a loved one,” said Susan Koester, Ph.D., deputy director for the Division of Neuroscience and Basic Behavioral Science and GTEx program director at the National Institute of Mental Health (NIMH). “GTEx researchers are deeply grateful for this priceless gift.”

The project continues to house a biobank of collected tissue samples, as well as extracted DNA and RNA for future studies by independent researchers. The summary-level data are available to the public through the GTEx Portal , and the most recent release of the raw data has been submitted to the Database of Genotypes and Phenotypes (dbGaP) , an archive of results from studies that investigate the genomic contributions to phenotypes (physical characteristics or disease states).

GTEx launched in 2010 and concluded in the summer of 2017. It was supported by the NIH Common Fund and administered by NHGRI, NIMH and the National Cancer Institute, all part of NIH.

As one example of how the atlas can be used, a new study published online in the journal Nature, describes the results of expression quantitative trait locus (eQTL) mapping in 44 different human tissues from 449 individuals. An eQTL is a small section of the genome that contributes to the differences in gene expression between genes and between individuals. Typically, eQTLs are identified by sequencing the genomes of genetically different individuals to determine the variation in the genome between those individuals. This is followed by determining how much each gene is being expressed. Lastly, the eQTLs are identified by establishing which specific variants are associated with differences in gene expression levels.

The authors of the study used GTEx data to catalog all known eQTLs in the human genome for the first time. As in the Nature study, GTEx data will help researchers understand the mechanisms of how genes are expressed in a variety of tissues, which will ultimately better inform our knowledge of how genes are mis-regulated in the context of disease. GTEx data can also be used to better understand the variations in gene expression that underlie differences among healthy individuals.

Although the GTEx project has officially wrapped up, plans for future work are already underway. An endeavour known as the Enhancing GTEx (eGTEx) project, which began in 2013, extends GTEx’s efforts by combining gene expression studies with additional measurements, such as protein expression. This work is being conducted on the same tissues as in the GTEx project, providing a richer resource that integrates the complexity of how our genomes function in biologically meaningful ways.

Read the studies:

  • doi: 10.1038/nature24277
  • doi: 0.1038/ng.3969

Cholera task force aims to reduce deaths by 90% by 2030

An ambitious new strategy to reduce deaths from cholera by 90% by 2030 was launched on 4 October 2017 by the Global Task Force on Cholera Control (GTFCC), a diverse network of more than 50 UN and international agencies, academic institutions, and NGOs that supports countries affected by the disease.

Cholera kills an estimated 95000 people and affects 2.9 million more every year. Urgent action is needed to protect communities, prevent transmission and control outbreaks.

The GTFCC’s new plan, Ending Cholera: A Global Roadmap to 2030, recognizes that cholera spreads in endemic “hotspots” where predictable outbreaks of the disease occur year after year.

The Global Roadmap aims to align resources, share best practice and strengthen partnerships between affected countries, donors and international agencies. It underscores the need for a coordinated approach to cholera control with countrylevel planning for early detection and response to outbreaks. By implementing the Roadmap, up to 20 affected countries could eliminate cholera by 2030.

“The World Health Organization is proud to be part of this new joint initiative to stop deaths from cholera. The disease takes its greatest toll on the poor and the vulnerable – this is quite unacceptable. This roadmap is the best way we have to bring this to an end,” said Dr Tedros Adhanom Ghebreyesus, Director General of the World Health Organization.

“Every death from cholera is preventable with the tools available today, including use of the Oral Cholera Vaccine and improved access to basic safe water, sanitation and hygiene as set out in the Roadmap,” said Dr Gebreyesus. “This is a disease of inequity that affects the poorest and most vulnerable. It is unacceptable that nearly two decades into the 21st century, cholera continues to destroy livelihoods and cripple economies. We must act together. And we must act now.”


1 in 10 infants not vaccinated

Worldwide, 12.9 million infants, nearly 1 in 10, did not receive any vaccinations in 2016, according to the most recent WHO and UNICEF immunization estimates. This means, critically, that these infants missed the first dose of diphtheria-tetanus-pertussis (DTP)- containing vaccine, putting them at serious risk of these potentially fatal diseases. Additionally, an estimated 6.6 million infants who did receive their first dose of DTP-containing vaccine did not complete the full, three dose DTP immunization series (DTP3) in 2016. Since 2010, the percentage of children who received their full course of routine immunizations has stalled at 86% (116.5 million infants), with no significant changes in any countries or regions during the past year. This falls short of the global immunization coverage target of 90%.

“Most of the children that remain un-immunized are the same ones missed by health systems,” says Dr Jean-Marie Okwo-Bele, Director of Immunization, Vaccines and Biologicals at WHO. “These children most likely have also not received any of the other basic health services. If we are to raise the bar on global immunization coverage, health services must reach the unreached. Every contact with the health system must be seen as an opportunity to immunize.”

Immunization currently prevents between 2–3 million deaths every year, from diphtheria, tetanus, whooping cough and measles. It is one of the most successful and cost-effective public health interventions.

National coverage estimates often mask large inequities in coverage within countries. The WHO report, State of inequality: Childhood immunization, highlights inequalities in childhood immunization coverage in low- and middle-income countries over the past 10 years. The report shows that global improvements have been realized with variable patterns of change across countries and that there is generally less inequality now than 10 years ago.

These findings were reinforced by a recent UNICEF study, which emphasized the cost effectiveness of investing in the poorest, most marginalized communities.

“Immunization is one of the most proequity interventions around,” says Dr Robin Nandy, Chief of Immunizations at UNICEF. “Bringing life-saving vaccines to the poorest communities, women and children must be considered a top priority in all contexts.”

Efforts to reduce inequalities related to household economic status and mother’s education are needed in many countries if immunization coverage is to be improved. Additionally, more than half of the global population resides in urban areas, including in rapidly growing slums in Africa and Asia. The urban poor is a group at high risk of being un- or under-immunized.


Artemisinin resistance develops in SE Asia

The spread of artemisinin resistance in Plasmodium falciparum and the subsequent loss of partner antimalarial drugs in the Greater Mekong subregion presents one of the greatest threats to the control and elimination of malaria, according to a September 2017 report in The Lancet, Infectious Diseases journal.

This is alarming as there is a danger that the resistant strains will spread from Southeast Asia to tropical Africa as has been seen from the previous experience with resistance to chloroquine, sulphadoxine/pyrimethamine (Fansidar) and mefloquine.

Artemisinin resistance is associated with mutations in the PfKelch gene. Initially multiple independent Kelch mutations were observed, but in a recent sinister development, a single dominant artemisinin-resistant P falciparum C580Y mutant lineage has arisen in western Cambodia, outcompeted the other resistant malaria parasites, and subsequently acquired resistance to piperaquine, according to the journal.

Cambodia had adopted dihydroartemisinin- piperaquine as 1st-line antimalarial treatment, but has now been forced toswitch its 1st line artemisinin combination treatment back to artesunate-mefloquine as a consequence.

This dominant multidrug-resistant parasite lineage, identified first in Pailin in western Cambodia and tentatively denoted as PfPailin, then spread to northeastern Thailand and southern Laos.

“We now find that the PfPailin lineage, with associated piperaquine resistance, has spread to the south of Viet Nam where it is responsible for alarming rates of failure of dihydroartemisinin- piperaquine -- the national 1st-line treatment,” the journal authors state

 


New assessment scale offers uniform standards to ascertain level of consciousness

More than half a dozen different examination scales are currently in use worldwide for assessing the level of consciousness of critically ill patients. At the World Congress of Neurology in Kyoto, researchers of the USA presented a new, composite tool that enables uniform assessment and could contribute to improved communication between different disciplines.

A new, simple clinical examination can often ascertain the level of the patients’ consciousness in neuro-critical care units more precisely than the examination scales currently in use. This is the conclusion of a study presented at the XXIII World Congress of Neurology (WCN 2017) in Kyoto in September.

There are more than half a dozen different scales in use worldwide to determine the level of consciousness in people suffering from impaired consciousness. One problem is that although all of the clinical assessment methods have proven reliability, they each apply a different set of criteria and rationale, which can make accurate diagnosis more difficult in day-to-day clinical operations.

“Neurologists, neurosurgeons, anaesthetists, psychiatrists, emergency rooms, intensive care units and prehospital disciplines all use differing terminology, different scales and different care routines for patients with impaired consciousness,” explained study author Dr Gregory Kapinos, Assistant Professor at Hofstra NorthwellSchool of Medicine in Manhasset, USA. “There is no consensus on defining drops in level or content of consciousness.”

To redress this situation, Dr Kapinos and his colleagues analysed the available examination scales. “We did not create a new assessment, but extracted the best components that were most pertinent or reliable from already standardized assessment methods,” Dr Kapinos says. “We also clarified the terminology used in different traditional scales.” The components extracted were recomposed into a larger new scale – the WCN scale. Established methods such as the Glasgow Coma Scale (GCS), the Richmond Agitation-Sedation Scale (RASS), the FOUR Score and the National Institutes of Health Stroke Scale (NIHSS) were compared with the newly composed tool.

The results were impressive: whether grading alertness, measuring response to specific stimuli, determining attention span or ascertaining integrative processing speed, the composite WCN scale can outperform the traditional assessment tools. “Our composite assessment method delivers significantly more consistent and valuable results than the standardized assessment methods,” Dr Kapinos said as a conclusion. “This means that members of different medical disciplines and nurses in neurological care can reach conclusions about degree of consciousness that are congruent and free from contradiction. Compared to commonly used consciousness scales, our tool offers precise terminology and better clinical documentation, providing a basis for improved inter-professional communication. And any deterioration is detected earlier.”

  • Bibliographic information
    WCN 2017 Abstract Kapinos et al, Proposing The WCN Scale: A Comprehensive Composite Assessment Of Consciousness In The Critically Ill Patient; XXIII World Congress of Neurology, Kyoto, Japan, 16-21 September

 


Outbreak of plague in Madagascar worries officials

ProMED-mail reports that an unusually deadly seasonal outbreak of plague has gripped the island nation of Madagascar. As of 6 October 2017, 258 have been sickened and 36 have died just since August 2017, according to Madagascar’s Ministry of Public Health. To try to stifle the spread, the government has forbidden public gatherings, including sporting events, and schools have closed for insecticide treatments that kill plague-spreading fleas. People have swarmed pharmacies, desperately seeking face masks and any antibiotics they can get. The WHO, on 6 October 2017, announced that it has released US$1.5 million in emergency funds and delivered nearly 1.2 million antimicrobial doses to help combat the outbreak.

Plague, caused by the bacterium Yersinia pestis, is endemic to Madagascar and pops up all year-round. But outbreaks can erupt between September to November, with seasonal shifts in rat and flea populations. Rats, which harbour the bacteria, tend to see their populations plump and peak around harvest times in July and August. A boom in the flea population, which transmits the disease, follows in tandem. But as crops are harvested and the weather cools, the rat population shrinks, and the surging, hungry batch of fleas turns to humans.

The report says the island has been battling the disease since it arrived there on steamboats from India in 1898. In recent years, the country has seen between 275 and 675 cases annually.

But this year is different. The disease is spreading not just in rural areas; it’s also spreading in cities. As of 30 September 2017, the disease had taken hold in 10 cities across the island, including the capital, Antananarivo.

“WHO is concerned that plague could spread further because it is already present in several cities and this is the start of the epidemic season, which usually runs from September to April,” Dr Charlotte Ndiaye, WHO representative in Madagascar, said. “Plague is curable if detected in time. Our teams are working to ensure that everyone at risk has access to protection and treatment. The faster we move, the more lives we save.”

It is also spreading in 2 different ways – by fleas and by people – which some have dubbed a “double plague”. Usually, plague infections arise as bubonic plague, spread by flea bites. In this case – the Black Death scenario Y. pestis moves from the site of a flea bite on a human to the lymphatic system, taking up residence and inflaming a lymph node. This causes a painful swelling called a bubo, where the infection gets its name. If it is left untreated, the infection can spread to the blood, causing septicaemic plague, or the lungs, causing pneumonic plague.

Pneumonic plague is the most severe form. It can become a life-threatening situation in just 24 hours and can begin to spread from person to person in droplets, coughed or sneezed. Most of the people infected in the current outbreak in Madagascar have the pneumonic form. Officials caught on to the outbreak on 11 September 2017, and cases have piled up since then.

Promed-MAIL explains that primary plague pneumonia has a short incubation period of 1-3 days, after which there is sudden onset of flu-like symptoms including fever, chills, headache, generalized body pains, weakness and chest discomfort. A cough develops with sputum production, which may be bloody, and increasing chest pain and difficulty in breathing. As the disease progresses, hypoxia and hemoptysis (coughing up blood) are prominent. The disease is invariably fatal unless antimicrobial therapy commences within 24 hours of exposure.

Patients with primary pneumonic plague generate large quantities of infectious aerosols that pose a significant risk to close contacts. CDC guidelines identify contacts within 2 meters [6.6 feet] as being at greatest risk and do not consider the organism likely to be carried through air ducts or vents. Persons who have been in contact with pneumonic plague patients or handling potentially infectious body fluids or tissues without appropriate protection should receive preventive antimicrobial therapy. The preferred antimicrobial agents for prophylaxis are tetracyclines, quinolones, or chloramphenicol.

 

Date of upload: 22nd Nov 2017

                                  
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