CDC Statement On Travel Warnings & Ebola Situation In West Africa

Credit CDC Ebola Outbreak Website

 

# 8900

 

In concert with today’s press conference, and travel warnings, the CDC has released the following statement on the Ebola situation – and their response – in Western Africa.

 

 

As West Africa Ebola outbreak worsens, CDC issues Level 3 Travel Warning

CDC surge scaling up response in Guinea, Sierra Leone, and Liberia

The Centers for Disease Control and Prevention (CDC) today issued a warning to avoid nonessential travel to the West African nations of Guinea, Liberia, and Sierra Leone. This Level 3 travel warning is a reflection of the worsening Ebola outbreak in this region.

CDC is rapidly increasing its ongoing efforts in the three nations. CDC disease detectives and other staff are on the ground:

• Tracking the epidemic including using real-time data to improve response
• Improving case finding
• Improving contact tracing
• Improving infection control
• Improving health communication
• Advising embassies
• Coordinating with the World Health Organization (WHO) and other partners
• Strengthening Ministries of Health and helping them establish emergency management systems

“This is the biggest and most complex Ebola outbreak in history. Far too many lives have been lost already,” said CDC Director Tom Frieden, M.D., M.P.H. “It will take many months, and it won’t be easy, but Ebola can be stopped. We know what needs to be done. CDC is surging our response, sending 50 additional disease control experts to the region in the next 30 days.”

CDC expects its efforts not only to help bring the current outbreak under control, but to leave behind stronger systems to prevent, detect and stop Ebola and other outbreaks before they spread.

In addition to warning travelers to avoid going to the region, CDC is also assisting with active screening and education efforts on the ground in West Africa to prevent sick travelers from getting on planes. On the remote possibility that they do, CDC has protocols in place to protect against further spread of disease. These include notification to CDC of ill passengers on a plane before arrival, investigation of ill travelers, and, if necessary, quarantine. CDC also provides guidance to airlines for managing ill passengers and crew and for disinfecting aircraft. Earlier this week, CDC issued a Health Alert Notice reminding U.S. healthcare workers of the importance of taking steps to prevent the spread of this virus, how to test and isolate suspected patients and how they can protect themselves from infection.

At this time, CDC and its partners at points of entry are not screening passengers traveling from the affected countries. It is important to note that Ebola is not contagious until symptoms appear, and that transmission is through direct contact of bodily fluids of an infected, symptomatic person or exposure to objects like needles that have been contaminated with infected secretions.

Over the next five years the United States has committed to working with at least 30 partner countries (totaling at least 4 billion people) to improve their ability to prevent, detect, and effectively respond to infectious disease threats -- whether naturally occurring or caused by accidental or intentional release of pathogens.

Improving these capabilities for each nation improves health security for all nations. Stopping outbreaks where they occur is the most effective and least expensive way to protect people’s health.

The President’s FY 2015 budget includes a request of $45 million to fund this global health security effort.

CDC: U.S. Issues Travel Warning To West African Nations With Ebola

 

# 8899

 

Although the CDC updated their Ebola travel advisories (Alert Level 2, Practice Enhanced Precautions) to Guinea, Sierra Leone and Liberia on Monday – today CDC Director Thomas Frieden announced an escalation to a Warning Level 3, Avoid Nonessential Travel – during a press conference.

 

While exposure to Ebola is a concern in these countries, the degradation of overall medical services in the region due to the Ebola outbreak was also cited as a reason for the decision to raise the alert level.

 

As of this posting, this travel warning has not been posted on the CDC’s Travel Health Notices website.

UPDATED 1415 hrs:

 

In describing the situation, Director Frieden stated that Ebola is worsening in Western Africa, and there are no quick or easy solutions, given the challenges in the region.  This outbreak is likely to continue for months to come, and the CDC is preparing to send 50 EIS (Epidemic Intelligence Service) officers to the region in the next month.

While the CDC is preparing for the possibility that an infected individual might arrive in this country via air travel (see CDC Teleconference & HAN Notice On Ebola), they also reassure that any significant spread in this country is unlikely due to its limited transmissibility, and our public health infrastructure.

 

Dr Frieden ended by stressing three key points (paraphrased).

 

• Ebola is worsening in West Africa.  It is the largest and most complex outbreak known to date. 
• CDC is surging their response in West Africa, and while it won’t be quick ot easy, they know what it takes to stop Ebola.  It will nr a marathon, not a sprint, and it will take 3 to 6 months . . . assuming things go right.
• We have strong systems in place to detect, isolate, and treat Ebola cases should they show up in the United States.

 

The CDC will likely have a transcript, and audio recording, from today’s teleconference posted on this website later today. 

VDU Blog: A Deeper Look At The MacIntyre MERS-CoV Paper

Credit FAO

 

 

# 8898

 

 

Yesterday, in  Debating A Controversial MERS Paper, we looked at a rebuttal in the online academic forum The Conversation - by researchers @influenza_bio, @MackayIM, @maiamajumder, @neva925, @stgoldst & @kat_arden -  of a controversial paper by Professor Raina MacIntyre  that suggested that the  `human release’  of MERS-CoV could be behind the erratic outbreaks we’ve seen in the Middle East.

At just over a thousand words, this rebuttal was geared for the general reader, and so a lot of details were glossed over.

 

Today Dr. Mackay and company have posted a much longer analysis of the MacIntyre paper – one that runs well over 3,000 words – which dissects the MacIntyre paper more thoroughly. 

 

While acknowledging that bioterrorism is always `possible’, they argue that – based on the evidence – it  is an extremely unlikely scenario for MERS.

 

Follow the link below to read:

 

Virus variability, dopey data and insufficient infection control do not support the theory that bioterrorism is behind the ongoing MERS-CoV outbreak.

A collaborative note from (alphabetically): @influenza_bio, @MackayIM, @maiamajumder, @neva925, @stgoldst, @kat_arden

Retraction Of Major Narcolepsy – Autoimmune Link Paper

Photo Credit CDC – Sleep and Sleep Disorders

 

# 8897

 

In August of 2010, roughly 9 months after the first vaccines for the pandemic H1N1 virus became available, we began to see reports of an increase in narcolepsy among children and adolescents in Northern Europe who had received a specific formulation of the vaccine; GSK’s Pandemrix ® (see Finland Suspends Use of Pandemrix Vaccine). 

 

In February of 2011, the Finnish National Institute for Health and Welfare released an interim report on what they  called  `a probable link’ between GSK’s Pandemrix vaccination, and an increase in narcolepsy in children and adolescents 4-19 years of age.  Two findings of note were:

 

• While the Pandemrix vaccine was taken by 31 million people across 47 countries, other than Finland, Sweden and Iceland, no other countries reported an increase in narcolepsy in 2010. 
• Iceland, unlike Finland, reported an increase in narcolepsy among unvaccinated children during this same time period.

 

As it turns out, Iceland wasn’t alone in seeing a spike in narcolepsy after the first pandemic wave, as a Stanford study appeared in August of 2011 in the Annals of Neurology called  "Narcolepsy Onset is Seasonal and Increased Following the H1N1 Pandemic in China", among a population who never received the flu vaccine.

 

While the cause of narcolepsy remains a mystery, it has long been  assumed to be an auto-immune disease, and so seeing spikes following a novel flu pandemic – or even  vaccination – made sense. Narcolepsy is probably more common than most people realize, with its prevalence estimated at being between 25 and 50 per 100,000 people.

The narcolepsy-Pandemrix link story continued with a series of studies and reports that found a link between the two, but not a cause.  While still a mystery, the point became somewhat moot, since Pandemrix was no longer in use.

 

That is, until December of 2013 when Immunologist Elizabeth Mellins and narcolepsy researcher Emmanuel Mignot at Stanford University School of Medicine published a paper in Science Translational Medicine  (Link) that was hailed as major breakthrough (see Ed Yong’s report in  Nature Narcolepsy confirmed as autoimmune disease) in understanding the disease.

Although I’m badly over-simplifying a complex paper, the authors found that a protein found in the brain – hypocretin – which helps keep us alert and awake, was similar enough to a protein in the H1N1 virus that the body’s immune system could occasionally mistake it for the virus and send T cells to destroy hypocretin-secreting-neurons, thus inducing narcolepsy.

 

This concept, known as “molecular mimicry”, was an elegant explanation, and was widely reported in the academic and mainstream press.  It also suggested that other infections could trigger similar reactions. 

That is, until yesterday when the paper was retracted by the authors.

This from  Stanford Medical News.

 

Stanford researchers retract study examining link between narcolepsy, H1N1

Stanford researchers have retracted a 2013 study that described a possible immunological connection between narcolepsy and the H1N1 influenza virus.

Jul 30 2014

A paper published Dec. 18, 2013, in Science Translational Medicine that described a possible immunological connection between narcolepsy and the H1N1 influenza virus is being retracted at the request of the authors at the Stanford University School of Medicine.

Sleep researcher Emmanuel Mignot, MD, PhD, a professor of psychiatry and behavioral sciences, and his co-authors requested the retraction because they were unable to replicate some of the results reported in the paper.

The journal published the retraction notice online today.

 

While this retraction doesn’t invalidate the theory that `molecular mimicry’ plays a role in the development of narcolepsy, it is now far from `confirmed’ as earlier reports indicated.

 

In a perfect world, the conclusions drawn from scientific research would always be unequivocal and we would be able to automatically accept their results as being the final word on any  subject.  But no research methodology is perfect, all studies are subject to limitations, and it isn’t unusual to end up with conflicting results from different research teams.

 

Science is often messy and there are few `Eureka!’ moments of sudden clarity. We usually get to the truth by fits and starts – and that can often take years or even decades to sort out.  

 

For some earlier blogs on the vagaries of research results, you may wish to revisit:

 

When Studies Collide 

When Studies Collide (Revisited)

Sierra Leone Declares State Of Public Emergency Over Ebola

 

# 8896

 

 

 

In a statement released last night on the Ebola crisis, Sierra Leone’s President Ernest Bai Koroma stated  `. . .  the disease is beyond the scope of any one country, or community to defeat. Its social, economic, psychological and security implications require scaling up measures at international, national, inter-agency and community levels.’

Noting that `Extra-ordinary challenges require extra-ordinary measures’, President Koroma officially declared a State of Public Emergency last night – expected to last  at least 60 to 90 days.  In his statement he outlined the following steps to be taken to combat the Ebola outbreak.

 

We are launching a National Response Plan to inaugurate Phase Two of our fight against the disease. I also hereby establish a Presidential Task Force on Ebola which I will chair to champion the implementation of the following:

• All epicenters of the disease will be quarantined;
• The police and the military will give support to health officers and NGOs to do their work unhindered and restrict movements to and from epicenters;
• Localities and homes where the disease is identified will be quarantined until cleared by medical teams;
• Public meetings and gatherings will be restricted with the exception of essential meetings related to Ebola sensitization and education;
• Active surveillance and house-to-house searches shall be conducted to trace and quarantine Ebola victims and suspects;
• Parliament is recalled to promote MPs leadership at constituency levels;
• Paramount chiefs are required to establish bye-laws that would complement other efforts to deal with the Ebola outbreak;
• Mayors, chairmen of councils and councilors are hereby required to support Ebola control measures in their local government areas;
• All deaths must be reported authorities before burial;
• New protocols for arriving and departing passengers have been instituted at the Lungi International Airport;
• Cancellation of all foreign trips by ministers and other government officials except absolutely essential engagements.

You can read the entire Presidential Statement at the link below:

 

Address to the Nation on the Ebola Outbreak By His Excellency The President Dr. Ernest Bai Koroma July 30, 2014

WHO Ebola Update – July 29th

 

# 8894

 

The World Health Organization African Regional Office has posted updated numbers on the Ebola outbreak.  Between July 24th and July 27th 122 new cases were reported, and 57 deaths.   Follow the link below to read the entire update.

 

Ebola virus disease, West Africa – update 29 July 2014

 

Epidemiology and surveillance

The World Health Organization (WHO) continues to monitor the evolution of the Ebola virus disease (EVD) outbreak in Sierra Leone, Liberia, Guinea and Nigeria. The Ebola epidemic trend in Sierra Leone, Liberia, and Guinea remains precarious, with continuing community and health-facility transmissions of infection.

Between 24 and 27 July 2014, a total of 122 new cases (suspect, probable, and laboratory-confirmed cases) as well as 57 deaths were reported from Liberia, Sierra Leone, Guinea and Nigeria.

The surge in the number of new EVD cases especially in Liberia, Sierra Leone and Guinea calls for concentrated efforts by all to address the identified problems such as health facility transmission and effective contact tracing.

In Nigeria, IHR focal person report confirms that the probable case notified was symptomatic at the time of arrival in Nigeria and that 59 contacts (15 from among the airport staff and 44 from the hospital) have been identified so far. The report also confirms that the patient travelled by air and arrived in Lagos, Nigeria, on 20th July via Lomé, Togo and Accra, Ghana.

The sample from this case is yet to be sent to the WHO Collaborating Centre at the Institute Pasteur in Dakar, Senegal, due to refusal by courier companies to transport this sample. Though only one probable case has been detected so far in Nigeria, Ebola virus infection in this country represents a significant development in the course of this outbreak.

The national authority in Nigeria, Togo and Ghana continue to work closely with WHO and partners in identification of contact and contact tracing as well as in preparing response plans.

(Continue . . .)

 

Hong Kong’s Ebola Response

Credit CDC PHIL

 

# 8893

 

Now that the tabloid press has discovered the Ebola outbreak in western Africa (and only 5 months after it began . . . ), and some have unabashedly begun promoting it as a `global pandemic threat’ , I’m finding it increasingly difficult to write anything about the outbreak without feeling like I’m aiding and abetting a media circus that has seriously jumped the shark. 

 

While it may not sell newspapers - the Ebola virus (as it stands now) -  is seriously lacking in the `global pandemic potential’ department.

 

It is not `airborne’ (unless flying coach or 1st class), and it isn’t all that easy to catch.

 

Health care workers, and family members – those most likely to come into contact with bodily fluids – are at greatest risk of exposure, along with those harvesting, preparing, or consuming infected bushmeat.  While one can argue that the virus could `mutate’ and become more transmissible over time, for now we’ve seen no evidence of that occurring. 

 

If it does, you can be sure I’ll post an update.

 

Hyperbolic headlines aside, there are legitimate concerns that an infected person could board an airplane in the outbreak zone, and travel to the UK, EU, North America, Hong Kong, or any other international destination. 

 

It has happened before with many other exotic diseases, and nothing prevents it from happening with Ebola. The general consensus is, however, that if an infected individual did arrive on our shores -  that with the public health resources available here – the risk to the general public would be low. 

 

As you might expect, public health agencies are alerting doctors, hospitals, and airlines on how to deal with this potential threat (see CDC Teleconference & HAN Notice On Ebola & CDC Interim Ebola Exposure Guidance For Airlines, Flight Crews). 

 

We saw the ECDC issue similar advice earlier this summer (see Rapid Risk Assessment on Ebola (June 9th)).

 

Today Hong Kong’s CHP, which has an enviable record of both being proactive, and willing to share information with the public, has issued the following  statement and sent letters to local doctors.

 

Ebola virus under watch

July 30, 2014

The Centre of Health Protection and the Hospital Authority have boosted surveillance and control measures for the Ebola virus in light of the outbreak in West Africa.

The centre’s Community Medicine Consultant Dr Chuang Shuk-kwan told reporters today more than 1,200 cases have been confirmed in Guinea, Liberia and Sierra Leone since March.

Anyone in Hong Kong with a fever who visited these three countries in the last three weeks will be sent to the Communicable Disease Centre in Princess Margaret Hospital for isolated treatment, she said.

The authority’s Chief Infection Control Officer Dr Dominic Tsang said the patient will be immediately tested for the virus.

Letters will be sent to all doctors today explaining the assessment criteria for Ebola, and reminding them to report suspected cases.

Travellers going to the three countries are advised to ensure good personal hygiene; avoid contact with ill people, body fluids and animals; cook food thoroughly; and, consult a doctor immediately if they feel ill.

Click here for information on the virus.

 

 

This is the letter sent to Hong Kong’s Physicians.

 

 

Our Ref. : (2) in DH SEB CD/8/15/1                     30 July 2014
Dear Doctor,

Updated Situation and Reporting Criteria of Ebola Virus Disease

Further to our letter sent to you on April 2, 2014, we would like to provide updates on the latest situation of the outbreak of Ebola Virus Disease (EVD). Since the first report of the EVD outbreak in West Africa in March this year, the cumulative numbers of cases attributed to EVD are continuously increasing.

<SNIP Case count updates >

The risk of infection for travellers is still low at the present moment. Person-to-person transmission was resulted from direct contact with body fluids or secretions of an infected patient. However, medical practitioners should always consider EVD in the differential diagnosis of febrile illness in any person with recent (within 21 days) travel history to affected areas/countries, i.e. Guinea, Liberia and Sierra Leone (as of July 29, 2014). The Centre for Health Protection will closely monitor the situation and update the affected areas from time to time.

Please refer to our website (http://chp.gov.hk/files/pdf/evd_affected_area.pdf) for the updated list of affected areas/countries. In this regard, we would like to solicit your assistance in notifying the CHP if you encounter patients fulfilling both the Clinical Criteria AND Epidemiological Criteria below:

Clinical Criteria

Suffering from a sudden onset of fever (≥ 38°C , 100.4°F);

OR

Having at least one of the following symptoms/signs: inexplicable bleeding, bloody diarrhoea, bleeding from gums, bleeding into skin (purpura), bleeding into eyes, or haematuria;

OR

Any inexplicable sudden death.

AND

Epidemiological Criteria

One or more of the following within 21 days before onset of illness:

Close contact* with a confirmed or probable case of Ebola Virus Disease or his/her bodily fluids;

 OR

Resided in or history of travel to an affected area/country#;

* Such as sleeping in the same household with a case, direct physical contact with the case (dead or alive) during the illness, direct physical contact with the (dead) case at the funeral, touched his/her blood or body fluids (including semen) during the illness, touched his/her clothes or linens, breastfed by the patient (baby).

# Affected countries (as of July 29, 2014): Guinea, Liberia, and Sierra Leone. For the updated list of affected countries/areas, please refer to the following website: http://chp.gov.hk/files/pdf/evd_affected_area.pdf

Patients meeting the above reporting criteria should be isolated immediately. Medical practitioners are reminded to notify the Central Notification Office (CENO) of CHP via fax (2477 2770), phone (2477 2772) or CENO On-line (http://ceno.chp.gov.hk/). Please also call our Medical Control Officer at 7116 3300 a/c 9179 for prompt investigation. CHP will make arrangement to send the patient to the Hospital Authority Infectious Disease Centre in Princess Margaret Hospital for isolation, testing and treatment.

For further information on EVD, please refer to the Annex or visit the CHP website at

http://www.chp.gov.hk/en/view_content/34199.html

Thank you for your ongoing support in combating communicable diseases.

Yours faithfully,

(Dr S K CHUANG)

for Controller, Centre for Health Protection Department of Health

The Laboratory Bio-Safety Backlash Continues

Credit CDC

 

# 8892

 

The groundswell of concern over controversial `gain of function’ laboratory experiments, and recent high-profile lapses in biosecurity at the nation’s top labs, continues to grow with a scathing editorial appearing yesterday in the Annals of Internal Medicine penned by Deputy Editor Deborah Cotton, MD, MPH.

 

While much of the editorial is behind a pay wall, you can find a readable scan of the first page at the link below.  Fortunately, Medscape Medical News  published a detailed summary, and interview with the author, yesterday (more on that after you return).

 

Editorials | 29 July 2014

Biocontainment Laboratories: Addressing the Terror Within 

Deborah Cotton, MD, MPH, Deputy Editor

Ann Intern Med. Published online 29 July 2014 doi:10.7326/M14-1668

Recently revealed safety lapses in U.S. government facilities that work with deadly pathogens suggest that, despite efforts to protect us from bioterrorism as well as naturally occurring infectious diseases, there is another grave bioterror threat: the risk emanating from biocontainment laboratories themselves. This commentary discusses possible factors contributing to the safety lapses and strategies to prevent future incidents.

(Continue . . . )

 

The following lengthy report from Medscape provides more detail on the above editorial, along with comments from the author, and additional input from by Nancy Kingsbury, PhD, of the Government Accountability Office and  by Richard H. Ebright, PhD, professor of chemistry and chemical biology at Rutgers University  (see House Subcommittee Hearing on Biosafety  for their recent testimony). .

 

Suspend Work, Close Most High-Level Biosafety Labs, Experts Say

Janis C. Kelly

July 29, 2014

( UPDATED July 29, 2014 ) Management of US government bioterrorism research facilities is so lax that work in biosafety level (BSL) 4 laboratories (which house deadly organisms for which there are no effective treatments or vaccines) should be suspended pending a complete safety overhaul, Annals of Internal Medicine deputy editor Deborah Cotton, MD, MPH, writes in an editorial published online July 28 in the journal

(Continue . . .)

 

Beyond suspension of work pending a a safety overhaul, experts are calling for a dramatic scale back in the number of BSL-3 and BSL-4 labs in the county that are allowed to work on the most dangerous pathogens.  Currently, there isn’t even a good count on the number of BSL-3 labs in operation, and there is no one single regulatory agency in charge of monitoring their operations.

 

While we continue to get bland assurances from researchers that their work is both safe and essential (“We’re scientists . . . trust us” )  we are also hearing from others – like the Director of the CDC - that there  remains an insufficient `culture of safety’ among research scientists.  

 

We are also seeing reports  that the number of laboratory `incidents’ may be far higher than is reported.

 

While many researchers will be justifiably dismayed by the draconian recommendations made in the above editorial, and I doubt that we’ll see anything close to the reduction in BSL-3 labs they are calling for, it is obvious that serious changes are needed.  

 

For the past ten years – spurred on in part by national security concerns – there’s been an `anything goes’ attitude when it comes to biomedical research.  Since the 9/11 attack, the number of BSL-4 labs in the United States has jumped from 2 to 14, and the number of BSL-3 labs has grown from around 400 to over 1400 (although the exact number is murky).

 

Although BSL-3 and BSL-4 labs are essential parts of national security, biomedical research, and the testing of pathogens - the more of them that are in operation - the better the chance of a seeing a serious accident.

 

How many are too many, will be one of the major decisions facing regulators.

 

Given the money, power, and prestige at stake, I don’t expect to see many BSL-3 labs voluntarily sacrifice themselves on the altar of public safety.  So we should expect more than a little resistance to any reductions.

 

For more on this growing debate, you may wish to revisit:

 

Scientists For Science: GOF Research `Essential’ & Can be Done `Safely’

Updating The Cambridge Working Group

ECDC Comment On Gain Of Function Research

CDC: Press Conference Transcript, Audio & Timelines For Lab Incidents

Cell Host & Microbe: 1918-like Avian Viruses Circulating In Birds Have Pandemic Potential

Lipsitch & Galvani: GOF Research Concerns

Debating A Controversial MERS Paper

Coronavirus – Credit CDC PHIL

 

# 8891

 

Last week, Professor Raina MacIntyre, Head of the School of Public Health and Community Medicine and Professor of Infectious Disease Epidemiology at UNSW, published a paper called The discrepant epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV), where she suggested that the unusual patterns of the MERS coronavirus outbreaks  might  indicate deliberate human release.

 

Professor MacIntyre went on to explain why a bio terror source ought to be at least considered in  MERS coronavirus: animal source or deliberate release?, published last week in The Conversation.

 

While best known for her work in respiratory virus transmission studies, over the past year we’ve looked at research from Dr. MacIntyre looking at whether the Flu Vaccine May Reduce Heart Attack Risk and just last month she and co-author Lauren M Gardner looked at some of the paradoxes presented by the MERS coronavirus. (see BMC Research Notes: Unanswered Questions About MERS-CoV.)

 

Dr. MacIntyre’s  latest paper, however, has been greeted with a good deal of skepticism, particularly among researchers and virologists, both on twitter, and in the media (see CIDRAP News Report).  

 

Today, a sextet of scientists and researchers – including well known infectious disease bloggers Dr. Ian Mackay and Maia Majumder - provide a rebuttal to Professor MacIntyre’s controversial hypothesis. Joining them are Dr.  Lisa Murillo from Los Alamos, Dr.  Katherine Arden from the University of Queensland, Dr. Nicholas G. Evans and Stephen Goldstein, both from the University of Pennsylvania.

 

Follow the link below to read their rationale, as published in The Conversation,  in its entirety.

 

 

30 July 2014, 5.40am BST

Middle East respiratory virus came from camels, not terrorists

When you hear hooves, shout camel, not bioterrorist. Delpixel/Flickr

The Middle East respiratory syndrome coronavirus (MERS-CoV) is a tiny, spiky package of fat, proteins and genes that was first found in a dying man in the Kingdom of Saudi Arabia in 2012.

 

Since then, we have learnt a little more about the virus. We know that nearly 90% of infections have originated in the Kingdom of Saudi Arabia. It is lethal in about a third of known cases, most of whom are older males, often with one or more pre-existing diseases of the heart, lung or kidney. So far it has claimed nearly 300 lives.

 

Camels have emerged as the most likely source of human MERS-CoV infections. In fact, blood samples collected between 1992 and 2013 show camels have been fighting MERS-CoV for at least 20 years.

 

But, in an unusual twist, research published last week calls on us to seriously consider, or at least acknowledge, that bioterrorism might explain the emergence of MERS-CoV in people. Raina MacIntyre, Professor of Infectious Disease Epidemiology at UNSW Australia, suggests that “deliberate release” may explain the paradoxical pattern of ongoing MERS-CoV infections.

(Continue . . .)

 

Although one can never totally eliminate the possibility that there is a human hand behind the spread of MERS, I confess that after reading Dr. MacIntyre’s paper last week,  I came away far less than convinced.  

 

While I briefly considered blogging the story, I saw that it had already been covered by CIDRAP News, and was being heartily debated on Twitter, and decided there was little of substance I could add.

A decision I’m glad of now, since others (far more qualified than myself) have now weighed in on the issue.   

The Journal Nature Weighs In On Lab Accidents & Biosafety

 

 

# 8890

 

In the wake of revelations regarding laboratory safety lapses both at the FDA and the CDC involving `select agents’ including anthrax, smallpox, and H5N1 avian influenza, and the ongoing Debate Over Gain Of Function research, we are seeing agencies, scientific journals, universities, politicians, consultants, newspaper editorial boards, scientific working groups, and individual scientists all publicly staking out their positions on these issues.

 

A little over two weeks ago, the Cambridge Working Group produced a consensus statement, which urges caution, and better regulation and oversight of laboratory research seeking to enhance the virulence, transmissibility, or host range of pathogens with pandemic potential (PPPs).

 

While just yesterday, the newly formed coalition Scientists for Science, posted a statement of their own, that called their work `essential’ and dismissed many of the concerns being raised over GOF research as being overstated.

 

Not everyone is convinced, however, as evidenced by last week’s ECDC Comment On Gain Of Function Research, which acknowledged the potential public health risks that these types of experiments can pose, and proposed that the overriding concern of researchers should be first, and foremost  `to do no harm.’

 

Today the Journal Nature has two articles on Laboratory safety standards (or the lack thereof).  First an article by Declan Butler, on the lack of universal, and consistent standards for laboratories conducting work on potentially dangerous pathogens.

 

Biosafety controls come under fire

Experts call for a stronger safety culture at secure sites after incidents involving anthrax and flu in a US laboratory.

Declan Butler

29 July 2014

Recent accidents involving deadly pathogens at a leading laboratory in the United States highlight the need for a major global rethink of biosafety controls, experts say.

The Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, reported two accidents involving anthrax and the deadly H5N1 influenza virus. Biosafety professionals argue that such incidents show that without a strong culture of biosafety, even highly secure facilities are susceptible to errors that could place workers and the public at risk.

(Continue . . . )

 

A second report, this time an editorial, suggests that lab accidents such as the ones making headlines this summer happen far more often than are ever reported, and calls for full transparency.

 

Safety doesn’t happen by accident

To create a strong biosafety culture, information on mishaps involving deadly pathogens must be reported and shared fully and transparently.

(Continue . . .)

ECDC Influenza Virus Characterization – June 2014

Credit NIAID

 

# 8889

 

Although we talk about seasonal flu strains like H1N1, H3N2, and influenza B as if they were single entities, in truth within each sub-type are numerous clades, sub-strains, and variants. 

 

These influenza viruses are constantly mutating (via antigenic drift) as they replicate and spread, and are engaged in a perpetual game of  viral king-of-the-mountain, as they jostle for dominance and superiority in the global community.

 

Success for these strains is always fleeting, though,  as they leave behind varying degrees of immunity in their hosts and must either evolve or eventually die out for lack of susceptible hosts.  All which makes the flu world dynamic and ever-changing, and presents a genuine challenge for vaccine manufacturers to stay ahead of.

 

To keep abreast of the changes to the flu strains in circulation, labs around the world send samples to the WHO Collaborating Centre in London for classification, and the ECDC publishes reports roughly once a month.  These reports can help give us some idea whether the strains contained the latest vaccine match up antigenically with those strains currently circulating.

 

As you might expect, given the diversity of flu strains in circulation, the best that can be hoped for is that the majority of viruses tested are antigenically similar to the components in the vaccine.  That said, we won’t really have a good idea of how well this year’s vaccine will perform until the flu season is over, next spring.

 

The summary is printed below.  The full report is available as a PDF File.

 

Influenza virus characterisation, June 2014

29 Jul 2014

Abstract

​During the 2013–14 season, A(H1N1)pdm09, A(H3N2), B/Victoria- and B/Yamagata-lineage influenza viruses have continued to co-circulate in EU/EEA Member States. The relative prevalence has varied between countries. Viruses with collection dates after 31 December 2013, from 22 countries, have been received by the WHO Collaborating Centre in London.

• Type A and type B viruses have been received at a ratio of nearly 20:1.
• A(H3N2) and A(H1N1)pdm09 viruses have been received in similar numbers.
• Recently circulating A(H1N1)pdm09 viruses belonged to genetic subgroup 6B. Viruses in subgroup 6B are antigenically similar to the vaccine virus, A/California/07/2009.
• Recently circulating A(H3N2) viruses have fallen within genetic group 3C represented by the recommended vaccine virus for the 2013–14 and 2014–15 seasons, A/Texas/50/2012, with viruses of genetic subgroup 3C.3 predominating. Antigenic analysis using antisera raised against cell-propagated H3N2 viruses indicates that the majority of circulating viruses are antigenically similar to those in circulation in the 2012–13 and 2013–14 influenza seasons. Antisera raised against two reference viruses representative of viruses in genetic subgroup 3C.3 – with HA gene sequences encoding several amino acid substitutions compared to other viruses in genetic group 3C.3 – have been prepared. These antisera recognised the majority of test viruses well.
• Two genetic clades of B/Yamagata-lineage viruses continue to circulate: clade 3 represented by B/Wisconsin/1/2010 and clade 2 represented by B/Massachusetts/02/2012 (the recommended vaccine component for the 2013–14 and 2014-15 influenza seasons). Viruses in each clade have been received in similar numbers but with viruses in clade 3 predominating in those samples collected in 2014.
• Antigenic characterisation of two viruses of the B/Victoria lineage was performed in June. Neither virus was recognised well by the antiserum raised against the egg-propagated reference virus, A/Brisbane/60/2008, a virus previously recommended as a component of the trivalent influenza vaccine and recommended as a component of quadrivalent influenza vaccines for 2013–14 and 2014–15 influenza seasons. The test viruses were not recognised well by antisera raised against other reference viruses propagated in eggs. The test viruses were better recognised by some, but not all, antisera raised against reference viruses exclusively propagated in cells. Phylogenetic analysis revealed that all B/Victoria-lineage viruses received in 2014 were in genetic clade 1A, the B/Brisbane/60/2008 genetic clade.

EID Dispatch: Human Infection with Influenza Virus A(H10N8) From LPMs

Credit FAO

 

# 8878

 

While H5N1 pretty much hogged the avian flu limelight in the ten years from 2003 until the spring of 2013, the past 18 months have seen a sharp increase in the number of emerging novel avian flu subtypes that have infected humans and/or poultry.

 

Since then we’ve seen an Expanding Array Of Novel Flu Strains, including the H7N9 epidemic in China, the 1st Known Human Infection With H5N6, Taiwan reported Infection With Avian H6N1, and last winter no fewert han three cases of H10N8 infection were reported in China.

 

Thus far, out of this new group of viruses, only H7N9 has shown genuine signs of pandemic potential.  But as we discussed last month (see EID Journal: Mutations Of A(H10N8) Virus in Chicken Eggs and MDCK Cells) there are hints that this new virus `might be undergoing rapid adaptation to mammals and developing antiviral drug resistance’.

 

Admittedly, last May we saw reassuring media reports suggesting that the H10N8 virus – while worthy of watching – wasn’t `currently’ considered a big pandemic threat (see H10N8 bird flu unlikely to threaten public health), based on receptor binding testing done by the MRC National Institute for Medical Research (MRC-NIMR).

 

But the only real constant with influenza viruses is that they are constantly changing. What can be said about a virus today may not hold true tomorrow, or a year from now.

 

Over the past year we’ve become increasingly aware of two factors that may help drive the evolution of novel avian flu strains. 

• The first being the ongoing genetic reassortments with the ubiquitous and relatively stable LPAI H9N2 virus, which  provided its internal genes to the H5N1, H7N9, and H10N8 viruses (see The Lancet: H9N2’s Role In Evolution Of Novel Avian Influenzas) and continues to aid and abet the creation of new clades.
• The second piece of the puzzle involves the genetic mixing that goes on in LPMs (Live Poultry Markets) – combined with enhanced human-poultry interaction – that appears to be exacerbating both the evolution of avian viruses, and their jumping to humans. 

Last month, in CDC: Risk Factors Involved With H7N9 Infection, we looked at a case-control study done on the H7N9 epidemic in China that pretty much nailed LPMs as the predominant risk factor for infection.

 

While even casual exposure to poultry in live bird markets was cited as the primary risk factor, people who owned, raised, or slaughtered birds at home, on farms, or in the wild were not found to be at any increased risk.

 

All of which serves as prelude for a dispatch, published yesterday in the CDC’s EID Journal, called:

 

Dispatch

Human Infection with Influenza Virus A(H10N8) from Live Poultry Markets, China, 2014

Tao Zhang, Yuhai Bi, Huaiyu Tian, Xiaowen Li, Di Liu, Ying Wu, Tao Jin, Yong Wang, Quanjiao Chen, Ze Chen, Jianyu Chang, George F. Gao, and Bing Xu

Abstract

Human infection with avian influenza virus A(H10N8) was initially reported in China in December 2013. We characterized H10N8 strains from a human patient and from poultry in live markets that infected persons had visited. Results of genome sequencing and virus characterization suggest that the virus strains that infected humans originated from these markets.

Avian influenza virus (AIV) is classified into 16 subtypes on the basis of hemagglutinin (HA) and 9 subtypes on the basis of neuraminidase (NA); additional bat-derived influenza-like genomes, H17N10 and H18N11, have recently been reported (1). Birds can be infected with AIV through direct contact with infected hosts or through contact with contaminated surfaces or materials, including water and food. In China, H10N8 virus was isolated from the environment of Dongting Lake in Hunan Province in 2007 (2) and from a duck in a live poultry market (LPM) in Guangdong Province in 2012 (3). This AIV was not then known to directly infect humans or other mammals.

In December 2013, H10N8 virus infection in a person was reported in Nanchang, Jiangxi Province, China (4); 2 more human cases followed. The initial reported case was in a 73-year-old woman who visited a local LPM 4 days before the onset of her illness (4). Because genetic information on AIV is essential for understanding of the biology of these viruses, their spread among avian species, and their potential transmission to humans, in January 2014, we conducted surveillance of several LPMs in Nanchang, including those visited by the 3 reported case-patients, to determine the source of these infections.

<SNIP>

Conclusions

Our results provide evidence that the novel avian influenza virus A(H10N8) that infected humans in Nanchang, Jiangxi Province, China, could have derived from strains circulating in LPMs. In the LPMs, the sale of freshly slaughtered poultry, live poultry transportation, and mixed trading of different domestic animals provide environments conducive to genome segment reassortment, gene mutation, and interspecies transmission of AIVs (8,9). Human-infecting H7N9 virus strains are believed to be directly related to those found in the live poultry traded in LPMs (10,11); closure of LPMs has been shown to partly control the spread of these infections (8). Moreover, serologic evidence recently confirmed the infection of dogs with an H10 subtype influenza virus in close proximity to LPMs in Guangdong Province (12). Other recent research has shown that the internal genes of the H5N1, H7N9, and H10N8 viruses are constantly reacquired from poultry H9N2 viruses (9,13,14). Taken together, these data suggest that LPMs act as gene sources, facilitating reassortment of AIV genome segments (15).

In summary, exposure to infected and/or virus-carrying poultry or to contaminated environments in LPMs and the emergence of mammal-adapted and drug-resistant viruses puts humans at high risk for infection with novel influenza viruses. Measures to improve poultry farming practices must be enforced, including strict biosecurity measures for the trade and transport of live birds, proper disposal of diseased and dead birds, and even closure of LPMs.

 

While the jury is still out as to whether an H5, H7, or H10 avian flu virus could actually adapt to humans well enough to spark a pandemic (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?) – given the likely lack of  immunity mankind has to these avian strains -  few scientists are willing to ignore the possibility.

 

All of which makes enhanced surveillance and biosecurity measures (such as LPM closures) in influenza hotspots like Eastern China all the more important, particularly considering the ease with which viruses can now spread globally via international travel and trade. 

CDC Teleconference & HAN Notice On Ebola

 

# 8877

 

While stressing that Ebola currently poses little risk to the general U.S. population, the CDC held a teleconference yesterday afternoon (see Transcript  & Audio recording) to provide an update on the outbreak in West Africa and to announce the release of a CDC HAN Advisory providing information for clinicians who might encounter travel associated cases.

 

HAN messages (Alert, Advisory, Update, or Info) are designed to ensure that communities, agencies, health care professionals, and the general public are able to receive timely information on important public health issues.

 

An `Advisory’ is a second tier message that provides important information for a specific incident or situation, but may not require immediate action.  First the  advisory, after which I’ll have a bit more.

 

Ebola Virus Disease Confirmed in a Traveler to Nigeria, Two U.S. Healthcare Workers in Liberia

Distributed via the CDC Health Alert Network
July 28, 2014, 16:30 ET (4:30 PM ET)
CDCHAN-00363

Summary

Nigerian health authorities have confirmed a diagnosis of Ebola Virus Disease (EVD) in a patient who died on Friday in a hospital in Lagos, Nigeria, after traveling from Liberia on July 20, 2014. The report marks the first Ebola case in Nigeria linked to the current outbreak in the West African countries of Guinea, Sierra Leone, and Liberia. Health authorities also reported this weekend that two U.S. citizens working in a hospital in Monrovia, Liberia, have confirmed Ebola virus infection. These recent cases, together with the continued increase in the number of Ebola cases in West Africa, underscore the potential for travel-associated spread of the disease and the risks of EVD to healthcare workers. While the possibility of infected persons entering the U.S. remains low, the Centers for Disease Control and Prevention (CDC) advises that healthcare providers in the U.S. should consider EVD in the differential diagnosis of febrile illness, with compatible symptoms, in any person with recent (within 21 days) travel history in the affected countries and consider isolation of those patients meeting these criteria, pending diagnostic testing.

Background

CDC is working with the World Health Organization (WHO), the ministries of health of Guinea, Liberia, and Sierra Leone, and other international organizations in response to an outbreak of EVD in West Africa, which was first reported in late March 2014. As of July 23, 2014, according to WHO, a total of 1,201 cases and 672 deaths (case fatality 55-60%) had been reported in Guinea, Liberia, and Sierra Leone. This is the largest outbreak of EVD ever documented and the first recorded in West Africa.

EVD is characterized by sudden onset of fever and malaise, accompanied by other nonspecific signs and symptoms, such as myalgia, headache, vomiting, and diarrhea. Patients with severe forms of the disease may develop multi-organ dysfunction, including hepatic damage, renal failure, and central nervous system involvement, leading to shock and death.

In outbreak settings, Ebola virus is typically first spread to humans after contact with infected wildlife and is then spread person-to-person through direct contact with bodily fluids such as, but not limited to, blood, urine, sweat, semen, and breast milk. The incubation period is usually 8–10 days (rarely ranging from 2–21 days). Patients can transmit the virus while febrile and through later stages of disease, as well as postmortem, when persons contact the body during funeral preparations.

On July 25, the Nigerian Ministry of Health confirmed a diagnosis of EVD in a man who died in a hospital in the country’s capital of Lagos (population ~21 million). The man had been in isolation in the hospital since arriving at the Lagos airport from Liberia, where he apparently contracted the infection. Health authorities are investigating whether passengers or crew on the plane or other persons who had contact with the ill traveler are at risk for infection.

In addition, health authorities have reported that two U.S. healthcare workers at ELWA hospital in Monrovia, Liberia, have confirmed Ebola virus infection. One of the healthcare workers, a physician who worked with Ebola patients in the hospital, is symptomatic and in isolation. The other healthcare worker, a hygienist, developed fever but is showing no other signs of illness. The physician is an employee of Samaritan’s Purse, a North Carolina-based aid organization that has provided extensive assistance in Liberia since the beginning of the current outbreak. The other healthcare worker works with Soudan Interior Mission (SIM) in Liberia and was helping the joint SIM/Samaritan’s Purse team.

The recent cases in a traveler and in healthcare workers demonstrate the risk for spread of EVD in these populations. While no EVD cases have been reported in the United States, a human case, caused by a related virus, Marburg virus, occurred in Denver, Colorado in 2008. Successful implementation of standard precautions was sufficient to limit onward transmission. Other imported cases of viral hemorrhagic fever disease were also successfully managed through effective barrier methods, including a recent Lassa fever case in Minnesota.

Recommendations

EVD poses little risk to the U.S. general population at this time. However, U.S. healthcare workers are advised to be alert for signs and symptoms of EVD in patients with compatible illness who have a recent (within 21 days) travel history to countries where the outbreak is occurring, and should consider isolation of those patients meeting these criteria, pending diagnostic testing.

For More Information

Additional information on EVD can be found at: http://www.cdc.gov/ebola

Interim Guidance on EVD for healthcare workers can be found at: http://www.cdc.gov/vhf/abroad/healthcare-workers.html

Travel notices for each country can be found at:
Guinea: http://wwwnc.cdc.gov/travel/notices/alert/ebola-guinea
Liberia: http://wwwnc.cdc.gov/travel/notices/alert/ebola-liberia
Sierra Leone: http://wwwnc.cdc.gov/travel/notices/alert/ebola-sierra-leone

 

Although the odds of having an Ebola infected individual fly out of Western Africa and arrive in the United States is considered low, it is certainly not inconceivable  - particularly given the incubation period (2 –21 days) and the number of American medical and humanitarian aid workers that are currently in the hot zone.

 

Last February, in The Global Reach Of Infectious Disease, we looked at rationale behind several national and international initiatives designed to deal with the growing threat of the international spread of infectious diseases. 

 

• In WHO: IHR & Global Health Security, we looked at the large number of member states which have yet to meet the core surveillance and response requirements of the International Health Regulations that went into force in 2007.
• A recent Assessment by the Director of National Security (see DNI: An Influenza Pandemic As A National Security Threat) found the global spread of infectious diseases – along with cyber attacks, terrorism, extreme weather events, WMDs, food and water insecurity, and global economic concerns.- constitutes a genuine threat to national security.
• While in CIDRAP On The Global Health Security Agenda, we looked at a 26 nation initiative to improve global health surveillance & emergency response in this age of rising infectious diseases. 

 

You’ll find more on the CDC’s Global Health Website at:

 

Why Global Health Security Matters

Disease Threats Can Spread Faster and More Unpredictably Than Ever Before

(Excerpt)

A disease threat anywhere can mean a threat everywhere. It is defined by

• the emergence and spread of new microbes;
• globalization of travel and trade;
• rise of drug resistance; and
• potential use of laboratories to make and release—intentionally or not—dangerous microbes.

(Continue . . .)

 

 

A sobering reminder that in this second decade of the 21st century, there is really no inhabited place on earth that is truly remote anymore, and virtually no serious emerging infectious disease outbreak that we can afford to ignore.

Scientists For Science: GOF Research `Essential’ & Can be Done `Safely’

Credit CDC PHIL

 

# 8876

 

With three recent high profile laboratory `incidents’ at CDC and FDA labs in the past couple of months  – and ongoing concerns in the biosecurity and biosafety community over controversial `Gain of Function’ research (experiments that seek to enhance the virulence, transmissibility or host range of dangerous pathogens) – scientists are staking out their positions on both sides of this contentious debate.

 

Yesterday, in Updating The Cambridge Working Group, I highlighted the growing roster of scientists who have signed on to their consensus statement, which urges caution, and better regulation, of lab research on dangerous pathogens.

 

Today, I was made aware of another group – Scientists for Science – via a tweet from Professor Vincent Racaniello, which states their position that biomedical research on potentially dangerous pathogens is not only scientifically essential, it can be conducted safely.

The impressive list of founding scientists includes Professor Racaniello, Yoshiro Kawaoka, and Ron Fouchier – all familiar names to readers of this blog.

 

As I’ve printed the Cambridge Working Group’s consensus statement and list of supporters, in the interest of fairness, I’ll do the same with this group as well.

 

Scientists for Science

Scientists for Science are confident that biomedical research on potentially dangerous pathogens can be performed safely and is essential for a comprehensive understanding of microbial disease pathogenesis, prevention and treatment. The results of such research are often unanticipated and accrue over time; therefore, risk-benefit analyses are difficult to assess accurately.

If we expect to continue to improve our understanding of how microorganisms cause disease we cannot avoid working with potentially dangerous pathogens. In recognition of this need, significant resources have been invested globally to build and operate BSL-3 and BSL-4 facilities, and to mitigate risk in a variety of ways, involving regulatory requirements, facility engineering and training. Ensuring that these facilities operate safely and are staffed effectively so that risk is minimized is our most important line of defense, as opposed to limiting the types of experiments that are done.

In contrast to recombinant DNA research at the time of Asilomar in 1975, studies on dangerous pathogens are already subject to extensive regulations. In addition to regulations associated with Select Agent research, experimental plans on other pathogens are peer reviewed by scientists and funding agencies, and the associated risk assessments are considered by biosafety experts and safety committees. Risk mitigation plans are proposed and then considered and either approved or improved by safety committees.

If there is going to be further discussion about these issues, we must have input from outside experts with the background and skills to conduct actual risk assessments based on specific experiments and existing laboratories. Such conversations are best facilitated under the auspices of a neutral party, such as the International Union of Microbiological Societies or the American Society for Microbiology, or national academies, such as the National Academy of Sciences, USA. We suggest they should organize a meeting to discuss these issues.

Scientists for Science have a range of opinions on how risk is best assessed. However, maintaining dogmatic positions serves no good purpose; only by engaging in open constructive debate can we learn from one another’s experience. Most importantly, we are united as experts committed to ensuring public health is not compromised and the reputation of science in general, and microbiology in particular, is defended.

We will use this forum to provide both scientists and the general public accurate information and to foster open and unbiased discourse on how to address these important contemporary issues in microbiology.

---

Founding Scientists

• Raul Andino, University of California, San Francisco
• Wendy Barclay, Imperial College London
• Constance Cepko, Harvard University
• Terence Dermody, Vanderbilt University
• Dickson Despommier, Columbia University
• Christian Drosten, University of Bonn Medical Centre
• Peter Doherty, University of Melbourne
• Paul Duprex, Boston University
• Rebecca Dutch, University of Kentucky
• Richard Elliott, University of Glasgow
• Mary Estes, Baylor College of Medicine
• Matthew Evans, Icahn School of Medicine at Mt. Sinai
• Ron Fouchier, Erasmus Medical Center
• Adolfo Garcia-Sastre, Icahn School of Medicine at Mt. Sinai
• Elodie Ghedin, New York University
• Yoshihiro Kawaoka, University of Wisconsin
• Wyndham W. Lathem, Northwestern University Feinberg School of Medicine
• Karla Kirkegaard, Stanford University
• Elke Muhlberger, Boston University
• Peter Palese, Icahn School of Medicine at Mt. Sinai
• Ann Palmenberg, University of Wisconsin
• Andrew Pekosz, Johns Hopkins University
• Julie Pfeiffer, University of Texas Southwestern Medical Center
• Glenn Rall, Fox Chase Cancer Center
• Vincent Racaniello, Columbia University
• Charles Rice, Rockefeller University
• Erica Ollmann Saphire, The Scripps Research Institute
• Stacey Schultz-Cherry, St. Jude Childrens Research Hospital
• Bert Semler, University of California, Irvine
• Peter Sarnow, Stanford University
• Michael Schmidt, Medical University of South Carolina
• Saul Silverstein, Columbia University
• Derek Smith, University of Cambridge
• Geoffrey Smith, University of Cambridge
• Benjamin tenOever, Icahn School of Medicine at Mt. Sinai
• Sean Whelan, Harvard University
• Harald zur Hausen, German Cancer Research Center

 

Since I’ve blogged my concerns over this issue many times in the past (see here, here & here), I’ll not detract from today’s announcement by repeating them again here. 

My only hope is that scientists on both sides of this issue will engage in productive talks, and devise some workable solutions, rather than just setting off another round of heated debate that goes nowhere. 

Well, one can always hope.