The importance of gut microbiota in C. difficile pathogenesis

Clostridium difficile infection (CDI) is a major cause of healthcare-associated infections worldwide. CDI can cause symptoms from mild diarrhea to life-threatening toxic megacolon. Antibiotics disrupt the normal intestinal microflora enabling C. difficile to proliferate in the colon and produce toxins. Currently, restoring the gut microflora through methods such as fecal microbiota transplantation is one of the most effective approaches for the treatment of CDI (read the review). Determining which components of the gut microbiota are required for protection against CDI remains unclear.

Posted by Dr. Tim Sandle

How to write a good science article

Science can easily be misreported, especially for the wilder headline seeking claims. How can a good science article be structured? Can “good science” be rendered bad from poor reporting or, more seriously, can “bad science” be presented as credible through poor reporting? The answer is yes — especially with the latter as countless articles claiming to have found the cure for cancer or encouraging people to eat a probiotic yogurt or munch on pomegranate seeds in order to cure all manner of ills would testify.

Laboratory technician testing water samples

Tim Sandle

One problem with science is its often slow progress, incremental findings, and occasional contradictions. As science blogger David Berreby has written recently, a concern with science is “there are many experiments, some of which contradict each other, some of which don't reproduce or are reinterpreted to mean something other than what their originators intended. With three steps forward and two back and one sideways, usually, with serious people saying we're marching in the wrong direction, science moves along.”

Taking this into account, there are three main types of science story:

Writing about a key scientific discovery (e.g. a bionic fingertip);

A story an intriguing or controversial scientist (like James Watson);

A scientific subject or concept that can be shown in process (e.g. fighting cancer with nanoparticles).

With these issues in mind, it’s still possible to write about science in a meaningful and engaging way.

Digital Journal

My top tips for good science writing are:

1. Be skeptical of things that claim to be “new.” Things that are “new” are either not so new since there are other studies having covered similar ground; or the research really is so new that no one else has attempted it and the results are therefore not reproducible.

2. Avoid, if possible, research that has not been published in a peer-reviewed journal. Papers submitted to conferences are the only exception since these will subject to rigorous debate.

3. Always cite the original science paper. Press releases, even research briefs, are full of headline-grabbing stuff but they are often produced by universities or government bodies, seeking to get the story to a media outlet. Sometimes they exaggerate the scientific findings and sometimes they misrepresent it. A key reason being is they are often written by PR people and not the authors of the paper.

4. If there’s a chance for a primary source, like a direct quote from a researcher, then take it – it helps put the findings into context.

5. Look out for related news and parallel studies; that adds an extra interest to the research being reported and shows its wider application. This can help, given the true significance of most research won’t often be known for several years.

6. If you are writing about science and you think the results or findings (or the interpretation) is questionable, then say so. Don’t simply reproduce “poor science” in an unquestioning way.

7. See if there were any vested interests with the research, such as who funded it. Sometimes this can ‘influence’ the direction of the research.

8. Treat the reader with respect.

In terms of where to go, some general news websites are better for science coverage than others and are better at presenting science stories in a more factually accurate way. Examples include BBC, The Guardian, New York Times, Scientific America, New Scientist and Wired.

To add to this, science journalism is not only about the "latest science," it can also be about “bad science” or scientific fraud. One good writer is Ed Yong, who runs investigative reports in the magazine Science.

Test tubes and other recipients in chemistry lab

Horia Varlan

There are also, occasionally, science scams. Sometimes this is the case of "Chinese whispers," where one journalist misinterprets a story and others repeat it; another way is when false information is put out to see how many journalists run with it. Here caution is required.

One classic example is with an invented material called "boimate." The foodstuff was said to be a mix of tomatoes and beef, put out as a joke by New Scientist. The story about the food was run by several reputable periodicals. Another scam is with fake journals, with slightly misspelled names.

A more recent example was the hoax that chocolate was good for your health. This was invented by John Bohannon, who set up a fake open access journal and website. The aim was to see how many websites and magazines ran with the story, without critically appraising it. Incidentally, Digital Journal didn't fall for the trick and we wrote our own review of what had taken place.

In terms of approaching a science article, try to:

1. Summarize what the research is about early on.

2. Avoid jargon where possible – science has a conspicuously compact and jargon-laden language. If technical terms are required, attempt to define them otherwise the reader’s interest will be lost.

3. Then go into detail about the research – what method was used. Use occasional metaphors and analogies, if this helps.

4. Then explain the significance of the research, without this the research won’t mean much to the reader and it becomes an article about ‘science research for science’s sake.’ Here it is important to try to bridge the gap between scientific research and people’s everyday lives.

5. If there is more than one point of view, to represent this were applicable.

6. Discuss any future applications, including where the research may go next.

7. Link to the research paper or conference proceedings.

8. Mention any related research likely to be of interest to the reader.

One question that is useful to keep in the forefront is "How can I sum up this topic in just one or two sentences that will make audiences want to read more?"

If you haven’t written a science article and want to try it, hopefully, these tips and ideas will be of benefit.

Class of drugs effective against Marburg virus and Ebola

A new drug has shown promise against both Marburg virus and Ebola. This may not be as surprising as it first seems, given the genetic similarities between the two viruses.

Filoviruses cause two types of viral haemorrhagic fever: Marburg and Ebola. Both Marburg virus and Ebola are deadly and contagious, being rated as the highest biohazards (at level 4.) Given the similar types of viral structure, researchers are attempting to develop therapies against both diseases.

Marburg virus causes severe disease in humans and nonhuman primates. It has received less coverage in the news than Ebola (unsurprising given the 2013-2015 issues in West Africa); it nonetheless requires study, given its potential to become an epidemic.

Scientists based at the University at Chicago have found that the way the two viruses try to enter host cells to replicate themselves can be blocked using the same class of drug. Moreover, this drug type is already in use.

The blocking mechanism comes from an understanding of how the Ebola and Marburg viruses gain entry into host cells. This is through a cell surface receptor which acts as a gateway. The cell surface receptor is formed from a protein class termed GPCR. There are thousands of different GPCRs in humans. These proteins are located on the surface of cells and it mediates several types of biological processes. Today, many types of drugs as designed to act via such gateway proteins.

The research group screened over 1,000 compounds and discovered that 20 GPCR antagonists demonstrated the ability to prevent the Ebola and Marburg viruses from entering host cells.

This finding opens up a new avenue of research. It should be possible to develop GPCR antagonists that can be effective against both Ebola and Marburg viruses. The research is published in the Journal of Virology, in a paper headed “Inhibition of Ebola and Marburg viral entry by G protein-coupled receptor.”

Posted by Dr. Tim Sandle

Research draws a connection between shingles and stroke

A new study has drawn a connection between the virus that causes the skin rash shingles with an increased chance of suffering from a stroke in later life.

The connection has been made by the American Academy of Neurology. Here researchers, from a review of medical data, connected the virus causing the diseases of chicken pox and shingles to problems with arteritis. Medical data indicated the virus to be found in 74 percent of the biopsies relating to the condition giant cell arteritis; whereas it was associated with just 8 percent of normal skin biopsies.

Shingles is caused by the virus herpes zoster. It describes a disease characterized by a painful skin rash with blisters. Symptoms of the condition, which affects 20-30 percent of adults, include a burning rash, together with headache, fever, and malaise.

Giant-cell arteritis is an inflammatory disease of blood vessels, commonly occurring in the large and medium arteries of the head. Symptoms include aching and soreness in and around the temples; jaw muscle pain while eating; and vision loss. The condition has been associated with strokes.

The new study connects increased rates of acute cardiovascular events such as ischemic stroke. In terms of epidemiology, it is established that many people who have had chicken pox in their childhood can contract shingles. Most often this is once a person reaches their 60s. It is unknown why the virus, which has remained dormant for decades, re-activates.

For the sample population, researchers drew on 42,954 Medicare beneficiaries in the U.S. This group had received a herpes zoster diagnosis (the virus responsible) and an ischemic stroke. In addition, these considered 24,237 beneficiaries who had myocardial infarction as well as a herpes zoster diagnosis during a 5-year period.

It was found among those diagnosed with herpes zoster, this group had a 2.4-times higher chance of an ischemic stroke occurring and a 1.7 times higher chance of myocardial infarction occurring during the first week after the herpes zoster virus causes symptoms of shingles. The risk then decreased over the 6 months following the herpes zoster diagnosis.

The research is published in the journal Public Library of Science Medicine, in a paper titled “Acute Cardiovascular Events after Herpes Zoster: A Self-Controlled Case Series Analysis in Vaccinated and Unvaccinated Older Residents of the United States.”

Posted by Dr. Tim Sandle

New 'layer' of fungi exposed

In order to optimally utilise fungi, and to fight them when necessary, we require greater insight into the functions that they can perform. Researchers at TU Delft and Utrecht University have exposed a new layer of functional complexity in fungi. They published their findings in Nature Scientific Reports.

The researchers used Schizophyllum commune as a model for their study of the functional consequences of the products of alternative splicing in fungi. This gave them evidence indicating the presence of thousands of extra products -- more than any other fungus studied. These alternative products may function as important regulators for the processing of nutrients.

The reference is:

Thies Gehrmann, Jordi F. Pelkmans, Luis G. Lugones, Han A. B. Wösten, Thomas Abeel, Marcel J. T. Reinders.Schizophyllum commune has an extensive and functional alternative splicing repertoire. Scientific Reports, 2016; 6: 33640 DOI: 10.1038/srep33640

Posted by Dr. Tim Sandle

Pharmig news # 65

A new edition of Pharmig news has been issued (edition 65). In this issue there is an article on the revision to the USP chapter (1231) on pharmaceutical water by Tim Sandle. There is also an article on the microbiological quality of non-sterile pharmaceutical products from M. Ratajczak and colleagues.

The magazine also includes a comprehensive regulatory round-up and the latest of Pharmig courses.

Copiers will have been sent to each member site. If you are not a member of Pharmig (Pharmaceutical Microbiology Interest Group) and you’d like to see a copy, please contact Pharmig.



Posted by Dr. Tim Sandle

A new class of antibiotics?

Researchers have made detailed, atomic-level images of a peroxiredoxin, which has revealed a peculiar characteristic of this protein that might form the foundation for an entirely new class of antibiotics.

Peroxiredoxin is needed by all cells to help eliminate hydrogen peroxide, a toxin, and in normal cells this process is healthy and valuable. But peroxiredoxins inside bacteria also help provide protection from our immune cells and increase the virulence of bacterial cells that cause infections.

The researchers were able to visualize peroxiredoxin chemistry in action. They found that when it's restrained and loses its mobility, it also loses its function. And if the normal function is lost, it can lead to cell death.

If a molecule can be found that selectively blocks the motions of peroxiredoxin only in bacterial cells -- which the researchers believe may be possible -- it could function as an entirely new way to kill those cells. This would leave normal cells undamaged and set the stage for new types of antibiotics.

With the increasing problem of antibiotic resistance to many existing drugs, this approach could have significant value, researchers said. It might also work in synergy with existing antibiotics to improve their efficacy.

For further details see:

Arden Perkins, Derek Parsonage, Kimberly J. Nelson, O. Maduka Ogba, Paul Ha-Yeon Cheong, Leslie B. Poole, P. Andrew Karplus. Peroxiredoxin Catalysis at Atomic Resolution. Structure, 2016 DOI: 10.1016/j.str.2016.07.012

Posted by Dr. Tim Sandle

Risk Assessment and Management for Healthcare Manufacturing

Tim Sandle has published a new book titled “Risk Assessment and Management for Healthcare Manufacturing: Practical Tips and Case Studies.”

Avoidance of hazards and assessment of risk have long been part of the manufacture of pharmaceuticals and healthcare products. A high quality drug product must be free from contamination and reliably deliver the intended therapeutic dose as stated on the label and to achieve this manufactures must always be mindful of risk.

Tim Sandle's newest book incorporates regulatory perspectives, scientific methods and practical examples to describe approaches to problem solving when assessing, managing and reviewing risk. The book is divided into four sections that present a formal approach to risk. The first section provides a look at risk assessments and hazards, exploring the origins, looking at key concepts and philosophies and assessing the regulatory perspective. An overview of available tools for risk assessment and problem solving leads into specific 'soft skills' that can help to run an effective meeting, oversee a project and report root cause analysis and risk outcomes. The book concludes with an extensive set of case studies to show real-world applications of the tools and techniques presented. The wide range of topics presented throughout the four sections includes risk considerations for aging pharmaceutical facilities, application of quality risk management to cleanroom design and process incident investigation.

Further details about the book and ordering details can be found via the PDA Bookstore: https://store.pda.org/ProductCatalog/Product.aspx?ID=3329

The contents of the book are:

Part A: Risk Assessment and Hazards

• Risk Assessment and Risk Management
• Regulatory Perspectives on Risk
• Pharmaceutical Processing Hazards
• Root Cause Analysis

Part B: Risk Assessment Tools and Problem Solving Approaches

• Question Based Approaches: The "Five Whys" and "What if" Methods
• Is/Is not Approach
• Simple Risk Assessment Tools
• Fishbone (Ishikawa) Diagram
• Contradiction Matrix and Knot Charts
• Pareto Charts and Control Charts
• Hazard Analysis and Critical Control Points
• Failure Modes and Effects Analysis
• Monte Carlo Method
• Fault Tree Analysis
• Hazard and Operability Study
• Six Sigma and Associated Quality Tools

Part C: Practical Tips

• Effective Meetings and the Process of Brainstorming
• Project Management and Research
• Reporting Risk Outcomes

Part D: Case Studies

• Application of Quality Risk Management to Cleanroom Design
• Case Study: Hepa Filter Failure
• Aseptic Transfer Risk Assessment: A Case Study
• Importance of Risk Assessment for Aseptic Transfer in Pharmaceutical Compounding
• Risk Assessment for Intervention Scoring in Relation to Aseptic Processing
• General Considerations for the Risk Assessment of Isolators Used for Aseptic Processes
• Risk Considerations for the Use of Unidirectional Airflow Devices
• Risk Consideration for Aging Pharmaceutical Facilities
• Process Incident Investigation
• Addressing Manufacturing Constraints by Increasing Production Throughput
• Risk Assessment of Production Formulation Stages
• Risk Based Approach to Internal Quality Auditing
• Risk Assessment for Data Integrity
• Assessment of Raw Material Handling and Expiration
• Risk Management and the Supply Chain
• Risks Associated with Clinical Trials
• Application of Risk Assessment to Develop an Environmental Monitoring Program
• Detection and Risk: Environmental Monitoring Data Deviations
• Application of Risk Assessment for Personnel Safety
• Risk Considerations for the Installation of a New Pharmaceutical Facility Autoclave
• Safety Risk Assessment for the Ozonation of a Purified Water System
• Error Risk Reduction: Concept and Case Study

The reference is:

Sandle, T. (2016) Risk Assessment and Management for Healthcare Manufacturing: Practical Tips and Case Studies, PDA / DHI, Bethesda, MD, USA.

Posted by Dr. Tim Sandle

Shingles And Asthma Linked Together

A new study has connected shingles to increased rates of acute cardiovascular events such as ischemic stroke. The same research, from the Mayo Clinic, has drawn a connection between developing shingles and asthma.

Shingles (caused by the virus herpes zoster) is a disease characterized by a painful skin rash with blisters. Symptoms include a burning rash, together with headache, fever, and malaise.

Moreover, research indicates that childhood asthma to be linked to higher risk of developing shingles as an adult. This was derived at after a review of medical records from adults aged 50 and over from Olmsted County, Minnesota. These data were cross-referenced with the frequency of asthma in people diagnosed with shingles.

It was found that the mean (average) age of the patients with shingles was 67 years. Using logistic regression, the researchers calculated that adults who had asthma had a 70% higher risk of developing shingles as compared with those without asthma.

The inference from this study is that older adults with asthma should consider being immunized against shingles by vaccination.

Speaking with Medline, Dr. Young Juhn, a general academic pediatrician and asthma epidemiologist at the Mayo Clinic Children's Research Center, noted: “As asthma is an unrecognized risk factor for zoster [shingles] in adults, consideration should be given to immunizing adults aged 50 years and older with asthma or atopic dermatitis as a target group for zoster [shingles] vaccination.”

Research detailing the connection has been published in the Journal of Allergy and Clinical Immunology. The research is titled “Asthma as a risk factor for zoster in adults: A population-based case-control study.”

Posted by Dr. Tim Sandle

EMA paper on production of water for injections (WFI) by non-distillation methods

The European Medicines Agency has published a question and answer paper on the production of water for injections (WFI) by non-distillation methods.

Water for injections in bulk is obtained from water that complies with the regulations on water intended for human consumption laid down by the competent authority or from purified water. It is produced either:

·         By distillation in an apparatus of which the parts in contact with the water are of neutral glass, quartz or a suitable metal and which is fitted with an effective device to prevent the entrainment of droplets; or

·         By a purification process that is equivalent to distillation. Reverse osmosis, which may be single-pass or double-pass, coupled with other appropriate techniques such as electro-deionisation, ultrafiltration or nanofiltration, is suitable. Notice is given to the supervisory authority of the manufacturer before implementation.

The reference is:

EMA/INS/GMP/489331/2016: Questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies

Posted by Dr. Tim Sandle

Will Big Data Influence Pharmaceuticals for the Better?

Today, it feels like everything is connected. You can access your files from a computer, a smart phone, a tablet or any other interconnected device — and that only accounts for your own personal files and devices.

Guest post by Megan Ray Nichols

Cloud storage and other big data creations have changed the way we look at and store information. What impact will these changes have on the pharmaceutical industry? Will these changes be able to alter the industry for the better, or could they possibly present new problems?

Waiting for Answers

One of the biggest problems researchers face in the pharmaceutical industry is the fact that information, in general, is treated as a proprietary and closely guarded secret. Individual researchers and companies spend a lot of time keeping their data protected from outside influence. They spend so much time protecting their information that when it comes time to share with the public, the investors, or other pharmaceutical companies, it becomes difficult or nearly impossible to disseminate the information.

Many companies have started to share their raw clinical trial information with the industry, but it’s a slow process. In the meantime, the data that might lead to the next wonder drug or medical breakthrough is sitting in limbo, gathering virtual dust because it can be so difficult to access.

Genomics and Data

One of the biggest uses for big data in the pharmaceutical industry is in the field of genomics. You need a lot of space and quite a bit of computing power to sequence a human genome — when you’re dealing with 25,000 genes and three billion base pairs of DNA, you’re looking at about 1.5 gigabytes of storage per genome sequenced. To put it in perspective, that’s about the size of a 1080p movie file.

If you’re sequencing the genomes of a couple hundred test subjects, you may find yourself carting around dozens of heavy hard drives in order to carry all of that information. Alternatively, though, you could look into cloud data storage.

The ability to share genomic data via cloud technology has two main benefits. First, it cuts down on the amount of physical storage space you need. All that’s required is a computer with Internet access to connect to all of your data.

Second, it makes it easier and faster to share raw research data with the rest of the pharmaceutical community. If a researcher in Tokyo makes a discovery that could shake the entire industry to its core, they don’t have to sit through the peer review process, waiting weeks or months to publish a paper that could change the world. All they have to do is upload their research to the cloud. It’s as simple as that.

Now, most researchers aren’t uploading their publishable discoveries, preferring instead to share their raw research data, but the platform is still there to provide a stepping stone for genomic data discoveries.

Quantifying Data

While cloud storage is a great platform for sharing research data, that’s not the only thing it’s good for. It can also be used to help researchers quantify the raw data that has been placed in the cloud.

Having sequenced genome information stored for a variety of different subjects is great, but it can be a bit daunting to sift through if you’re specifically looking for subjects of a specific race, gender or age.

Cloud storage, when paired with a little bit of simple software, allows researchers to search through the stored data to find specific traits without having to pick through each individual genome to find what they’re looking for. Cambridge Semantic’s program Semantic Web is just one of the tools researchers can use to sift through the raw data to find the traits they’re looking for.

Crowdsourcing Our Genetics
Crowdsourcing has become a great tool for people who need to raise money, gather information, or in many cases, even make dramatic scientific discoveries. Stanford’s Folding@Home Project, for example, has been using personal computers around the globe for 16 years to find the answers to puzzles that have otherwise eluded scientists.

FoldIt, on the other hand, is a more interactive game that allows users to actively work toward the solution rather than watching the proteins passively fold. In 2011, users found the answer to a problem that had eluded scientists for 15 years. The amazing part is that collectively, FoldIt players were able to find the answer in three weeks.

If big data can do that for the pharmaceutical industry while just using random Internet visitors, imagine what they could do with a crowd of industry professionals around the globe?

Risks vs. Rewards
Bringing big data into the pharmaceutical industry has the potential for great rewards. Unfortunately, whenever you bring the Internet into the data equation, there’s always some risk as well.

The first risk you take is that the data you’re going to find is just random junk with no real use or application. Even if you severely limit the number of people who can access your data cloud, there’s still a chance that someone will upload some useless data that could potentially skew any and all results.

The second, and arguably the most dangerous risk, is data privacy. All it takes is one person with nefarious intentions gaining access to your data cloud, and all of your patient’s information could be at risk. Hackers are targeting medical information now more than ever because it’s more valuable than credit card information and not checked nearly as often.

It is possible to reduce this risk by removing personal information from the data, beyond the bits of information needed to classify the raw information. Removing names, insurance information and other personal identifiers can help to protect your subjects while still allowing you to take advantage of the raw study data.

What It Means for Big Data and Pharmaceuticals

Overall, the use of Big Data in the pharmaceutical industry is going be a force for great good and the launching point for many ingenious advances in the industry. There’s no telling what amazing things will fall from that cloud next!

Moist-heat sterilization of blood bags

Vittorio Mascherpa has written an interesting article on the sterilization of blood collection bags. The abstract reads:

“This article provides basic information on the sterilization of blood bags systems by moist-heat. Problems of pressure compensation and steam penetration into the system parts without water inside, and the process choice between single and double autoclaving are discussed.”

The article can be accessed here.

Posted by Dr. Tim Sandle

WHO guidance on variations to multisource pharmaceutical products

The World Health Organization has updated Annex 10 of its GMPs “WHO general guidance on variations to multisource pharmaceutical products.”

According to the document:

“A marketing authorization (MA) holder or applicant is responsible for the quality, safety and efficacy (QSE) of a finished pharmaceutical product (FPP) that is placed on the market, throughout its life cycle. After the FPP has been authorized for marketing, the manufacturer will often wish to make changes (variations) for a number of reasons, for example, to respond to technical and scientific progress, to improve the quality of the FPP, to apply updates to the retest period for the active pharmaceutical ingredient (API) or shelf life of the FPP, to meet market requirements such as for scale-up or additional manufacturing sites, or to update product information (e.g. the information on adverse reactions). Such changes, regardless of their nature, are referred to as variations and may require the approval of the national medicines regulatory authority (NMRA) prior to implementation.”

The document can be accessed here.

Posted by Dr. Tim Sandle

History of Pharmig

The history of the Pharmaceutical Microbiology Interest Group (Pharmig)

History of Pharmig by Tim Sandle on Scribd

Posted by Dr. Tim Sandle

More flexibility for authorisation of biocidal products

News on the regulation of biocides in Europe:

ECHA/NA/16/31

The regulation on the authorisation of same biocidal products has been updated to add new possibilities requested by industry. Companies are now able to get a national authorisation when a Union authorisation application exists for an identical product. The regulation will enter into force on 1 November.

Helsinki, 12 October 2016 – The Same Biocidal Products Regulation lays down a procedure for companies to get a secondary authorisation for a product based on either an existing authorisation or an on-going authorisation application for an identical product.

• Following the update of the regulation, companies can now also use this authorisation procedure for:
• a product when it is part of a product family for which an authorisation (or authorisation application) exists;
• a product family when it is part of a larger product family for which an authorisation (or authorisation application) exists;
• national authorisation when a corresponding Union authorisation (or authorisation application) exists.

The regulation was updated by the European Commission after a request from industry stating that the changes would help reduce the costs and administrative burden for companies.

The regulation was published in the Official Journal of the European Union on 12 October and will enter into force on 1 November 2016.

To allow for the new possibilities, ECHA will launch updated versions of the biocides IT tools – R4BP 3 and the SPC Editor – when the regulation enters into force.

Support will be available: a new web page, a practical guide and updated submission manuals will be published and a webinar on this topic will take place on 9 November 2016.

Source: ECHA

Posted by Dr. Tim Sandle